Advances in Copper Complexes as Anticancer Agents - Chemical

Biography. Carlo Santini was born in 1967 in Roccafluvione, Ascoli Piceno, Italy. He obtained his degree in Chemistry with full marks and honours in 1...
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Advances in Copper Complexes as Anticancer Agents Carlo Santini,*,† Maura Pellei,† Valentina Gandin,‡ Marina Porchia,§ Francesco Tisato,*,§ and Cristina Marzano‡ †

Scuola di Scienze e Tecnologie−Sez. Chimica, Università di Camerino, via S. Agostino 1, 62032 Camerino, Macerata, Italy Dipartimento di Scienze del Farmaco, Università di Padova, via Marzolo 5, 35131 Padova, Italy § IENI-CNR, Corso Stati Uniti 4, 35127 Padova, Italy ‡

2.5.9. κ4N,N′,N″,O Systems 2.6. Polydentate and/or Macrocyclic Systems 2.6.1. Tridentate Ligands 2.6.2. Tetradentate and Macrocyclic Ligands 2.7. P-Donor Phosphine Systems 2.8. C-Donor N-Heterocyclic Carbene Systems 2.9. N-N Diimine (N-N) Systems 2.9.1. (N-N)/Amino Acids Systems 2.9.2. Clip-phen Systems 2.9.3. (N-N)2(X) Systems 2.9.4. (terpy)(N-N) and (terpy)2 Systems 3. Mechanistic Approaches and Proposed Biological Targets 3.1. Copper Complexes as DNA Targeting Drugs 3.2. Copper Complexes as Topoisomerase I,II Inhibitors 3.3. Copper Complexes as Proteasome Inhibitors 4. In Vivo Antitumor Studies 5. Concluding Remarks Author Information Corresponding Authors Author Contributions Notes Biographies Acknowledgments Abbreviations Acronyms of Cancer Cell Lines Cited in This Review Acronyms of Nonmalignant Cell Lines Cited in This Review References

CONTENTS 1. Introduction 2. Copper Complexes as Anticancer Agents 2.1. S-Donor Systems 2.1.1. Thiosemicarbazones (TSCs) 2.1.2. Thiosemicarbazides 2.1.3. Dithiocarbamates (DTCs) 2.1.4. Thioureas 2.1.5. Dithiolates 2.2. O-Donor Systems 2.2.1. Pyridine N-Oxides 2.2.2. κ2O,O-Donor Systems 2.3. N,O-Donor Systems 2.3.1. Phenol Analogues to 8-Hydroxyquinoline 2.3.2. Naphthoquinones 2.3.3. Carboxylates 2.3.4. Triethanolamines 2.3.5. Other N,O-Donor Systems 2.4. N-Donor Systems 2.4.1. Pyrazoles 2.4.2. Pyrazole−Pyridine Systems 2.4.3. Imidazoles 2.4.4. Triazoles, Tetrazoles, and Oxazoles 2.4.5. Indoles 2.4.6. Other N-Donor Systems 2.5. Schiff Base Systems 2.5.1. κ2N,N′ Systems 2.5.2. κ2N,O Systems 2.5.3. κ2S,N Systems 2.5.4. κ3N,N′,N″ Systems 2.5.5. κ3N,N′,O Systems 2.5.6. Hydrazones 2.5.7. κ3N,O,O′ Systems 2.5.8. κ3N,O,S Systems © 2013 American Chemical Society

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1. INTRODUCTION Medicinal inorganic chemistry offers additional opportunities for the design of therapeutic agents not accessible to organic compounds.1−3 The wide range of coordination numbers and geometries, available redox states, thermodynamic and kinetic characteristics, and intrinsic properties of the cationic metal ion and ligand itself offer the medicinal chemist a large variety of reactivities to be exploited. The widespread success of cisplatin in the clinical treatment of various types of neoplasias has placed coordination chemistry of metal-based drugs in the frontline in the fight against cancer.1,4 Although highly effective in treating a variety of Received: February 28, 2013 Published: October 8, 2013 815

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to the central role played by copper in angiogenesis, a process critical for tumor growth,45−47 invasion, and metastasis.48 Angiogenesis is a complex set of functional processes that promote formation of new blood vessels from existing blood vessels. In this field, several research groups have shown that angiogenesis requires copper as a crucial cofactor that stimulates cytokine production, extracellular matrix degradation, endothelial cell proliferation, and migration mediated by integrin and angiogenin (Ang).45,46,49 For example, affinity of Ang for endothelial cells is largely augmented in the presence of copper ions.50 The role of the metal in this interaction is still under scrutiny, but combination of experimental (potentiometric and spectroscopic measurements)51 and theoretical (DFT)52 evidence points to coordination of Cu(II) with peculiar peptide fragments encompassing sequences hAng64-68 and hAng60-68. Links among copper homeostasis/metabolism regulation and the X-linked inhibitor of apoptosis (XIAP) protein have recently emerged.53 XIAP promotes ubiquitination and degradation of COMMD1 (copper metabolism gene MURR1 domain containing 1), a protein that stimulates the efflux of copper from the cell, thus regulating copper export from the cell and, potentially, acting as an additional intracellular sensor for copper levels. Biochemical studies demonstrated that XIAP can directly bind copper ions through cysteine domains (CxxC motifs) that are distributed across the whole protein. The interaction between XIAP and copper results in a marked conformational change of XIAP, determining the inability of this potent antiapoptotic protein to inhibit caspases and leading to activation of caspase-dependent cell death cascades. Hence, intracellular copper accumulation and generation of the copperbound form of XIAP increase the susceptibility of cells to apoptotic stimuli. Furthermore, the cupredoxin azurin has recently been shown to more preferentially enter cancer than normal cells and form a complex with the tumor suppressor protein p53, stabilizing it and increasing its intracellular level, thereby inducing apoptosis via caspase-mediated mitochondrial pathways or cell cycle arrest at G1 phase, depending on cell types.54 Several strategies aimed at development of new anticancer therapeutics targeting the elevated tumor-specific copper level have been proposed.55−58 Actually, control of angiogenesis, tumor growth, and metastasis could be attained by chelating the excess of copper. In an attempt to do so, small molecules with copper-binding ability that are easily synthesized and structurally manipulated have become an attractive tool.59,60 Examples include trientine (trien), D-penicillamine (D-pen), and tetrathiomolybdate (TM). trien and D-pen were used to treat mice bearing hepatocellular carcinoma xenografts showing significant inhibition of the tumor growth associated with suppression of tumor angiogenesis.61 Analogously, TM displayed encouraging antiangiogenic and antitumor effects in animal models bearing human squamous cell carcinoma xenografts.62 TM was then selected for clinical trials in humans.63,64 While copper chelators have been harnessed as potential therapeutic agents for treatment of some types of cancer,65 their clinically approved use has generally been restricted to patients with heavy metal poisoning or diseases with severe metal accumulation (e.g., Wilson disease). Recently, it has been demonstrated that mixtures of copper salts with dithiocarbamates (DTCs) or clioquinol (CQ) spontaneously bind with tumor cellular copper forming a proteasome inhibitor and an apoptosis inducer. The antiangio-

cancers, the cure with cisplatin is still limited by dose-limiting side effects5 and inherited or acquired resistance phenomena, only partially amended by employment of new platinum drugs.6−9 These problems have stimulated an extensive search and prompted chemists to develop alternative strategies, based on different metals, with improved pharmacological properties and aimed at different targets.10 In this field, copper complexes showed encouraging perspectives.11−15 Copper-based complexes have been investigated on the assumption that endogenous metals may be less toxic for normal cells with respect to cancer cells. However, copper can also be toxic due to its redox activity and affinity for binding sites that should be occupied by other metals. The altered metabolism of cancer cells and differential response between normal and tumor cells to copper are the basis for development of copper complexes endowed with antineoplastic characteristics. Copper is an essential element for most aerobic organisms, employed as a structural and catalytic cofactor, and consequently it is involved in many biological pathways.16−18 Taking this into account, much attention has been given to research on the mechanisms of absorption,14,19,20 distribution,21−23 metabolism, and excretion of copper,24−26 as well as on its role in development of cancer and other diseases.11,27,28 The fundamental aspects of the chemistry and biochemistry of copper,29,30 the role of this metal in medicine31,32 and the pathology and treatment of Menkes and Wilson diseases,33,34 and the chelation therapy approach in neurodegenerative disorders characterized by accumulation of abnormal protein components mediated by copper35 have extensively been surveyed in recent review articles to which readers are addressed for a comprehensive knowledge of the multifaceted functions played by this metal ion in physiology. The copper concentration in the human body is tightly regulated at the levels of cells, organs, and body,36 since copper free ions are potentially harmful. Once absorbed in the small intestine and stomach (adult human dietary recommendation is estimated at between 1.5 and 3.0 mg Cu/d),37,38 distribution of copper is regulated by the liver into the bloodstream through ceruloplasmin and albumin. Then, sophisticated mechanisms control the transport of copper across the cell membrane mainly via the copper transporter protein (CTR1) during import and the Cu ATP7A/B tranporters during export. All these proteins contain many copper-coordinating residues, notably methionine, histidine, and cysteine. Human copper transporter (hCTR1) contains three trans-membrane segments39 with amino and carboxyl termini located on opposite sites of the plasma membrane. Beyond genetically derived Menkes syndrome (deficiency of copper caused by diverse mutations in the copper-transporter gene ATP7A-chromosome location Xq12-q13, OMIM 309400) and Wilson disease (overload of copper caused by a defect in the ATP7B gene-chromosome location 13q14.3-q21.1, OMIM 277900), abnormal accumulation of copper is associated with several pathological states including neurodegenerative disorders (Alzheimer, Parkinson, CreutzfeldJakob, etc.), rheumatoid arthritis, gastrointestinal ulcers, epilepsy, diabetes, and cancer. In numerous ex vivo cancerous tissues (e.g., breast, prostate, lung, and brain), the concentration of copper was found to exceed that of the normal tissues.40−43 In addition, in the serum of breast cancer patients, the level of copper can reach 1.67 μg/ mL, much higher than in the healthy controls (0.98 μg/mL).44 Detailed molecular mechanisms for tumor-associated copper elevation are not completely elucidated. Several authors point 816

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genesis effects of copper chelators47,66−68 as well as the potential use of proteasome inhibitors69,70 in cancer therapies have been extensively reviewed by other authors and will not be considered further in this survey. Somewhat reversing the anticancer strategy based on sequestration of copper to prevent establishment of the tumor blood supply, tumor cells may represent a suitable, selective target for a copper-based antitumor drug. For the success of copper-based anticancer strategies the chemical framework and ligand donor atom set is of crucial importance since it can modulate the hard/soft properties of the metal, the lipophilic/hydrophilic balance of the resulting complexes, and their solubility in extracellular fluids as well as the ability to permeate the bilayer lipidic membrane. Other important aspects that should be taken into account in the design of copper complexes include their stability toward transchelation reactions with physiological molecules (individual amino acids, peculiar peptide sequencies, or whole proteins). These processes may sometimes preclude the expected tumor targeting or, on the contrary, may sometimes facilitate the cellular internalization of the metal.71−74 This review describes advances in the synthesis, design, and development of copper complexes as anticancer agents in the last 4 years (section 2). Interest in this field has rapidly grown in recent years, as illustrated by the increasing number of publications reported since 2000 (see Figure 1). This summary covers the period 2008−2012 and follows our previous efforts in the same area.11,12

little but important examples of Cu(I) compounds. Since copper(I/II) complexes are (i) redox active, (ii) frequently labile, and (iii) atypical in their preference for distorted coordination geometries, they are much less structurally predictable than other first-row transition metal complexes. Copper(I) strongly prefers ligands having soft donor atoms such as P, C, thioether S, and aromatic amines. Although twocoordinated linear and three-coordinated trigonal arrangements are known, Cu(I) complexes are mostly four-coordinated species adopting a tetrahedral geometry. In Cu(II) complexes the coordination number varies from four to six, including fourcoordinate square-planar (sp), five-coordinate trigonal bipyramidal (tbp), and six-coordinate octahedral (oc) geometries. The variety of accessible arrays allows for a great assortment in the choice of the ligands (from mono- to hexadentate chelates) and of the donor atoms (N, O, S, and halides).76 The redox potential of the physiologically accessible Cu(I)/Cu(II) couple varies dramatically depending upon the ligand environment due to the donor set, geometry, substituent electronic and steric effects, and chelation.77 For example, in the one-electron oxidation of Cu(I) complexes toward dioxygen, a wide range of reduction potentials (from −1.5 to +1.3 V vs standard hydrogen electrode)77 is known for copper complexes. In addition, such an electron transfer always involves important modifications of the stereochemistry of the pertinent oxidized/ reduced complexes. This feature together with the possibility to release coordinating groups ongoing, for example, from octahedral Cu(II) to tetrahedral Cu(I) species, are chemical factors that illustrate the complexity of the Cu(I)/Cu(II) system in physiological media.37,78 Section 2 describes copper complexes grouped according to (i) the ligand donor atom set, (ii) increasing ligand complexity, and (iii) ligand similarity. The molecular structure of most of these complexes has been illustrated in appropriate figures. Copper complexes are termed with consecutive Arabic numbers; ligand(s) comprised in the coordination sphere of copper are termed with HmLn annotation (m = 0, 1, 2, 3; n corresponding to the Arabic number of the complex). Only discrete copper complexes have been included in this review. Other preparations referred to as ‘mixtures of copper compounds’ comprising copper(II) salts mixed with ligands without a clear structural identification of the resulting copper complex have not been considered. For the different classes of ligands described, emphasis has been devoted, in particular cases, on identification of structure−activity relationships (SARs). Potent (or significant, remarkable) cytoxicity refers to IC50 values in the low micromolar to submicromolar range. Moderate cytoxicity refers to IC50 values > 10 μM.

Figure 1. Number of articles in Web of Science on the topic “copper and anticancer” from 2000 to 2012.

Although many copper complexes have been proposed as promising cytotoxic agents on the basis of in vitro assays very few data have been so far reported on their mechanisms of action. The final two sections (sections 3 and 4) summarize recent findings on (i) identification of the main molecular targets and cellular pathways involved in the copper complexesinduced antiproliferatice effects and (ii) the state of art of in vivo studies on the antitumor activity of copper compounds. This overview would like to be a useful tool for the research community actively involved in the copper-based anticancer drug discovery.

2.1. S-Donor Systems

2.1.1. Thiosemicarbazones (TSCs). This class of ligands comprises a wide variety of compounds that share the R1R2C NNH(CS)NR3R4 framework (Figure 2). TSCs exist as thione−thiol tautomers and can bind to a metal center in the thione or in the anionic forms (Figure 2).

2. COPPER COMPLEXES AS ANTICANCER AGENTS Copper forms a rich variety of coordination complexes with oxidation states Cu(II) and Cu(I), and very few examples of copper(III) compounds are reported.75 The coordination chemistry of copper is dominated by Cu(II) derivatives with

Figure 2. TSC frameworks. 817

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A number of bonding modes have been observed for TSCs in their neutral or anionic forms, and depending on the substituents, they can behave as N,S bidentate, N,S,D (D = N,O) tridentate, or N2,S,D (D = O, S) tetradentate ligands. The ability of TSCs to form stable complexes with transition metal ions makes them versatile pharmacophores.79,80 Historically, TSCs have been explored as antiviral, antifungal, and antibacterial agents.80 The antitumor activity of copper−TSCs has been reported as early as 1960s,81,82 and developments are still in progress.65,83−93 2.1.1.1. κ2N,S Systems. Among the bidentate κ2N,S-TSCs ligand adducts, the Cu(II) complexes [Cu(L1)Cl(H2O)], [Cu(HL1)(H2O)2SO4], [Cu(L1)(H2O)2NO3], and [Cu(L1)(H2O)2(Ac)] of the 2-hydroxy-8-propyl-tricyclo-[7.3.1.0.2,7]tridecane-13-one-thiosemicarbazone (HL1) (Figure 3a−d) were tested for their in vitro effects on HeLa cell proliferation. For all tested complexes the antiproliferative activity ranged from 1 to 10 μM.94

Figure 4. Binuclear formylpyridine-TSC copper(II) complexes of (a and b) HL3a = pyridine-2-carbaldehyde-TSC or formylpyridine-TSC and (c) HL3b = pyridine-2-carbaldehyde 4-N-methyl-TSC.

chains in which the copper atom of one complex coordinated with the thiocarbamide nitrogen atom of the neighboring complex.96 3a1, 3a2, and 3a3 complexes at a concentration of 10−5 mol/L selectively inhibited growth of 60−90% of HL60 cells.96 Interaction of 3a3 and [Cu(L3b)(NO3)] (3b1, HL3b = pyridine-2-carbaldehyde 4-N-methyl-TSC (Figure 4c)) with [poly(dA-dT)]2, [poly(dG-dC)]2, and calf thymus DNA (CTDNA) has been probed and they exhibited toxicity against V79 cells in the low micromolar range (IC50 = 6.14 and 2.43 μM, respectively).97 Currently, the most promising therapeutic compounds among all investigated TSCs are triapine (3-aminopyridine-2carboxaldehyde TSC, 3-AP) (Figure 5a) and di-2-pyridylketone-4,4-dimethyl-3-TSC (Dp44mT) (Figure 5b).59 The latter showed potent antitumor activity98−101 and marked and selective activity against tumor xenografts in mice.59 Related studies exploring the biological activity and redox properties of copper complexes of ApT and DpT analogues have shown that these compounds, particularly monovalent

Figure 3. (a−d) Copper complexes of bidentate κ2N,S-TSC ligands derived from 2-hydroxy-8-propyl-tricyclo[7.3.1.0.2,7]tridecane-13-one (HL1); (e) copper complexes of bidentate κ2NS-TSCs ligands derived from cuminaldehyde (p-isopropyl benzaldehyde) (HL2a−d).

Binuclear copper(II) complexes 2a−d of TSC derived from cuminaldehyde (Figure 3e) have shown nucleolytic cleavage activities on pUC18 plasmid DNA using gel electrophoresis in the presence and absence of H2O2. All these copper(II) complexes behaved as efficient chemical nucleases with hydrogen peroxide activation.95 2.1.1.2. κ3N,N′,S Systems. Many TSC ligands have substituents attached on the imino nitrogen atom (Figure 2), e.g., R1 = pyridine, so that they become tridentate donors (κ3N,N′,S). The copper(II) complexes [Cu(L3a)Cl]·DMSO (3a1) and [Cu(L3a)Br]·DMSO (3a2) (HL3a = pyridine-2carbaldehyde-TSC) (Figure 4a) showed a distorted bipyramidal coordination polyhedron of the complexing ion in which the TSC sulfur atom served as a bridge and occupied the copper fifth coordination site. In the crystal structure, the [Cu(L3a)]NO3·DMSO (3a3) complex (Figure 4b) formed polymer

Figure 5. (a) 3-Aminopyridine-2-carboxaldehyde TSC or triapine (3AP), (b) 2-pyridyl-N4-substituted TSCs (DpT), and (c) 2acetylpyridine-N4-substituted TSCs (ApT). 818

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Figure 6. Structure of (a) [Cu(L4a−m)]Cl complexes (4a−m), (b) pyridine 2-carbaldehyde TSC ligand (HL5), and (c) [Cu(L6a−b)X] complexes.

[Cu(TSC)]+ species, were potent cytotoxic agents. Further, the Cu(I)/Cu(II) redox cycling of these complexes, like their Fe(II/III) analogs, played a significant role in their biological activity.102 This work and others strongly supported the hypothesis that the copper complexes rather than any dissociated ligands or cellular metabolites were responsible for the biological effects in vitro and in vivo. 102−104 Interestingly, the study of the Cu(II) coordination chemistry of these compounds revealed that both 1:1 and 1:2 Cu/ligand complexes could be isolated and that the 1:2 complexes dissociated to give significant amounts of the 1:1 species. The higher biological activity of the 1:1 complexes suggested that they may be the active species in cells, while the 1:2 complexes could be precursors to the 1:1 complex formed by partial dissociation. Moreover, the copper complexes of HDp44mT ligand containing an electron-withdrawing substituent exhibited higher Cu(II/I) redox potentials and higher antiproliferative activity than the Cu complexes of HAp44mT (Figure 5c).102 Recently, an interesting evaluation of the Topo IIα inhibition activity of a series α-heterocyclic-N4-substitued TSCs (HL4a−m) and their corresponding [Cu(L4a−m)]Cl complexes (4a−m) were reported by Lewis and co-workers (Figure 6a).105 4a−m complexes were shown to catalytically inhibit Topo IIα at concentrations (0.3−7.2 μM) over an order of magnitude lower than their corresponding free ligands. The copper(II) chelate of the pyridine 2-carbaldehyde TSC (HL5) (Figure 6b) was evaluated for in vitro and in vivo anticancer activity. Results demonstrated that HL5 activity (low micromolar range) was enhanced 4- to 5-fold by copper chelation and completely attenuated by iron. Importantly, once formed, the copper complex retained activity in the presence of additional iron or iron-containing biomolecules and mediated its effects primarily through induction of ROS with depletion of cellular GSH and protein thiols. Moreover, HL5/Cu2+ chelate was shown to have activity in an HL60 xenograft model.106 8-Quinolinecarboxaldehyde TSC (HL6a−b) and copper formed compounds with a 1:1 metal:ligand ratio in which the ligand was either the neutral molecule or the monohydric acid anion (Figure 6c). Its acidic properties were enhanced not only as a result of copper coordination but also by the electronic effects of substituents in the thiosemicarbazide moiety. In particular, HL6b was coordinated only in the anionic form. The tendency of the complexes to dimerization and association with

acid anions or sulfur atoms of the organic ligands as bridges was established. However, only the monomeric species [Cu(HL6a)(NO3)2]· 2H2O was able to suppress 41 M and SK-BR-3 cancer cell growth with IC50 values of 0.84 and 0.20 μM, respectively.107 2.1.1.3. κ3N,O,S Systems. Many copper complexes with tridentate κ3N,O,S-TSC ligands were prepared. The oxygen donor atom usually derived from compounds with proven biological relevance such as salicylaldehyde, 1,2-naphthoquinone, formyluracil, or pyridoxal (see Figure 7).

Figure 7. Structure of copper complexes (7a−h) of 5-formyluracilTSC ligands (HL7a−h).

Copper(II) derivatives 7a−h of 5-formyluracil TSC were neutral, pentacoordinated when synthesized from copper chloride (Figure 7a). On the contrary, nitrate derivatives consisted of hexacoordinated monocations and nitrate anions (Figure 7b).108 On varying the substituents on the TSC moiety, the coordination geometry was practically unaffected for the complexes with the same counterion. Instead, interactions with CT-DNA and nuclease activity verified on plasmid DNA pBR 322 were strongly affected. A series of copper(II) complexes containing 2-oxo-1,2dihydroquinoline-3-carbaldehyde N-substituted TSC (HL8a−c, Figure 8) has been prepared and characterized in order to study the effect of ligand substitution at terminal N on the structures of the complexes and on their biological activities.109,110 The bovine serum albumin (BSA) binding properties of the complexes suggested that the binding affinity increased with the increasing size of the substituent of the TSC moiety. The cytotoxic studies showed that the complexes [Cu(L8a)Cl819

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aromatic requirements at position 1 of pyrazolone ring were crucial for inducing better cytotoxic activity. Flow cytometric analyses indicated that apoptosis could be the possible mechanism of cell death and that oxidative stress might have been responsible for the triggering of the apoptotic process.112 2.1.1.4. κ4N,N′,S,X (X = O, S) Systems. Two potentially tetradentate TSC ligands (H2L11a−b) were synthesized to chelate copper ions through a unique κ4N,N′,S,O-TSC system, affording uncharged copper compounds 11a and 11b (Figure 10a). These complexes inhibited proliferation of cisplatin-

Figure 8. Structure of (a) [Cu(L8a)Cl(MeOH)]Cl, (b) [Cu(L8b)Cl](MeOH), and (c) [Cu(L8c)NO3].

(MeOH)]Cl (Figure 8a) and [Cu(L8b)Cl](MeOH) (Figure 8b) exhibit good cytotoxic activity against HeLa and NIH 3T3 cell lines. The IC50 values indicated that the square-planar complex [Cu(L8b)Cl](MeOH) was less toxic but more selective against cancer cells over the square-pyramidal [Cu(L8a)Cl(MeOH)]Cl complex.109 The water-soluble copper(II) complex [Cu(L8c)NO3] (Figure 8c) strongly bound to CT-DNA via an intercalation mode with an intrinsic binding constant of 2.33 × 106 M−1.110 The analogous water-soluble copper(II) complex [{Cu(L9)(CH3OH)}2](NO3)2·H2O, 9 (Figure 9a), of the dimethylsubstituted TSC ligand HL9 interacted with CT-DNA through intercalation and cleaved the pBR322 plasmid DNA.111 Complex 9 also exhibited a strong binding to BSA over the ligand. Investigations of antioxidative properties showed that 9 had strong radical scavenging properties. Further, the cytotoxic effect of the complex was examined on HeLa, HepG2, and Hep-2, showing that 9 exhibited moderate cytotoxic specificity on HeLa cell lines (IC50 = 13.1 μM).111 Two copper(II) chloride complexes of 4-TSC-5-pyrazolones (HL10a−b, Figure 9b) were recently synthesized and characterized.112 While both ligands existed as different tautomers in the solid state and in DMSO solution, Cu(II) ion coordinated the ligands only in the thiolate form giving a square-pyramidal geometry. In the two crystal structures, the copper(II) complex cation formed polymeric chains {[Cu(L10a−b)Cl]+}n with a bridging chloro atom. Both copper(II) complexes [Cu(L10a)Cl] and [Cu(L10b)Cl] displayed a dose-dependent cytotoxicity toward HL60, REH, C6, mouse L929, and mouse B16 cell lines, while uncoordinated ligands showed no cytotoxic action. Complex 10a was more toxic against all tested cells in comparison with complex 10b. As both ligands coordinated Cu(II) in the same tautomeric form, it was clear that the planar

Figure 10. Structure of (a) Cu(II) complexes (11a−b) of tetradentate κ4N,N′,S,O-TSC systems and (b) Cu(II) complexes (12a−c) of tetradentate κ4N,N′,S,S’-TSC ligands.

resistant SK-N-DZ NB cells and caused S-phase cell cycle arrest, cytopathologic effects, and apoptosis of the SK-N-DZ cells. Increased expression of p53 protein molecules was detected in the SK-N-DZ cells treated with 11a. The terminal amino-substituted complex 11b showed stronger anticancer activity than 11a.87 Copper(II) complexes bearing tetradentate κ4N,N′,S,S′-TSC ligands (H2L12a−c), Knoevenagel condensate β-diketone Schiff base of TSC, possessed cytotoxic activity in the submicromolar range against MDA-MB-231, HCT-116, and NCI-H23 cancer cells (Figure 10b). In addition, 12a was found to be able to significantly extend the lifespan of Ehrlich Ascites Carcinoma (EAC) bearing mice.113 2.1.2. Thiosemicarbazides. Complexes of thiosemicarbazide and 1,4-substituted thiosemicarbazide are of general interest as models for bioinorganic processes.114,115 Acylthiosemicarbazide contains O, S, and N as potential donor atoms and is liable to form complexes by loss of hydrazinic proton via enolization/thioenolisation via formation of several tautomeric forms (Figure 11). A recent investigation focused on the design of a glycosyl saccharide derivative (D-glucopyranose)-4-phenylthiosemicarbazide (HL13). Introduction of a thiosemicarbazide anchoring

Figure 9. Structure of (a) [{Cu(L9)(CH3OH)}2](NO3)2·H2O, 9, where HL9 = 2-oxo-1,2-dihydroquinoline-3-carbaldehyde 4(N,N)-dimethyl TSC and (b) [Cu(L10a−b)Cl] complexes of 4-TSC-5-pyrazolones HL10a−b. 820

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also against the cisplatin-resistant subclones C13 and A431/Pt, with IC50 values in the submicromolar range. 2.1.4. Thioureas. A series of copper(I) complexes 16a−l of N,N′-disubstituted thioureas (HL16a−l) (Figure 14) has been Figure 11. Tautomeric forms for N1-acyl-N4-substituted thiosemicarbazide.

group provided a well-defined binding environment as well as increased the stability of the resulting metal complexes.116 The authors claimed a potential benefit of utilizing this approach relied on the availability of a pendant carbohydrate moiety able to interact with carbohydrate transport and metabolic pathways in the body. The copper complex 13 (Figure 12) inhibited EAC in Swiss albino mice.116 Figure 14. Structure of copper(I) complexes 16a−l of N,N′disubstituted thioureas.

screened for their in vitro cytotoxic activity in several human cancer cell lines (A498, EVSAT, H226, IGROV, M19, MCF-7, and WiDr) exhibiting a moderate cytotoxicity comparable to that of cisplatin and etoposide.121 2.1.5. Dithiolates. The in vitro and in vivo antiproliferative activity of a series of neutral, mixed-ligand copper(II) complexes of general type [Cu(amine)(L17)] (amine = NH3, ethylenediamine (en), diethylenetriamine (dien), and dipropylene-triamine (dpta); L17 = 1,1-dicyano-2,2-ethylenedithiolate(2−)), [Cu(tz)(L17)] (tz = 2-amino-thiazole (2a-tz), 2amino-5-methyl-thiazole (2a-5mtz) and 2-amino-2-thiazoline(2a-2tzn)) were studied and related to their chemical and physicochemical properties. Among the tested Cu(II) compounds, the [Cu(2a-5mtz)(L17)(H2O)] complex 17 (Figure 15) significantly increased the lifespan of leukemia P388-

Figure 12. Structure of the copper(II) complex 13 of glycosyl saccharide derivative (D-glucopyranose)-4-phenylthiosemicarbazide ligand (HL13; R = Ph).

2.1.3. Dithiocarbamates (DTCs). After discovery of the proteasome inhibitory activity of “organic copper compounds”, i.e., mixture of copper(II) salts and bidentate ligands including dithiocarbamate (DTC), Dou and co-workers reported several studies concerning the activity of discrete, well-characterized Cu(II)−DTC complexes. Taking into account that disulfiram (DSF, tetraethylthiuram disulfide) mixed with copper has a marked anticancer activity in vitro and considering that DSF can be converted in vivo to diethyldithiocarbamate (L14a), the complex [Cu(L14a)2] was prepared and characterized. Its toxicity as well as its ability to inhibit proteasome (proteasome in treated cells and purified 20S proteasome) were compared with those of isostructural Zn and Ni complexes.117 Analogously, the complex [Cu(L14b)2] 14b (Figure 13a) was synthesized and its ability of inducing apoptosis in tumor cells was demonstrated.118,119

Figure 15. Structure of [Cu(2a-5mtz)(L17)(H2O)], 17.

bearing mice in vivo.122 In general, dithiolate complexes with thiazole ligands were found to be the most effective in both in vivo and in vitro SCE and PRI studies. Their activity has been correlated with the high polarity and electrostatic interactions and not with their lipophilicity. 2.2. O-Donor Systems

2.2.1. Pyridine N-Oxides. Heterocyclic amine N-oxides and their parent bases, including pyridine and its derivatives, belong to the class of organic compounds of large medical applicability. It has recently been reported that substituted pyridine-N-oxides exhibit antitumor activities.123−125 A series of CuCl2 complexes with methyl derivatives of 4nitropyridine-N-oxide was found to be moderately active cytostatics when studied in vitro. It was also found that the biological action of chloro complexes was affected by spatial and electronic properties of the organic coligand,126 including the position of the methyl substituent(s). These results prompted the same authors to consider the use of nitrate

Figure 13. Structure of (a) pyrrolidine DTC copper complex 14b and (b) the methyl-, ethyl-, and tert-butyl-esters of sarcosine DTC copper complexes 15a−c (R = Me, 15a; R = Et, 15b; R = tert-butyl, 15c).

The correlation between the nature of the DTC ligand and the chemical and biological properties of the corresponding copper complexes (Figure 13) has further been studied.120 Electrochemical and stability data correlated with the cytotoxic activity; in fact, the most stable complex 15b proved to be the most cytotoxic species in vitro against 2008 and A431 cells and 821

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agent in normoxia, this effect being related to its SOD-like activity.129 2.2.2. κ2O,O-Donor Systems. Plumbagin (HL20; 5hydroxy-2-methyl-1,4-naphthoquinone) is a potent toxic natural product which has been used for treatment of rheumatoid arthritis, dysmenorrhea, bruising, and cancer. Reaction of HL20 with Cu(II) salts afforded [Cu(L20)2]· 2H2O, 20a (Figure 18). Using bipy as a coligand, HL20 reacted

anion instead of chloride. Hence, nitrato copper(II) complexes 18a−f of substituted pyridine-N-oxides (L18a−f) were isolated as mononuclear, five-coordinated, trans isomers [Cu(NO3)2(H2O)(L18a−c)2] (Figure 16a) or four-coordinated

Figure 18. Structure of plumbagin (HL20) copper(II) complexes 20a and 20b.

with Cu(II) to give [Cu(L)(bipy)(H2O)]2(NO3)2·4H2O, 20b (Figure 18).130 In vitro cytotoxicity assays of HL20 and related Cu(II) complexes against several cancer cell lines (786-0, MCF7, HepG2, CNE2, HCT-116, BEL-7404, and NCI-H460) showed that 20b was 27 times more effective than cisplatin against NCI-H460 cells. The copper compounds exhibited enhanced cytotoxicity compared to free plumbagin. Their DNA binding properties were investigated, and results indicated that the two complexes were noncovalently bounded and mainly intercalated the neighboring DNA base pairs. Cu(II) complexes also inhibited Topo I activity more efficiently than plumbagin.130 Isoflavones belong to one of subclasses of flavonoids showing extensive biological activities and antitumoral actions.131−133 Several researchers have reported the interaction of metals with isoflavone134 (HL21a) and 4′,7,8-trihydroxy-isoflavone.135 Complexes of different transition metals including copper (21a) were investigated (Figure 19). All metal complexes showed stronger DNA binding ability and were generally more active against a panel of human cancer cell lines with respect to free isoflavone.

Figure 16. Structure of nitrato copper(II) complexes 18a−f of substituted pyridine-N-oxides.

[Cu(NO 3 ) 2 (L 1 8 d ) 2 ], [Cu(NO 3 ) 2 (L 1 8 e ) 2 ], and [Cu(NO3)2(L18f)2] (Figure 16b) species.127,128 The organic ligands and copper complexes were tested in vitro for the cytotoxic activity against MCF-7, SW707, and murine P-388 cancer cells. All complexes were significantly cytotoxic toward P-388 cells. Complexes without or with only one methyl group exhibited remarkable cytotoxic activity against SW7-07 and MCF-7 cells. Generally, for all cell lines, complexation increased cytotoxicity.127,128 Trying to improve the bioactive profile of these hypoxiaselective cytotoxins and promote a metal−ligand synergism, new Cu(II) complexes of general formulas [Cu(HL19a−c)2] 19a−c with unsubstituted and disubstituted 3-aminoquinoxaline-2-carbonitrile N1,N4-dioxide derivatives (HL19a−c) were developed (Figure 17) and tested for cytotoxicity against V79 cells under hypoxic and aerobic conditions.129 Although the complexes were structurally similar only the highest lipophilic 19b showed cytotoxic selectivity in hypoxia. On the contrary, 19a was not selective but showed a good profile as a cytotoxic

Figure 19. Proposed structure of the bis-substituted [Cu(L21a)2] complex 21a.

In addition, the analogous copper(II) complex 22 of 4′methoxy-5,7-dihydroxy-isoflavone (HL22) (Figure 20a) showed moderate cytotoxic effectiveness against five human cancer cell lines (A549, HeLa, HepG2, SW620, and MDA-MB-435), with IC50 values in the 10−50 μM range.136 Other biologically active flavonoids such as hesperetin (HL23a; 5,7,3′-trihydroxy-4′-methoxy-flavanone), naringenin (HL23b; 4′,5,7-trihydroxyflavanone), and apigenin (HL24; 4′,5,7-trihydroxyflavone) have been reported to exhibit antitumor effects against breast cancer and hepatoma cell

Figure 17. Structure of Cu(II) complexes 19a−c of 3-aminoquinoxaline-2-carbonitrile N1,N4-dioxide ligands. 822

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Figure 20. Structure of (a) complex [Cu(L22)2], 22, (b) complexes [Cu(L23a)2(H2O)2]·nH2O, 23a and [Cu(L23b)2(H2O)2]·nH2O, 23b, and (c) complex [Cu(L24)2(H2O)2]·nH2O, 24.

lines.137−139 In addition, some metal complexes of hesperetin and naringenin showed antioxidant and anticancer activities.140,141 In particular, copper(II) complexes 23a−b and 24 (Figure 20b and 20c) have been tested in vitro against HepG2, SGC-7901HeLa cells. Copper complexes including hesperetin and apigenin inhibited more efficiently SGC-7901 and HepG2 cell growth with respect to the free ligands and to 23d.142 3,5,7,30,40-Pentahydroxyflavone (HL25; quercetin), as well as all bioflavonoids, protects DNA from damage induced by ROS including •OH, H2O2, and O2•−.143 In a recent study, [Cu(L25)2(H2O)2], 25 (Figure 21a) promoted cleavage of plasmid DNA, producing single- and double-strand breaks, and intercalated into the stacked DNA base pairs. Moreover, 25 induced oxidative DNA damage involving generation of ROS. Cytotoxicity experiments carried out in A549 cells confirmed its

apoptosis-inducing ability with a cytotoxicity higher than that of quercetin alone. In treated cells the levels of surviving protein expression decreased, whereas the relative activity of caspase-3 significantly increased, suggesting that the antitumor mechanism induced by 25 involved not only oxidative DNA damage with ROS generation but also a specific interaction with DNA.144 The mononuclear Cu(II) complex [Cu(L26a)2] (Figure 21b) promoted an intercalative interaction with CT-DNA with a calculated binding constant value of 2.5 × 104 M−1. Complex 26a showed a moderate cytotoxic potency toward ECA109 (IC50 = 20.8 μM) and SGC-7901 (IC50 = 25.7 μM) cells.145 Insertion of a pendant piperidinyl-ethoxy group onto the isoeuxanthone moiety did not enhance the biological properties of the corresponding 26b complex (Figure 21b).146 In the xanthone-derivatized complex [Cu(L27)(CH3CN)2](ClO4)2, 27 (L27 = 1,8-(3,6,9-trioxaundecane-1,11-diyldioxy)xanthone, Figure 21c) the enhanced planarity and metal conjugation allowed a slightly increased DNA base-pair intercalation.147 Interaction with CT-DNA via intercalation was also observed with copper complexes of (−)-epicatechin gallate and (−)-epigallocatechin gallate, strong antioxidant polyphenols obtained from green tea extracts.148 Santonic acid, derived from the natural molecule santonin obtained from the active ingredient of the extract of Artemisia, was used to coordinate copper(II), giving the dinuclear tetragonal complex [Cu2(sant)4(H2O)2]. In the solid-state EPR studies evidenced the presence of two antiferromagnetically coupled copper centers. The compound showed cytotoxic activity against four cell lines (MC3T3-E1, UMR-106, Caco-2, TC7) and determined great alteration in the nuclei and cytoplasms of treated cells, as confirmed by cell morphology studies.149 The research of new complexes providing a synergistic effect of copper with active drugs has not been limited to natural derivatives but also included anticancer antibiotics such as chromomycin (Chro)150 and 1,4-dihydroxy-9,10-antraquinone2-sulfonate (NaQSH2), an analog of the core unit of anthracycline.151 CuII(Chro)2 exhibited cytoxicity against HepG2 cells, possibly due to competition of spermine for Cu(II) in the bis-substituted Chro complex in the nucleus of the cancer cells. The GI50 value (0.2 μM) of the CuII(Chro)2 complex at 48 h was 25-fold lower compared to that of the free

Figure 21. Structure of (a) quercetin complex [Cu(L25)2(H2O)2], 25, (b) the [Cu(L26a−b)2] complexes 26a and 26b, and (c) complex [Cu(L27)(CH3CN)2](ClO4)2, 27. 823

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copper(II)−quinolones complexes have been reported where the quinolone acted as a bidentate ligand coordinating the metal through ketone and carboxylate oxygens. In a series of five neutral metal complexes [Fe(MFL)3], [V(O)(MFL)2], [Cu(MFL)2(H2O)2], [Ni(MFL)2(H2O)2], and [Mn(MFL)2], the copper derivative showed the strongest DNA binding via intercalation and the highest in vitro antiproliferative activity against A549 cancer cells (IC50 5.4 μg/mL).158 Squarepyramidal, ternary Cu(II) complexes 31a−f were prepared with CPF and bidentate N,S-donor ligands (L31a−f; Figure 24). 159 By changing the electronic properties of the intercalative ligand, a variation on the DNA interaction ability and on the cytotoxicity of the compounds was observed.

Chro control. The Cu(II) complex of NaQSH2 interacted with CT- DNA at physiological pH. 2-Thenoyltrifluoroacetone (HL28), a known inhibitor of the mitochondrial electron flux, gave the planar [Cu(L28)2] complex 28 (Figure 22a).152 The authors stated that the

Figure 22. Structures of (a) [Cu(L28)2], 28, and (b) [Cu(L29)2], 29.

antitumor activity of 28 against K562 leukemia cells was also due to the liphophilicity and electronegativity of the fluoromethyl group of the ligand. Another bis-β-diketone-type ligand, the curcumine derivative diacetylcurcumin (HL29 = 1E,6E-1,7-bis(4-acetoxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) has been used to coordinate copper with the aim to obtain a fluorescent nontoxic probe. Complex 29 (Figure 22b) bore two-photon excited fluorescence, but it did not show significant cytotoxic activity against A549, HeLa, and MCF-7 cell lines.153 The antihypertensive drug valsartan (vals) acted as a bridging ligand with copper(II) through its carboxylate group giving dinuclear compounds [Cu(vals)(H2O)3]2 and [Cu(vals)(H2O)2DMSO]2 which differed only by a coordinated solvent molecule. Whereas Valsartan in concentrations up to 100 mM had no effect on two selected cell lines (normal MC3T3-E1 and tumoral UMR-106), copper complexes showed antiproliferative activity toward both cell lines in the micromolar range.154 The role of the trimethylated aminoacid L-carnitine (βhydroxy-γ-butyrobetaine; L30) as antioxidant in many pathologies and also in inhibiting cancer development is well documented.155,156 The dinuclear complex [Cu2(L30)2Cl2(H2O)2]Cl2, 30 (Figure 23), was tested on two

Figure 24. Structure of copper complexes 31a−f containing ciprofloxacin and L31a−f.

Copper quinolones complexes have also been introduced in octamolybdates polyoxometalates (POMs) systems determining formation of a series of different isomers. A general increase of the antitumoral properties of the copper assemblies was observed compared to those shown by POMs.160 A very recent study reported on the chemical mechanism of the peroxidant reaction of Cu(II) ions and polyphenolic systems (stilbene-chroman hybrid with a cathecol moiety) which could be responsible for DNA damage, cell cycle arrest, and apoptosis in HepG2 cells.161 2.3. N,O-Donor Systems

2.3.1. Phenol Analogues to 8-Hydroxyquinoline. 8Hydroxylquinoline (HL32a) (Figure 25a) is a monoprotic

Figure 23. Structure of complex [Cu2(L30)2Cl2(H2O)2]Cl2, 30.

leukemia cell lines (HL-60 and K562) and compared with the activity of copper and L-carnitine as individual entities.157 Complex 30 exerted a concentration-specific antileukemic action (IC50 values in the low micromolar range). Moreover, necrotic phenomena were observed in 30-treated K562 cells. Antibacterial quinolone and fluoro-quinolone species, such as moxifloxacin (MFL) and ciprofloxacin (CPF), have been extensively used together with diimine ligands for synthesis of ternary copper compounds (vide infra), but other examples of

Figure 25. Structure of (a) 8-hydroxyquinoline (HL32a) and clioquinol (HL32b), (b) analogs of 8-hydroxyquinoline with substitutions at the 8hydroxyl group (L32c−d), and (c) complex [Cu(L32c)2]Cl2, 32c. 824

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Figure 26. Tautomeric forms of 3-(2-R-phenylhydrazono)-naphthalene-1,2,4-trione derivatives.

bidentate chelating agent able to form a bis-substituted copper complex that inhibited proteasome activity, resulting in proliferation suppression and apoptosis induction in cultured breast and prostate cancer cells.162,163 Since the bis(8hydroxyquinoline)-substituted benzylamine derivatives (L32c−d) (Figure 25b) were more efficient cytotoxic agents than the hydroxyquinoline analogs, the mononuclear copper complexes [Cu(L32c−d)2] were synthesized. In particular, [Cu(L32c)2] (Figure 25c) discriminated between human breast cancer (MDA-MB-231) and noncancer cells (MCF-10A), showing a potential for selective anticancer treatment.162,164 2.3.2. Naphthoquinones. The 1,2- and 1,4-naphthoquinone nuclei are commonly encountered in natural products, and their derivatives exhibit a wide range of pharmacological properties including anticancer activities.165,166 Such properties are due to the interference of quinones in the electron transport chain by electron reduction processes, generating semiquinone radical (Q•−) and hydroquinone anion (Q2−).167,168 Incorporation of an azo group into 2-hydroxy-1,4-naphthoquinone has led to promising anticancer agents in which metal complexation with copper(II) resulted in increased cytotoxicity.169 The relative stability of the tautomeric forms of 3-(2-R-phenylhydrazono)-naphthalene-1,2,4-trione derivatives (Figure 26) is a function of the substituents.170 Some of these ligands and related [Cu(L33a−o)2] complexes 33a−o (Figure 27) have shown in vitro antitumor activity against several cancer cell lines (SF295, HCT-8, and MDA-MB435).

Figure 28. Structures of (a) complex 34 of the 2-aminothiazole-4acetate ligand (HL34), (b) meclofenamic acid (N-(2,6-dichloro-mtolyl)anthranilic acid) (HL35), and (c) copper N-(2-hydroxyacetophenone) glycinate complex 36.

anthranilic acid; HL35)172 (Figure 28b) displayed a centrosymmetric tetramer assembly around the planar cyclic Cu2(OH)2 unit with the two endo- and two exo-cyclic Cu atoms symmetrically bridged by four meclofenamato ligands through the carboxylato oxygens.173 Meclofenamic acid and its related copper complex have been evaluated for antiproliferative activity in vitro against MCF-7, T24, and A-549 cancer cells and mouse fibroblast L-929 cells. Complex 35 demonstrated a selective antiproliferative activity against T-24 cancer cells (IC50 = 5.3 μM) and a remarkable SOD activity.173 A series of three water-soluble dicopper(II) complexes of benzoic acid derivatives has been synthesized and structurally characterized.174 All compounds induced oxidative DNA cleavage in the presence of H2O2 and noticeable DNA cleavage activity independent from the functional group attached to the benzene ring (Cl, F, NO2). Such complexes exhibited selective cytotoxic effect against HepG2 cancer cells (2-fold higher) compared to that exerted against Chang normal cells. Copper N-(2-hydroxyacetophenone) glycinate complex 36 (Figure 28c) induced apoptosis in MDR cells employing generation of host protective cytokines through induction of ROS,175 and decreased P-gp expression in CEM/ADR5000 cells. These observations redirected the same authors to speculate that the redox-active complex 36 might be effective at eradicating cancer cells. In particular, the apoptotic potential of 36 on doxorubicin-resistant CEM/ADR5000 leukemia cells was reported, 176 concluding that the copper complex preferentially killed cancerous cells, especially both leukemic cell types irrespective of their MDR status, while leaving normal cells totally unaffected.177 2.3.4. Triethanolamines. The dinuclear complex [Cu2(L37a)2(H2Tea)2] (Figure 29) as well as the linear trinuclear complexes [Cu3(L37a)4(H2Tea)2], [Cu3(L37b)4(H2Tea)2], and [Cu3(L37a)2(H2Tea)2(NO3) 2] (where HL37a = thiophene-2-carboxylic acid, HL37b = 2(thiophen-2-yl)acetic acid, and H3tea = triethanolamine) have been prepared and pharmacochemically studied.178 In vitro antioxidant activity of free ligands and their corresponding copper complexes included (a) interaction with 1,1-diphenyl-2picrylhydrazyl stable free radical, (b) HO•-mediated oxidation of DMSO, (c) scavenging of superoxide anion radicals, (d)

Figure 27. Structure of Cu−naphthoquinone complexes 33a−o.

Free hydrazono HL33f and complex 33o exhibited higher growth inhibition of HCT-8 cells (96.03%) than the positive control doxorubicin (dox) (91.67%). The results indicated that the presence of −NO2 and −I groups were relevant for the antitumor activity. Formation of an organic free radical observed in the EPR spectrum of [Cu(L33o)2] might be responsible for the cytotoxic activity.170 2.3.3. Carboxylates. The cytotoxicity assays on the complex of the catalytically hydrolyzed 2-aminothiazole-4acetate ligand [Cu(L34)2], 34 (Figure 28a), showed that copper coordination greatly increased the cytotoxicity in comparison with that induced by the ligand, especially on tumor HeLa cells (EC50 = 0.67 μM).171 The copper(II) complex [Cu4(L35)6(OH)2(DMSO)2]· 2DMSO, 35 of meclofenamic acid (N-(2,6-dichloro-m-tolyl)825

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groups in axial positions (Figure 31). The antiproliferative activity of these complexes on A375 cells was comparable to that elicited by cisplatin.182

Figure 29. Structure of the dinuclear [Cu2(L37a)2(H2Tea)2] complex. Figure 31. Structure of complex 39.

inhibition of lipid peroxidation, and (e) soybean lipoxygenase inhibition. The results indicated selectivity of the complexes to different free radicals as a consequence of their physichochemical features. The majority of the copper(II) complexes effectively inhibited lipid peroxidation. The complexes were evaluated as potential antiproliferative agents against human cancer and normal cell lines. Results showed that these compounds induced cell cycle arrest in G2/M phase, thus triggering apoptosis.178 2.3.5. Other N,O-Donor Systems. Two μ-oxamidobridged binuclear complexes, [Cu2(L38)(pic)2], 38a, and [Cu2(L38)(Me2phen)2](ClO4)2·H2O, 38b (H2L38 = N1,N2bis(2-(2-hydroxyethylamino)ethyl)oxalamide (Figure 30), pic

2.4. N-Donor Systems

2.4.1. Pyrazoles. Polydentate nitrogen-containing donor ligands derived from poly(pyrazol-1-yl)methanes with [RR′C(Az)2] (Az = azolyl groups; R = H or Az) as general structure and bearing organic functional groups (R′) on the bridging carbon have attracted considerable attention, and their coordination chemistry toward main group and transition metals has been extensively studied.183−185 These intriguing heteroscorpionate ligands186,187 present different types of functional groups, which successfully broaden the scope of their applications. Nitroimidazole and glucosamine conjugated heteroscorpionate ligands, namely, 2,2-bis(3,5-dimethyl-1H-pyrazol-1-yl)-N(2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl)acetamide (HL40) (Figure 32a) and 1,3,4,6-tetra-O-acetyl-2-{[bis(3,5-dimethyl-

Figure 30. Structure of N1,N2-bis(2-(2-hydroxyethylamino)ethyl)oxalamide (H2L38).

= 2,4,6-trinitrophenol and Me2phen = 2,9-dimethyl-1,10phenanthroline) have been synthesized and structurally characterized.179 The cytotoxicities of the two binuclear copper(II) complexes were tested in vitro against SMMC7721 and A549 cell lines showing moderate activity (IC50 in the range 10−25 μM). Analyses on the interactions of the two binuclear complexes with herring sperm DNA (HS-DNA) suggested that both complexes interacted with HS-DNA via intercalation with intrinsic binding constants of 1.73 × 105 M−1, for 38a and 1.92 × 106 M−1 for 38b.179 The same research group has reported the synthesis and structural characterization of a one-dimensional copper(II) polymer [Cu2(L38)(tpa)]n·nH2O (Htpa = therephtalic acid). Also, this derivative was able to interact with HS-DNA via an intercalation mode and showed cytotoxicity against SMMC7721 and A549 cells.180 Bis-substituted copper(II) guanidine complexes [Cu{PhCONHC(NHR)NPh}] have been structurally characterized (R = n-butyl, cyclohexyl), and eight new complexes have been tested for their cytotoxicity and antibacterial and antifungal activities. They were generally less active than the reference cisplatin drug, and only the aryl-substituted compounds diplayed a promising cytotoxic activity.181 A compound of the flavonoid family the chromone derivative 5-amino-8-methyl-4H-benzopyran-4-one (L39) reacted with copper(II) salts giving mono- and bis-substituted complexes. In the latter complex 39, the copper ion resided in a distorted octahedron with both O,N-chromone ligands symmetrically coordinated in the equatorial plane with two perchlorato

Figure 32. Structure of (a) 2,2-bis(3,5-dimethyl-1H-pyrazol-1-yl)-N(2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl)acetamide ligand (HL40), (b) 1,3,4,6-tetra-O-acetyl-2-{[bis(3,5-dimethyl-1H-pyrazol-1-yl)acetyl]amino}-2-deoxy-β-D-glucopyranose ligand (HL41), (c) copper(II) cores [(L40)2Cu]2+ and [(L41)2Cu]2+.

1H-pyrazol-1-yl)acetyl]amino}-2-deoxy-β- D -glucopyranose (HL41) (Figure 32b), were synthesized by direct coupling of preformed side chain acid and amine components.188 In the related copper(II) complexes {[(L40)2Cu]Cl2}, 40, and {[(L41)2Cu]Cl2}, 41, the local structure [Cu(L)2]2+ was described by four Cu−N and two Cu−O interactions to form a pseudo-octahedron core (Figure 32c). Complexes 40 and 41, as well as the corresponding uncoordinated ligands were evaluated for their cytotoxic activity toward a panel of six tumor 826

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Figure 33. Structure of pyrazole−pyridine ligands (L42a−l) and substituted bis(pyrazolyl)alkanes (L43a−l).

cell lines (A431, HCT-15, A549, Capan-1, MCF-7, and A375). Uncoordinated ligands proved to be ineffective against all cell lines, whereas copper complexes displayed a similar growth inhibitory potency in the micromolar range (7−14 μM), slightly lower than that shown by cisplatin. Interestingly, in HCT-15 colon adenocarcinoma cells, the cytotoxicity of copper(II) complexes exceeded that of the reference drug by a factor of about 3. Moreover, both copper(II) complexes overcame acquired resistance to cisplatin.188 2.4.2. Pyrazole−Pyridine Systems. Pyrazole−pyridine ligands (L42a−l) and substituted bis(pyrazolyl)alkanes (L43a−l) are two classes of ligands with molecular backbones endowed with N,N copper-coordinating abilities (Figure 33). To establish a relationship between the structure of the ligand and the cytotoxic activity of the resulting Cu(II) complexes (prepared by mixing an equimolar amount of CuCl2· 2H2O and L42/43a‑l ligands in methanol), specific structural modifications were applied to these N-donor chelate ligands.189 Additional sulfur binding strongly depended on the types of thioether fragments introduced. Molecular structures were grouped in mononuclear and dinuclear categories. In the first case, the metal geometry was flattened tetrahedral (complexes [Cu(L42/43x)Cl2]; L42/43x = L42d, L42e, L43c, L43g, L43i, and L43l), whereas for the dinuclear systems (complexes [Cu(L42/43y)Cl2]2; L42/43y = L42b, L42c, L42g, L42h, L42i, L43e, and L43f) the metal geometry was square pyramidal, with the apex of the pyramid occupied by a bridging chloride anion. Exceptions were represented by compounds [Cu(L42f)Cl2] and [Cu(L42l)Cl2] that exhibited a trigonal bypyramidal geometry by virtue of the presence of the N,N,S ligand donor set and by compound [Cu(L43a)2Cl]2[CuCl4] that formed chains constituted by the tetrahedral [CuCl4]2− anion and the octahedral [Cu(L43a)2]2+ cation. Testing the anticancer activities of the complexes in HT1080 cells, the highest activity was observed for classes with flexible thioether groups. Among the 20 compounds, [Cu(L42i)Cl2]2 was the most active (IC50 = 3 μM). The relationship between the calculated log P value of the ligand and the cytotoxicity of the respective complex suggested that for each class of compounds there was an optimal log P value (between 4 and 6) at which activity was maximal. Cellular uptake experiments assessed that the ligand comprised in the most active compound [Cu(L42i)Cl2]2 (Figure 34) was internalized

Figure 34. Structure of complex [Cu(L42i)Cl2]2, 42i.

30-fold more efficiently than the ligand included in the less lipophilic [Cu(L42g)Cl2]2. This evidence strongly suggested that passive diffusion accounted for membrane crossing; in addition, the pyrazole−pyridine ligands behaved as copper ionophores that exacerbated the intrinsic toxicity of the metal by increasing its intracellular concentration. The thioether-free pyrazole−pyridine ligands 5-(2-hydroxybenzoyl)-3-methyl-1-(2-pyridinyl)-1H-pyrazole-4-phosphonic acid dimethyl ester (L44a) and 5-(2-hydroxyphenyl)-3-methyl1-(2-pyridinyl)-1H-pyrazole-4-carboxylic acid methyl ester (L44b) and the corresponding Cu(II) complexes [Cu(L44a)Cl2], [Cu(L44b)Cl2] (Figure 35a), [Cu(L44a)2](ClO4)2, and [Cu(L44b)2](ClO4)2 (Figure 35b),190,191 have been synthesized and evaluated as potential anticancer compounds. The complexes exhibited square-planar geometries around the Cu(II) center. Only the bis-substituted complex [Cu(L44b)2](ClO4)2 distin-

Figure 35. Structure of (a) [Cu(L44a)Cl2] and [Cu(L44b)Cl2], (b) [Cu(L44a)2](ClO4)2 and [Cu(L44b)2](ClO4)2. 827

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Figure 36. Structures of copper complexes with benzimidazole-derived ligands L45a−e.

N atoms in the solid state. The complex [Cu(L47a)Cl2], 47a, displayed a square-pyramidal coordination (Figure 38).196 A

guished itself as a promising agent with IC50 values in the range of 6.5−8.0 μM in HL-60 and WM-115 cell lines.190 Insertion of a chromene group onto the pyrazole−pyridine framework produced similar mononuclear, square-pyramidal and dinuclear, tetragonal pyramidal Cu(II) complexes that showed negligible cytotoxic activity against HL-60, NALM-6, and WM-115 cells.192 2.4.3. Imidazoles. A series of copper(II) complexes with 2methylbenzimidazole (L45a), 2-phenylbenzimidazole (L45b), 2chlorobenzimidazole (L45c), 2-benzimidazolecarbamate (L45d), and 2-guanidinobenzimidazole (L45e) was prepared, and their cytotoxic activity was evaluated against PC3, MCF-7, HCT-15, HeLa, SKLU-1, and U373 cancer cell lines, showing that [Cu(L45d)Br2] and [Cu(L45e)Br2] (Figure 36) had significant cytotoxic activity.193 These results showed that the cytotoxic activity was related to the easy displacement of halides from the coordination sphere of the metal.193 The copper complexes [Cu(L46a)Cl(H2O)]Cl·3H2O, 46a, and [Cu(L46b)Cl2(H2O)2]·H2O, 46b, of 2-methyl-1H-benzimidazole-5-carbohydrazide (L46a) and 2-methyl-N-(propan-2ylidene)-1H-benzimidazole-5-carbohydrazide (L46b) (Figure 37) displayed cytotoxicity against A549 (IC50av = 20 μM) and MCF-7 (IC50av = 7 μM) tumor cell lines.194 A series of copper(II) complexes of tri- or tetra-dentate bis(2-methylbenzimidazolyl)amine ligands (L47a−d)195 has been prepared and fully characterized in solution as well as in the solid state.196 All ligands acted as tridentate donors toward the cupric ions through one central amine and two benzimidazole

Figure 38. Structures of copper(II) complexes 47a−d of tri- or tetradentate bis(2-methylbenzimidazolyl)amine ligands.

water ligand and a bridging perchlorate group defined the distorted octahedral environments of complexes [Cu(L47b)(ClO4)H2O]ClO4, 47b (Figure 38), and [Cu(L47c)(ClO4)(H2O)]ClO4, 47c (Figure 38). [Cu(L47d)Cl]Cl, 47d, had presumably a square-pyramidal coordination geometry, with an additional thioether group attached to the central N atom in the axial position (Figure 38). The antiproliferative activity screening revealed that 47a was endowed with the lowest inhibitory effect, indicating that an additional substituent on the central nitrogen was necessary for eliciting cytotoxic activity. The authors speculated that the nearly planar arrangement of the two benzimidazole units and the cupric ion was not a requirement for biological activity. Interestingly, 47c and 47d had a significant inhibitory effect on K562 cancer cells compared to the low toxicity exhibited against healthy bone marrow cells.

Figure 37. Structures of [Cu(L46a)Cl(H2O)]Cl·3H2O and [Cu(L46b)Cl2(H2O)2]·H2O. 828

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cells showed that 49 upregulated genes involved in the unfolded protein response (UPR) and response to heavy metals. The cytotoxic effects of 49 were associated with inhibition of the ubiquitin-proteasome system and accumulation of ubiquitinylated proteins in a manner dependent on protein synthesis. The occurrence of the UPR during the 49induced death process was shown by the increased abundance of spliced XBP1 mRNA, transient eIF2α phosphorylation, and a series of downstream events, including attenuation of global protein synthesis and increased expression of ATF4, CHOP, BIP, and GADD34.203 Yan et al.204 synthesized two novel chloro-bridged and bromo-bridged 1,2,4-triazole-based Cu(II) complexes, [Cu2(L50a)Cl3]·0.5[CuCl4]·EtOH, 50a, and [Cu2(L50b)Br3]Br· H2O, 50b (Figure 40b) (L50a = 3,5-bis{[bis(2-methoxyethyl)amino]methyl}-4H-1,2,4-triazol-4-amine). The apparent CTDNA binding constant (Kapp) values were 2.98 × 106 and 4.05 × 106 M−1 for complexes 50a and 50b, respectively. Furthermore, both compounds displayed efficient oxidative cleavage of supercoiled DNA in the presence of external activating agents. Coordination of monodentate 5-amino-2-tert-butyltetrazole (L51) via the endocyclic N4 atom to the Cu(II) ion produced the five-coordinated [Cu(L51)3Cl2] complex 51 (Figure 40c) endowed with low cytotoxic activity against HeLa cells.205 Analogously, the octahedral copper(II) complex of 3,5-bis(2′pyridyl)-1,2,4-oxadiazole showed moderate cytotoxicity against HepG2and HT29 cells. Cell morphological changes were observed by light microscopy, and an apoptotic death was proposed.206 The interaction of the cationic species with native DNA indicated that the copper complex was a DNA groove binder with binding constant Kb = 2.2 × 104 M−1. 2.4.5. Indoles. Reaction of copper(II) salts with Paullonetype 6-N-(2-N′,N′-dimethylaminoethylamino)-7,12-dihydroindolo-[3,2-d][1]benzazepine (HL52a), 9-bromo-6-N-(2-N′,N′dimethylaminoethylamino)-7,12-dihydroindolo[3,2-d][1]-benzazepine (HL52b), N-(9-bromo-7,12-dihydroindolo[3,2-d][1]benzazepin-6(5H)-yliden-N′-(1-pyridin-2-yl-methylidene)azine (HL 53a ), or N-(9-bromo-7,12-dihydroindolo[3,2-d][1]benzazepin-6(5H)-yliden-N′-(1-pyridin-2-yl-ethylidene)azine (HL53b) afforded the copper(II) complexes [Cu(HL52a)Cl2], 52a, [Cu(HL52b)Cl2], 52b (Figure 41a), [Cu(HL53a)Cl2], 53a, [Cu(HL53b)Cl2], 53b (Figure 41b), and [Cu(L53b)(Ac)(CH3OH)], 53c (Figure 41c).207 52a, 52b, and 53b showed markedly different but remarkably high antiproliferative activities against various cancer cells (CH1, A549, SW480, A2780 cisplatin sensitive, and A2780 resistant) with IC50 values in the micromolar range for four-coordinate complexes 52a−b or in the nanomolar range for five-coordinate complexes 53a− c. The high cytotoxicity of the metal-free paullones HL52a and HL52b was at least preserved upon binding to copper(II) and even enhanced in the case of HL52a compared to 52a in CH1 cells.207 As an extension of the previous study, the same authors investigated the effect of substitution of the folded sevenmembered azepine ring in indolo[3,2-d]benzazepines by a flat six-membered pyridine ring (indolo[3,2-c]quinoline ligands) on the corresponding copper(II) complexes.208 Potentially tridentate ligands HL54a−d and HL54e−h reacted with copper(II) chloride to give five-coordinate complexes [Cu(HL54a−h)Cl2], 54a−h (Figure 41d), stable in aqueous solution. All complexes were highly cytotoxic, with IC50 values in the nanomolar to low micromolar range. Substitution of the seven-membered azepine

The synthesis and structures of two copper(II) complexes with a benzothiazolesulfonamide ligand, [Cu(L48)2(py)2], 48a (Figure 39), and [Cu(L48)2 (en)2], 48b (Figure 39) (HL48 =

Figure 39. Structures of complexes 48a and 48b.

N-2-(4-methylbenzothiazole)toluenesulfonamide, py = pyridine, en = ethylenediamine), were described.197 48a exhibited a square-planar geometry, and 48b displayed a distorted octahedral array. HL48 showed different coordination modes: through the benzothiazole N in 48a and through the sulfonamide N in 48b. The ability of the complexes to cleave CT-DNA was studied in vitro through ascorbate activation and tested by monitoring expression of the yEGFP gene containing the RAD54 reporter. Both 48a and 48b were found to cleave DNA in vitro, and 48b was found to be more effective in inhibiting Caco-2 and Jurkat T cell growth.197 2.4.4. Triazoles, Tetrazoles, and Oxazoles. There are several copper(II) compounds involving a 1,2,4-triazole moiety that show a wide range of biological and pharmacological activities.198,199 The Cu(II) complex [Cu(L49)Cl2], 49 (Figure 40a), emerged from a number of triazole−metal-based compounds screened for their cytotoxicity in human cancer cells.199−201 It was found that 49, by inhibiting caspase-3, impaired execution of the apoptotic program, thus addressing the cells to alternative death pathways, such as paraptosis.202 Gene expression profiling of the human fibrosarcoma HT1080

Figure 40. Structures of (a) complex 49, (b) the cationic portion of complexes 50a-b, and (c) complex 51. 829

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Figure 41. Structures of Paullone-type complexes: (a) 52a−b, (b) 53a−b, (c) 53c, and (d) 54a−h.

Figure 42. Structures of (a) monomer of 3∞[Ph3SnCu(CN)2.(L55b)2], 55b, (b) heterobimetallic Cu−Sn2 complex with 1,10-phenanthroline and bridging ethylendiamine, 56, and (c) ionic bis(N-2-aminoethylaziridine)copper chloride complexes, 57a−b.

cells (IC50 = 2.1 and 2.3 μM, respectively), inducing apoptosis via activation of caspase-3. Another heterobimetallic CuII−Sn2IV complex (56) comprising 1,10-phenatroline and ethylenendiamine (Figure 42b) proved to be a catalytic inhibitor of human Topo I (IC50 of 20 μM). Valuable information about its binding mode in the active site of DNA-Topo I has been obtained by molecular docking studies. In addition, it showed a noticeable cytotoxic activity against a panel of nine human cancer cells (GI50 < 10 μg/mL).210 Although azirine is classified as a mutagenic substance, several aziridine derivatives, i.e., mitomucins and acynomycins, have demonstrated chemioterapic properties due to their poor stability toward ring opening, which in turn enables alkylation and cross-linking to form DNA interstrands. Ring opening can be mediated by transition metals, giving rise to bis- or trischelate N,N′-aminoethylaziridine Cu(II) complexes 57a and 57b (Figure 42c). Both compounds showed antiproliferative activity against HL-60, NALM-6, and WM-115 cells, but only 57b was more active than cisplatin and carboplatin reference drugs.211 Also, the Cu(II) complex, including N,N-bis(2-chloroethyl)aminobenzoyl picolynoyl hydrazide (BABPH) containing a double hydrazide, was tested against murine L1210, K562, and BEL-7402 cell lines.212

ring in Paullones by a pyridine ring resulted in a 6−9-fold increase of cytotoxicity in SW480 cells. The presence of an electron-releasing group (methyl) or electron-withdrawing substituents (Cl, Br) compared to H in position 8 of the indoloquinoline backbone (X group in Figure 41d) did not affect the cytotoxicity of the corresponding complexes, whereas copper(II) compounds 54e−h with Schiff bases obtained from 2-acetylpyridine and indoloquinoline hydrazines were 10−50 times more cytotoxic than those with ligands prepared from 2formylpyridine (complexes 54a−d) and indoloquinoline hydrazines.208 2.4.6. Other N-Donor Systems. One of the few papers including in vivo studies described copper cyanide polymers containing Me3Sn cation and ethylnicotinate (L55a) as well as Ph3Sn cation and 3-methylpyridine (L55b), namely, the supramolecular coordination polymers 3 ∞[Me 3 SnCu(CN)2(L55a)2], 55a, and 3∞[Ph3SnCu(CN)2(L55b)2], 55b. Copper atoms were tetrahedricallly coordinated to two CN groups and two L55n ligands, and tin atoms were bonded to the three methyl or phenyl groups and to the N atom of cyano groups. Figure 42a illustrates the monomer of complex 55b.209 Two-dimensional layers were created via H bonds between parallel chains containing [−CN(R3Sn)NC−] spacers connecting the copper sites. Such infinite layers were connected by interlayer H bonds, forming 3D frameworks. Both compounds exhibited high antiproliferative activity in vitro against ZR-75-1 830

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2.5. Schiff Base Systems

suggesting that this approach might yield potent curcumin analogs.216 Since the metabolic stability of the C−F bond is much higher than that of the C−H or C−OH bond, also the fluoro analogs of the Knoevenagel condensates of curcumin and their square-planar copper complexes were examined217,218 and evaluated for their proteasome inhibitory activity against purified rabbit 20S proteasome. Following a previous work on the synthesis of the mononuclear copper compound [(MeCONHCH2CH2N CHPy)(CuCl2)],219 Zhao et al. reported the synthesis, characterization, and cytotoxicity of a metallodendrimer Cu(II) complex. 2 2 0 Surface-modified first-generation poly(amidoamine) dendritic Schiff base (L62) was coordinated with copper chloride, yielding the [(L62)[CuCl2]7] metallodendrimer, 62 (Figure 45). Compound 62 showed increased cytotoxic activities compared to the mononuclear analog against MOLT-4 and MCF-7 cell lines (IC50 about 10 μM).219,220

2.5.1. κ N,N′ Systems. The copper(II) complexes [Cu(HL58)2](ClO4)2, 58a (Figure 43a), [Cu(L58)H2O]ClO4, 58b 2

Figure 43. Structures of imine−copper(II) complexes 58−60.

(Figure 43b), [Cu(L59)H2O](ClO4)2, 59 (Figure 43c), and [Cu(L60)](ClO4)2, 60 (Figure 43d), displayed high efficiency for DNA cleavage, comparable to other examples in the literature.213 Overall, data indicated that [Cu(HL58) 2]2+ behaved as a delocalized lipophilic cation and induced mitochondrial sited ROS production. This event resulted in mitochondrial dysfunction and ATP decrease, which in turn triggered adenosine monophosphate-activated protein kinase (AMPK)-dependent apoptosis.214 Square-planar copper(II) complexes of the type [M(L61a−d)(bdt)] (L61a−d = Schiff base derived from condensation of 3-(3phenylallylidene)pentane-2,4-dione and para-substituted aniline; X = −NO2 (L61a), −H (L61b), −OH (L61c), and −OCH3 (L61d); bdt = benzene-1,2-dithiol) have been synthesized and structurally characterized (Figure 44).215 Mechanistic inves-

Figure 45. Structure of the metallodendrimer complex 62.

2.5.2. κ2N,O Systems. A number of Cu(II) complexes including coumarin derivatives have shown considerable anticancer activity against a number of tumor cells.221 Condensation of 7-amino-4-methyl-coumarin with substituted salicylaldehydes yielded a series of Schiff bases, and subsequent reaction of these ligands with copper(II) acetate yielded Cu(II) complexes,222 eliciting negligible cytotoxicity against HT29 and MCF-7cells. Thiocarbohydrazone was used as the diamine with 3acetylcoumarin to construct a potentially tetradentate ONNO donor ligand having a toxophoric CS functional group away from the coordination sites available for biological interaction. The tautomerism of these ligands and the well-known tendency of oxygen and sulfur donors to act as bridging ligands allowed various structural possibilities for the corresponding metal complexes. In [Cu(L63)(X)2(H2O)2] (X = Cl, NO3, or 1/ 2SO4), 63a−c (Figure 46a), and [Cu(L63)(Ac)2], 63d (Figure 46b), the Schiff base ligand acted as N,O- or N,N-bidentate through the azomethine nitrogen, lactone carbonyl oxygen, and respective anion counterparts223 exhibiting distorted octahedral structures. In the in vivo EAC model all compounds significantly prolonged the lifespan as compared to cisplatin.223 Condensation of substituted aromatic aldehydes with 7amino-4-methyl-quinolin-2(1H)-one has led to isolation of quinolin-2(1H)-one-derived Schiff bases (HL64a−o). The copper(II) complexes [Cu(L64a−o)2], 64a−o, were prepared and fully characterized (Figure 47).224 Selected ligands (HL64a−g) and related complexes 64a−g were screened for

Figure 44. Structures of copper(II) complexes derived from Knoevenagel condensate Schiff base ligands (L61a−d) and benzene1,2-dithiolate (bdt).

tigations showed a DNA major groove binding and chemical nuclease activity in the presence of hydrogen peroxide involving formation of hydroxyl radical as ROS. In vitro cytotoxic activities suggested that all complexes produced a potent cytotoxic effect against EAC cells (IC50 values in the low micromolar range).215 In an attempt to slow down the rapid metabolism of curcumin, its Knoevenagel condensates and their copper complexes were prepared. The complexes inhibited TNF-αinduced NF-kB activation and proliferation of KBM-5 cells, 831

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Figure 48. Structures of (a) complex 65 and (b) complex 66.

Figure 46. Structures of thiocarbohydrazone-substituted complexes (a) 63a−c and (b) 63d.

Binuclear mixed-ligand copper complexes have been obtained by coordination of the bridging reduced Schiff base ligand N,N′-(p-xylylene)dialanine acid (H2PDIMAIa) and a N,N-donor heterocyclic base (phen, dpq, dppz). X-ray structure of the binuclear complex [Cu2(phen)2(PDIMAIa)(H2O)2](ClO4)2 showed each of the Cu(II) ions in a distorted squarepyramidal geometry with a N3O2 donor set. The complexes showed DNA-binding affinity and active scavenging effect on OH radicals and exhibited increased cytotoxic activity with respect to the free ligands or copper(II) salts against HepG2, HL60, and PC3 tumor cell lines (IC50 in the range 1.4−2.7 μM).228 2.5.3. κ2S,N Systems. Mononegative bidentate S,N-Schiff bases derived from S-benzyl- and S-methyl dithiocarbazate (HL67a−b) have been used for the synthesis of square-planar copper(II) complexes 67a−b (Figure 49). In particular, the

their in vitro anticancer potential against HepG2 cell line. Most of the complexes were found to be more active (IC50 in the range 17−129 μM) than the corresponding free ligands, with 64d being the most active of the series with activity (IC50 = 17.9 μM) comparable to that of cisplatin.224 The bis-substituted complex [Cu(L65)2], 65, comprising the Schiff base derived from 5-bromosalicylaldehyde and 2aminomethylthiophene, namely, 4-bromo-2-((thiophen-2ylmethylimino)methyl)phenol (HL65) (Figure 48a), showed a marked antiproliferative activity against HCT-116 and Hep-2 cells. Moreover, 65 showed activity in the submicromolar range against larynx cancer cells triggering apoptosis.225 The coordination of the pyrazolone derivative N-(1-phenyl3-methyl-4-propyl-pyrazolone-5)-salicylidene hydrazone (H 2 L 66 ) toward copper(II) gave a dinuclear complex [Cu2(L66)2CH3OH]·2CH3OH, 66,226 in which the two Cu centers displayed two different coordination environments (square planar and square pyramidal) (Figure 48b). 66 Showed an efficacy about 7-fold higher than that of the free ligand against OVCAR-3, HepG2 cells (IC50 5.0 μg/mL).226 Looking for natural derivatives with intrinsic biological activity, Vyas et al. used retinoids (able to bind nuclear retinoic acid receptors (RARs) and exert anticancer properties) for synthesis of new copper complexes. 227 trans-2-Octenal hydrazones (2-octhyH) gave 1:1 complexes of general formula [Cu(2-octhy)(H2O)Cl], which were tested against several human cell lines (breast cancer MCF-7, BT-20, MDA-MB231 cell lines and PC3 prostate cancer cell line) with different expression of RAR subunits. Copper compounds were particularly effective in inhibiting growth of cell lines which express RAR α, confirming the hypothesis that copper conjugation enhanced the biological activity of active ligands.

Figure 49. Structures of complexes 67a−b.

complex 67b exhibited marked and selective activity against MCF-7 cells (IC50 = 0.45 μM) but was inactive against MDAMB-231 cells.229 The same cell specificity was observed for uncoordinated Schiff bases benzyl N-[1-(thiophen-2-yl)ethylidene] hydrazine carbodithioate and benzyl N-[1-(thio-

Figure 47. General structure of Schiff base ligands and their copper(II) complexes 64a−o. 832

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and concomitant deprotonation to give the anionic ligand 4methyl-2-N-(2-pyridylmethylene)aminophenolate. The squareplanar copper complex [Cu(L69b)Cl], 69b (Figure 51b), showed high antiproliferative, time-dependent activity in human A2780 cisplatin-sensitive and A2780-resistant cells and murine L1210(0) cisplatin-sensitive and L1210(2) cisplatinresistant cells. In all cases the IC50 values were similar to those of cisplatin in cisplatin-sensitive sublines (IC50 = 3.4 μM) and lower in cisplatin-resistant cells (IC50 = 8.3 μM), attesting the 69b ability to overcome cisplatin resistance.236 The copper(II) complex [Cu(L70)(OAc)(H2O)]·2H2O, 70 (Figure 52) (HL70 = N-2-pyridiylmethylidene-2-hydroxy-5-

phen-3-yl)ethylidene] hydrazine carbodithioate and the corresponding bis-substituted copper complexes.230 2.5.4. κ 3N,N′,N″ Systems. A series of copper(II) complexes containing Schiff base ligands derived from the tridentate ligand 2-((2-phenyl-2-(pyridin-2-l)hydrazono)methyl)pyridine (L68) has been checked for their anticancer activities.231,232 The copper(II) complexes [Cu(L68)(X)](ClO4) (X = N3, SCN, OAc, OBz, CN, H2O, ClO4), [Cu(L68)(X)](ClO4)2 (X = Im, 2,2′-bipy, L68, H2O), [Cu(L68)(N3)(ClO4)]2, [Cu(L68)(SCN)(ClO4)]2, and [Cu(L68)(Cl)2], 68 (Figure 50), have been reported.231,232 These series

Figure 50. Structure of complex 68. Figure 52. Structure of complex 70.

of compounds showed varying degrees of antiproliferative effects which were consistent with those of similar copper complexes already published.233 All complexes exhibited enhanced cytotoxicity in MCF-7, PC-3, and HEK 293 cells compared to CuCl2 and free L68, being 4−18 times more potent than cisplatin.231 Moreover, all complexes showed excellent nuclease activity in the presence of H2O2 and 2mercaptoethanol. The most promising compound 68 (Figure 50) showed IC50 values around 5 μM in PC3, HEK 293, and MCF-7 cells. On rat breast tumor models, 68 was found to inhibit tumor growth, triggering apoptosis through upregulation of the caspase pathway and inhibition of the Akt, matrix metalloproteinase 9, and α-methyl acyl CoA racemase. Further, 68 did not show any prominent systemic toxicity.231,232 2.5.5. κ3N,N′,O Systems. 2.5.5.1. Pyridine-Based Ligands. Square-planar Cu(II) complexes chelated by a N,N′,Otridentate Schiff base containing phenolic and pyridyl rings as coordinating groups have a recognized ability to cleave DNA in a catalytic way and without requiring the presence of a reductant cofactor.234 Also, the uncoordinated ligand 4-methyl-2-N-(2pyridylmethyl)aminophenol (Hpyramol) (HL69a) (Figure 51a) was reported to cleave DNA oxidatively and catalytically without any added reductant and to exhibit high to moderate antitumor activity against selected cancer cell lines.235 The dehydrogenated ligand form (Hpyrimol) (HL69b) (Figure 51a) appears to be formed by direct HL69a oxidation. Upon metalion coordination HL69a undergoes oxidative dehydrogenation

chlorophenylamine), adopted a square-pyramidal coordination with an apical water, three of the basal positions being occupied by the N,N′,O tridentate ligand and the fourth by an acetate oxygen.237 The apparent DNA binding constant of 6.40 × 105 M−1 suggested moderate intercalative binding mode. Moreover, its efficient oxidative cleavage of supercoiled DNA was due to ROS production. 70 inhibited the growth of HeLa cells in a dose-dependent manner (IC50 = 16.1 μM), whereas the free Schiff base ligand displayed no cytotoxicity. 70 induced a Sphase cell cycle arrest and triggered the intrinsic mitochondrial apoptotic pathway owing to activation of caspase-9 and caspase3.237 2.5.5.2. Pyrazole-Based Ligands. Tridentate pyrazolecontaining Schiff bases HL71a−c (Figure 53a)238,239 were used

Figure 53. Structures of (a) the tridentate pyrazole-containing ligands HL71 and (b) complex 71c.

to prepare a series of “3 + 1”-type Cu(II) complexes behaving as monomeric species in aqueous solution.240 The X-ray structural study showed instead that the complex with HL71b crystallized as a dinuclear compound, [Cu2(μ-Cl)2(L71b)2], while the solid-state structure determined for [Cu(L71c)Cl], 71c (Figure 53b), was best described by monomeric units. The in vitro evaluation of [Cu(L71)Cl]-type complexes revealed moderate cytotoxic activity against a panel of human cancer cell lines. In general, introduction of halogens (chloride or iodide) in the phenolic ring of the ligands enhanced the cytotoxicity of the complexes, mimicking the behavior already observed in related tridentate N,N,O ligands containing phenolic and pyridyl rings, which were used to prepare Ga(III) and Cu(II)

Figure 51. Structures of (a) hydrogenated and dehydrogenated forms of HL69 and (b) complex 69b. 833

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complexes acting as proteasome inhibitors.241−243 HL71a−c and related copper(II) complexes have shown similar cytotoxicity activity against cisplatin-sensitive A2780 and cisplatin-resistant A2780R cell lines, indicating no cross-resistance phenomena due to the involvement of different mechanisms and/or targets in the cell killing.240 2.5.6. Hydrazones. The Cu(II) hydrazone complex [Cu(L72)2], 72 (Figure 54), containing the N′-(phenyl-

and promoted apoptosis in H322 cells through elevating the protein level of integrin β4.249 Some 2-oxo-quinoline-3-carbaldehyde Schiff bases (HL74a−c) and their Cu(II) complexes 74a−c (Figure 56) were found to

Figure 54. Structure of complex 72.

(pyridine-2-yl)methylidene)benzohydrazide ligand (HL72)244 exhibited a distorted octahedral geometry with a 1:2 metal:ligand stoichiometry. 72 interacted with CT-DNA with a binding constant of 2.468 × 105 M−1 and caused almost complete conversion of pUC19 DNA from supercoiled to the nicked circular form. HeLa cells were poorly affected by the complex (IC50 = 173 μM), whereas no damage was observed in NIH 3T3 normal cells.244 Following previous studies on the nuclease activity of [Cu(Phimp)X] complexes, 245 a new compound [Cu(tBuPhimp)Cl] (tBuPhimpH = (E)-2,4-di-tert-butyl-6-[[phenyl(pyridine-2-yl)hydrazono]methyl]phenol) was reported. Differently from unsubstituted Phimp derivatives, this complex was able to cleave efficiently DNA in the absence of an external agent, probably due to a self-activating mechanism generating singlet oxygen or singlet oxygen-like species. Its DNA cleavage activity matched well with the antiproliferative activity against MCF-7 cells (IC50 4.7 vs 17.9 μM cisplatin).246 2.5.7. κ3N,O,O′ Systems. 2.5.7.1. Hydrazone Systems. A number of salicylaldehyde pyrazole hydrazone (H2L73a−i) derivatives (Figure 55) and related copper complexes were

Figure 56. Structures of complexes 74a−c.

interact with CT-DNA through intercalation.250 The cytotoxic activity studies indicated that [Cu(L74a)(H2O)(EtOH)]NO3, 74a, [Cu(HL74b)(NO3)(MeOH)]NO3, 74b, and [Cu(L74c)(H2O)(EtOH)]NO3, 74c, exhibited higher effectiveness compared to the corresponding ligands attributable to the extended planar structure induced by the p−π* conjugation resulting from metal chelation. In HeLa cells, all copper complexes were not significantly cytotoxic, whereas 74c distinguished itself as the most promising derivative against HL-60 cells (IC50 = 8 μM).250 The 4-methyl-N′-((2-oxo-1,2-dihydroquinolin-3-yl)methylene)benzohydrazide (HL75) and its two copper(II) complexes [Cu(HL75)Cl2]·2H2O, 75a, and [Cu(L75)NO3]· DMF, 75b (Figure 57), revealed a different structure of the two

Figure 57. Structures of complexes 75a−b. Figure 55. Structure of salicylaldehyde pyrazole hydrazone ligands (H2L73a−i).

species (square pyramidal and square planar, respectively).251 The change of counterion (Cl− to NO3−) in the copper(II) salt precursors also altered the coordination mode of hydrazone. The structural planarity of the nitrato complex played an important role in determining both a superior DNA binding property and enhanced cytotoxic potency in HeLa cells (IC50 = 19.3 μM). Antioxidative activity tests showed that HL75 and its copper(II) complexes had significant radical scavenging activity against free radicals.251

found able of inhibiting the growth of A549 lung carcinoma cells.247,248 These copper complexes turned out to be stronger growth inhibitors against A549 cells than their corresponding H2L73a‑1 ligands via apoptosis induction. Among them, the CuL73e complex exhibited an advantage in selectivity and efficacy 834

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2.5.7.2. Semicarbazone Systems. Copper(II) complexes containing semicarbazone ligands have displayed a wide spectrum of biological properties.252−254 The in vitro cytotoxic studies of a series of salicylaldehyde N,N-disubstituted semicarbazone derivatives (HL76a−e) and their corresponding Cu(II) complexes 76a−e (Figure 58) were assayed against four

2.5.7.3. Other N,O,O′ Systems. The taurine Schiff base copper complex [Cu(L78)(phen)H2O], 78 (Figure 60a) (H2L78

Figure 58. Structures of complexes 76a−e.

human cancer cell lines (MOLT-4, MCF-7, A-549, and SK-II) as well as on benign fibroblasts.252 Copper(II) complexes demonstrated higher in vitro activities (in the micromolar range) compared to those shown by the uncoordinated ligands and the reference cisplatin drug. By means of proteomic investigation, 10 and 11 out of the 33 identified proteins were found to display apparent modified expression in 76a- and 76ctreated MOLT-4 cells, respectively. By downregulating TBP, PABP 1, Hsp 96, metabolic proteins, RhoGDI, and Stathmin/ Op18, these complexes induced apoptotic cell death in MOLT4 cells as a consequence of deregulating transcription, translation, protein folding, glucose metabolism, signal transduction, and mitosis. The ligand 2-oxo-1,2-dihydroquinoline-3-carbaldehyde semicarbazone (HL77a), its N(4)-phenyl derivative (HL77b), and their three copper(II) complexes 77a−c (Figure 59),

Figure 60. Structures of complexes 78 and 79.

= 2-(2-hydroxybenzylideneamino)ethanesulfonic acid), inhibited the cellular proteasomal chymotrypsin-like activity and induced apoptosis in dose- and time-dependent manners in human breast cancer and leukemia cells.256 Consistently, in Jurkat T cells a dose-dependent increase in levels of ubiquitinated proteins and proteasome target proteins p27 and Bax was observed. At 2.5, 5, and 10 μM 77 induced ∼10%, 50%, and 81% cell death, respectively, and at 5 and 10 μM induced significant production of PARP p85 cleavage fragment. Analogously, the L-glutamine-o-vanillin copper complex 79 (Figure 60b) displayed proteasome-inhibitory and apoptosisinducing activities in Jurkat T and MDA-MB-231 cells but not in normal MCF-10A cells.257 2.5.8. κ3N,O,S Systems. Compounds having the ability to photocleave duplex DNA in red light, especially in an oxygenindependent pathway, are of importance as potent agents in photodynamic therapy (PDT) of cancer.258−261 Copper(II) complexes [Cu(L80)(N-N)], 80a−c (Figure 61), of a Schiff base thiolate salicylidene-2-aminothiophenol (H2L80) and diimine bases N-N (N-N = 1,10-phen; dipyrido[3,2-d:2′,3′f]quinoxaline, dpq; and dipyrido[3,2-a:2′,3′-c]phenazine, dppz) showed anaerobic DNA cleavage activity in red light under argon via a type-I pathway, while DNA photocleavage in air proceeded via a hydroxyl radical pathway.262 Molecular docking calculations suggested DNA groove and/or partial intercalative binding of the complexes. Moreover, DFT calculations revealed a thyil radical pathway for the anaerobic DNA photocleavage and suggested the possibility of generation of a transient copper(I) species due to bond breakage between the copper and the sulfur to generate the thyil radical. Compound 80c exhibited significant photocytotoxicity in HeLa cells (IC50 = 8.3 μM) in visible light while showing lower toxicity in the dark (IC50 = 17.2 μM).262 2.5.9. κ4N,N′,N″,O Systems. In Cu(II) complexes 81a−f and 82−84 of Schiff bases obtained by condensation of 2-[N(α-picolyl)-amino]benzophenone with different amino acids (Figure 62) the ligands were coordinated to the metal center in

Figure 59. Structures of complexes 77a−c.

structurally similar to the above-discussed compounds, were prepared and investigated for their biological properties.255 N(4)-Phenyl substitution in the semicarbazone moiety and the change of the counterion (Cl− to NO3−) in Cu(II) precursors affected the structure and nature of the complexes as well as the resulting pharmacological properties. The charged, squarepyramidal complex 77c was found to be the strongest CT-DNA intercalative binder of the series and the most effective in BSA binding due to hydrophobic and electrostatic interactions. Moreover, all three complexes showed cytotoxic activity against HeLa, Hep-2, HepG2, and A431 (IC50 = 3.26 μM for 77c) cancer cells without affecting normal, murine NIH 3T3 fibroblasts.255 835

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Figure 61. Structures of complexes 80a−c and diimine coligands (N-N).

Figure 62. Structures of complexes 81−84 of Schiff bases obtained by condensation of 2-[N-(α-picolyl)-amino]benzophenone with different chiral amino acids.

a ON3-tetradentate manner.263 Cytotoxicity assays indicated that the substituents of the aromatic rings strongly influenced the biological activity. The bromide-containing complex 84 showed the highest cytotoxicity in the series against A-549, HCT-8, and BEL-7402 cells. Moreover, all complexes were more cytotoxic than 5-fluorouracil reference drug and circumvented drug-resistance mechanisms.263

nuclease activity not correlated with the in vitro antiproliferative effects against MCF7, A549, and HCT-116 cells.264 The ligand N,N-bis(benzimidazol-2-ylmethyl)amine (HL87) and various diimine (N-N = bipy, phen, 5,6-dmp, and dpq) have been used to synthesize four mixed-ligand [Cu(HL87)(NN)](ClO4)2 complexes. Diffractometric and theoretical studies showed that HL87 could be mer or fac coordinated to the metal in the solid state depending on the diimine ligand, but in solution it always adopted a fac coordination. The presence of N-N ligands conferred a noticeable DNA binding affinity which was modulated not only by the nature of the imine itself but also by the hydrophobic interaction of the benzimidazole moiety with the DNA surface. In particular, 87 (Figure 64a), which strongly bound DNA and efficacely cleaved doublestrand DNA, diplayed the best antiproliferative activity against SiHa cells (IC50 0.9 μM).265 Looking for copper complexes exerting nuclease activity, the neutral ligand bis(2-pyridylmethyl)amine (L88a) was used to prepare a series of copper compounds which revealed SOD biomimetic activity and catalytic efficiency of O2− scavenging. The square-pyramidal complex [Cu(L88a)(Cl)2], 88a, exhibited significant hydrolytic cleavage of genomic DNA and a good anticancer activity against Caco-2 cells.266 Using chelating ligands obtained via amine functionalization of the L88a framework it was possible to obtain either mononuclear Cu, 88b, or heteronuclear Cu−Pt complexes, 88c (Figure 64b).267 DNA binding ability and DNA cleavage activity was enhanced using Cu−Pt complexes, due to the preferential affinity of Pt(II) for DNA. Functionalized bis-dipicolylamine derivatives (L89n) were used for preparing copper complexes as proteomimetics of the Src homology 2 domain (SH2). Due to a probable action based upon mimicry of the SH2 domain, the compounds were able to disrupt Stat3−Stat3 protein−protein interactions; moreover, complex 89c (Figure 65) elicited antiproliferative activity

2.6. Polydentate and/or Macrocyclic Systems

2.6.1. Tridentate Ligands. Copper complexes comprising the tridentate N,N,N-ligands N-((1H-imidazole-2-yl)methyl)2-(pyridine-2-yl)ethanamine (HL85a), N-((1-methyl-1H-imidazole-2-yl)methyl)-2-(pyridine-2-yl)ethanamine (HL85b), and 2(pyridine-2-yl)-N-((pyridine-2-yl)methyl)ethanamine (HL86) (Figure 63) adopted a distorted octahedral geometry giving, as an example, the species [Cu(HL85a)(CH3CN)(ClO4)2], 85a (Figure 63c). Several experiments on the interaction of these complexes with DNA (studies on DNA binding and on CTDNA conformational changes and cleavage) revealed a strong

Figure 63. Structures of (a) ligands HL85a−b, (b) ligand HL86, and (c) complex 85a. 836

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Figure 64. Structures of (a) complex 87 and (b) complexes 88a−c.

series of binuclear complexes in which each copper generally adopted a square-pyramidal geometry with 4,5-diazafluorene-9one or acetato groups completing the coordination sphere, as in [Cu2(L90)(OAc)2(ClO4)2].270 The compounds showed oxidative DNA activities and cytotoxicity against HeLa cells via an apoptotic cell death mechanism. Mono-, di- and trinuclear copper complexes, 91a−c, comprising a terpyridine ligand functionalized with piperidine and bis(2-pyridylmethyl)amine (L91a−c) (Figure 67) were designed as DNA nucleases and cytotoxic agents.271,272 DNA cleavage potency depended on the number of copper centers (tricopper > dicopper > monocopper), 91c being able to exert its activity without the presence of external coreductant. This derivative showed a high cytotoxicity against a wide panel of

against DU145, OCI-AML2, and MDA-468 cells (average IC50 9.3 μM).268

Figure 65. Proposed structure of complexes 89a−c.

Bis-tridentate tetrakis(2-pyridyl-methyl)benzene-1,4-diamine (L90) has been employed for synthesis of mononuclear, dinuclear, and mixed-ligand copper complexes to be initially tested as artificial nucleases.269 Copper adopted different distorted arrangements, e.g., square pyramidal in [Cu2(L90)(H2O)4][ClO4]4, 90a (Figure 66a), or octahedral in [Cu2(L90)(2,2′-bipy)2(ClO4)2](ClO4)2, 90b (Figure 66b). 90a displayed the highest cleavage efficiency, likely due to the presence of labile water molecules and unsaturated metal coordination sites. L90 was then utilized for synthesis of another

Figure 67. Mono-, bi-, and trinuclear copper(II) complexes containing terpyridine-functionalized with piperidine, 91a, and bis(2pyridylmethyl)amine 91b−c.

Figure 66. Structure of complexes 90a and 90b. 837

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cell lines (tumoral U2OS, SH-SY5Y, cisplatin-resistant MOLT4, and normal HEK 293T and GM05757) without tumor selectivity. Cellular uptake studies assessed the presence of the complex both in the cytoplasm and in the nucleus, whereas immunoblotting analysis and DNA-flow cytometric studies demonstrated its ability to induce cellular DNA damage, confirming the link between in vitro DNA cleavage ability and cellular toxicity. Coordination of the dipeptide glycylglycine (H2L92) and piperazine (ppz) with copper(II) gave the water-soluble dinuclear complex [Cu2(L92)2(ppz)(H2O)4], 92 (Figure 68),273 able to oxidatively cleave DNA, bind to the DNA

Figure 69. Proposed structures of (a) complexes 93a−b, (b) complex 94, and (c) complexes 95a−b.

Figure 68. Structure of complex 92.

U87 cancer cell lines showed that all complexes were potent cytotoxic agents with IC50 values ranging from 3 to 90 μg/mL. The presence of free functional groups likely contributed to the anticancer activity of the copper derivatives via interaction with the cell membrane.277 N-Substitution of di(picolyl)amines led to tetradentate ligands, bis(2-pyridylmethyl)amino-2-propionate (HL96a) and ethylbis(2-pyridylmethyl)amino-2-propionate (HL96b), which in turn gave trigonal bipyramidal [Cu(L96a)(H2O)]ClO4 and [Cu(L96a)Cl], 96a, complexes (Figure 70a) and square-

minor groove, inhibit Topo 1 activity at very low concentration (12.5 μM), and be a SOD mimic (IC50 0.086 μM). Moreover, 92 determined a selective growth inhibition against A498, A549, and Mia PaCa-2 cells.274 2.6.2. Tetradentate and Macrocyclic Ligands. Macrocycles have been extensively studied and used in biomedicine for synthesis of both diagnostic and therapeutic agents due to (i) the possibility of incorporating different donor atoms, (ii) the versatility of lateral chains which allow further coordination, conjugation, and hydrophilicity modulation, and (iii) similarity with sites of proteins and enzymes. A 22-membered, neutral N6O4-macrocycle, 1,4,8,12,15,19hexaazacyclo-docosane-2,3,13,14-tetraone (L93), gave a series of copper(II) compounds. The cytotoxicity for L93 and its complexes [Cu(L93)Cl]Cl·2.5H2O, 93a, and [Cu(L93)NO3]NO3·3.5H2O, 93b, against three tumor cell lines showed that coordination improved the antitumor activity of the ligand (IC50 for breast cancer cells were ∼8.5, 3, and 4 μg/mL for L93, 93a, and 93b, respectively (Figure 69a).275 Coordination of an oxadiazole macrocyclic ligand (L94 = 9,12,15,18,27,28-hexaaza-29-oxatetracyclo[24.2.1.02,7.020,25]enneicosa-2,4,6,20,22,24,26,281-octaene) to copper(II) and zinc(II) produced cationic complexes able to interact with CT-DNA. Copper derivative [Cu(L94)(ClO4)]ClO4·H2O, 94 (Figure 69b) displayed a DNA intrinsic binding constant higher with respect to the zinc complex, but it was less active in reducing cancer cell survival, suggesting that DNA binding was not the only mechanism which has to be taken into account to explain cytotoxic activity. Biological studies showed that when the compounds were delivered through the cell membrane by a lipidic carrier the cell survival was sensibly reduced, up to 58% with 94.276 Potentially hexadentate amide-based macrocyclic ligands 4(2-pyridylmethyl)-1,7-dimethyl-1,4,7-triazonane-2,6-dione (L95a) and 4-(2-pyridylethyl)-1,7-dimethyl-1,4,7-triazonane-2,6dione with an appended pyridine ring (L95b) gave mononuclear copper complexes through only a N2O coordination (terminal Namine, appended Npyridine, Oamide) as illustrated by the X-ray structure of [Cu(L95b)(CH3CN)2](ClO4)2, 95b (Figure 69c). Copper complexes were found to be less cytotoxic than gentamycin on normal HEK cells. Cytotoxicity studies on the

Figure 70. Structures of (a) complex 96a and (b) complexes 97a and 97b.

pyramidal [Cu(HL96b)Cl2]. HL96a derivatives efficiently interacted with CT-DNA and elicited promising anticancer activity against MCF-7, Eca-109, A549, and HeLa cells.278 Tetranuclear copper complexes containing different bridging ligands N-benzoato-N′-(2-aminoethyl)oxamide (H3L97a) or Nbenzoato-N′-(1,2-propanediamine)oxamide (H3L97b) and bipy with formulas [Cu4 (L 97a ) 2 Cl 2(bipy) 2 )]·4H 2 O, 97a, and [Cu4(L97b)2Cl2(bipy)2]·2H2O, 97b (Figure 70b), showed cytotoxic effects against SMMC-7721 and A549 cells which well correlated with their DNA-binding abilities. 97a was always found to be more active than 97b, suggesting a determining 838

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Figure 71. Structures of (a) dinuclear complex 100 and (b) 101.

electron-rich d10 metal ion. Although Cu(I) is the chemical form generally accepted by the bioinorganic community to describe the active internalization of physiological copper in mammalian cells through copper transporter (CTR) proteins, still very few studies report on the action of Cu(I) complexes as antitumor agents. This is likely related to the intrinsic difficulty to stabilize copper(I) species, especially in aqueous media. Only formation of quite robust metal−ligand interactions, such as those displayed in the case of copper−phosphine (and copper− NHC) species, prevent hydrolysis and activation of the redox machinery. Two different coordination spheres have been particularly investigated in the field of copper−phosphine compounds, with the corresponding tetrahedral complexes showing both easy synthesis and appealing biological properties: the homoleptic, monocationic [Cu(P)4]+ arrangement and the mixed-ligand, neutral [Cu(N-N)(P)(X)] assembly, where P represents a monodentate phosphine, N-N an aromatic diimine, and X a halide. The work by Berners−Price on 1:2 hydrophilic adducts of copper(I) halides with 1,2-bis(di-2-pyridylphosphino)ethane (P-P)287 joined the extensive studies performed in the 1980s288,289 on group 11 metals including lipophilic bisaryldiphosphines. Despite crystallization of the three copper complexes as dimeric structures, copper-“P-P” complexes also existed as bis-chelated, monomeric, and tetrahedral [Cu(PP)2]X complexes in solution. The lack of selectivity toward tumorigenic and nontumorigenic cells and the robustness toward dissociation of these copper adducts made them more promising candidates in the radiopharmaceutical field.290 The above conclusion was in agreement with experimental evidence illustrated by other authors on a similar bis-chelated PP complex including hydrophilic, alkyl bis[bis(hydroxymethyl)phosphine]ethane (bhpe).291 The negligible cytotoxic activity shown by [Cu(bhpe)2]+ was attributed to its robust inertness toward dissociation, whereas complexes of similar “CuP4” stoichiometry, but containing monodentate phosphines, exhibited moderate to high antiproliferative activity. In these species, the original [Cu(P)4]+ complexes underwent dissociation to coordinative unsaturated [Cu(P)3]+ and [Cu(P)2]+ adducts at micromolar concentration.291 The more favored was displacement of P from the [Cu(P)4]+ parent complex the more favored was in turn the ability of the metal ion to interact with a pharmacological target, thereby promoting the antiproliferative effect. Several [Cu(P)4]+-type complexes

role for the substituted aliphatic fragment in the ligand backbone.279 Other crystallographically determined tetranuclear compounds have been obtained using 2-{N′-[2-(dimethylamino)ethyl]oxamido}benzoate (H3L98) together with diimine phen or bipy and picrate as counteranion. Such complexes were able to interact with HS-DNA via intercalation and showed in vitro antitumor activity correlated to their DNA-binding ability.280 The same research group reported a one-dimensional copper(II) coordination polymer built using dissymmetrical N,N′-bissubstituted oxamide ligands. The compound {[Cu2(L99)(dabt)](pic)·H2O}n (H3L99 = N-(2-carboxylatophenyl)-N′-[3(dimethylamino)propyl]oxamidate; dabt = 2′2′-diamino-4′4′bithiazole; pic = picrate) has been structurally characterized showing cytotoxicity against SMMC-7221 and A549 cells (IC50 = 12.6 and 15.8 μg/mL, respectively).281 The protonation equilibria in aqueous solution of a dicopper(II) complex [Cu2(μ-OH)(L100)(H2O)2](ClO4)2, 100 (Figure 71a) (HL100 = 4-methyl-2,6-bis[(6-methyl-1,4diazepan-6-yl)iminomethyl]phenol), its interactions with DNA, its cytotoxic activity, and its uptake in tumoral cells have been studied.282,283 100 promoted hydrolytic cleavage of doublestrand plasmid DNA under anaerobic and aerobic conditions and inhibited growth of GLC4 and K562 cells (IC50 values of 14.8 and 34.2 μM, respectively) without affecting macrophage viability. There was a good correlation between cell growth inhibition and intracellular copper content. In particular, 100 entered cells approximately 2-fold higher than CuCl2. Starting from antipyrine284,285 N,N′-tetra(4-antipyrylmethyl)-1,2-diaminoethane (L101a) and (2,3-dimethyl-1-phenyl-3pyrazolin-5-one) the N,N′-bis(4-antipyrylmethyl)piperazine (L101b) were prepared, and the mixed-valent compound [CuII(L101a)][CuI(NCS)2Cl](DMF)2, 101 (Figure 71b), was synthesized and structurally characterized.286 In contrast to the ligand, the corresponding complex 101 decreased the viability of both cultured tumor (MCF-7, A549, 8MGBA, Hep G2) and nontumor (MDBK, Balb/c 3T3) cell lines in a time- and concentration-dependent manner.286 2.7. P-Donor Phosphine Systems

The distinctive characteristic of all of complexes described in this section is the oxidation state (1+) of the metal, which is mostly comprised in a four-coordinated tetrahedral environment. The copper coordination sphere is either partially or totally filled by phosphine ligands that efficiently bind the 839

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including hydrophilic phosphines such as tris(hydroxymethyl)phosphine (L102),292 tris(hydroxypropyl)phosphine (L103),293 and 1,3,5-triaza-7-phosphaadamantane (L104)294 were prepared. The most promising complex of the series, [Cu(L102)4]+, 102, (Figure 72a) was tested in vitro against a wide panel of human

Figure 73. Tetrahedral structure of the dimeric, neutral complex 107a.

phosphines, L108n. These compounds exhibited strong antitumor activity (in the 2−7 μM range) against MDAH-2774 and cisplatin-resistant SKOV3 cells.301 2.8. C-Donor N-Heterocyclic Carbene Systems

N-Heterocyclic carbenes (NHCs)302 are an interesting class of ligands with donor properties similar to phosphines. Their chemical versatility implies not only a wide variety of structural diversity and coordination modes but also a capability to form stable complexes with a large number of transition metals with different oxidation states.303−305An attractive feature of NHCs chemistry is the easiness with which a series of structurally similar complexes with varying lipophilicity can be synthesized simply by changing the substituents on the imidazolium salt precursor.306,307 As potential anticancer drugs, metal−NHCs constitute a recent and very rapidly growing field of research.308,309 The relatively high stability of copper(I)−NHCs would allow them to reach biological targets inside the cell, and subsequently, Cu(I)−NHC complexes could react with intracellular oxygen or hydrogen peroxide, producing ROS in situ, ultimately leading to cellular damages.310 The effect of carbene complexes [CuICl(L109a−b)], 109a−b, and [CuIX(L110a−c)], 110a−c, was evaluated on MCF-7 cells (Figure 74).311 All candidates, with

Figure 72. Structures of the cationic portion of (a) complex [Cu(L102)4][PF6], 102, and (b) complex [Cu(L105)2][BF4], 105.

tumor cell lines showing remarkable cytotoxic activity,292 roughly 1 order of magnitude higher than that shown by the cisplatin reference drug. In particular, on a panel of selected human colon carcinoma cell lines corresponding to different stages of disease progression (LoVo, DLD-1, SW480, HCT-15, and Caco-2 cells) 102 killed these tumor cells more efficiently than cisplatin and oxaliplatin, and it overcame platinum drug resistance.295 102 preferentially reduced cancer cell viability, whereas nontumor cells were poorly affected. Colon cancer cells died via a programmed cell death whose transduction pathways were characterized by the absence of hallmarks of apoptosis. Looking for coordinative unsaturated assemblies, the same authors described the linear, disubstituted [Cu(L105)2]+, 105 (Figure 72b) (L105 = tris(cyanoethyl)phosphine). Although appealing from the coordination point-of-view, the cytotoxic activity shown by 105 was moderate because of the peculiar intramolecular “umbrella-shaped” coordination of the two L105 ligands causing low availability of the metal to interact with biological substrates.296 Mononuclear and dinuclear copper(I) chloride complexes [CuCl(L106)3]·(CH3CN) and [Cu2(μ-Cl)2(L106)3] comprising triphenylphosphine (L106) have been tested against LMS and MCF-7 cells, showing remarkable cytotoxic activity (IC50 values in the 5−6 μM range).297 Two distorted tetrahedral complexes [Cu(Fchy)(L106)2] including ferrocene-containing bidentate hydrazone ligands (HFchy) were synthesized from the bivalent copper precursor [CuCl2(L106)2]. These compounds showed moderate in vitro cytotoxicity against HeLa and A431 tumor cells and little damage to NIH 3T3 nontumor cells.298,299 Several mixed-ligand copper(I) complexes of cyclodiphosphazanes (L107a−b = [tBuNP(NC4H8X)]2 (X = O, NMe) were prepared by reaction of the labile, octanuclear copper(I) complexes [Cu8(μ2-I)8(L107a−b)4] with various pyridyl ligands followed by addition of phen or bipy.300 Among the resulting tetrahedral, dinuclear complexes, [Cu2(phen)2I2(L107a)], 107a (Figure 73), showed potent cytotoxic activity against HeLa, MCF-7, and MDA-MB cells.300 Cancer cell treatment with 107a damaged DNA integrity, blocked cell cycle in the G1 phase, and induced apoptosis via a p53-dependent pathway. Adopting a similar [Cu(N-N)(P)(X)] arrangement, Starosta and co-workers prepared complexes replacing cyclodiphosphazanes with a series of hydrophilic tris(aminomethyl)-

Figure 74. Structures of (a) 1,3-disubstituted imidazolidine complexes [CuICl(L109a−b)], 109a−b, and (b) 1,3-disubstituted imidazole complexes [CuICl(L110a−c)], 110a−c.

the exception of the hindered complex, where R = adamantly (110c), exhibited cytotoxic activity in the submicromolar range with IC50values significantly lower than that of the reference cisplatin drug. The biological action of 109a caused cell cycle arrest in the G1 phase probably due to nuclease-like activity and O2-activating properties, which led to DNA strand breaks. This action followed a Fenton-type reaction path similarly to other copper complexes such as [CuI(phen)2]+ or [CuI(ClipPhen)]+.312−314 The mechanism of action of 109a was believed to imply the metal as a direct dioxygen activator in the presence of DNA as the reaction was inhibited by 1 O2 scavengers.308,311,315 840

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2.9. N-N Diimine (N-N) Systems

CS as a polymer surrounding the active copper complex to increase its bioavailability.327 The most recent synthetic study in Casiopeina-like compounds has been focused on the use of the phen building block to generate the N6-donor ligand 2,9-bis(2′,5′-diazahexanyl)-1,10 phenantroline (L113). The corresponding [Cu(L113)]2+ complex, 113 (Figure 76), was found to be cytotoxic against HeLa cells (IC50 = 1.84 μM).328

2.9.1. (N-N)/Amino Acids Systems. Ruiz-Azuara and coworkers investigated the antineoplastic properties of a class of mixed-chelate, cationic complexes named Casiopeinas having general formulas [Cu(N-N)(α-L-aminoacidato)]NO3 and [Cu(N-N)(O-O)]NO3, where N-N is an aromatic substituted diimine (phen or bipy and substituted analogs) and O-O is acetylacetonate (acac) or salicyaldehydate (salal).316−319 These compounds have been described as four-coordinate, squareplanar molecules, [Cu(L111)(glycinato)]NO3, 111 (Cas II-gly; L111 = (4,7-dimethyl-1,10-phenantroline)), and [Cu(L112)(acetylacetonato)]NO3 (Cas III-ia; L112 = (4,4′-dimethyl-2,2′bipyridine)) being the two most investigated prototypes of a wide series of similar complexes (Figure 75).

Figure 76. Structure of complex 113.

By changing the substituents at the Cu(N-N) moiety with inclusion of extended planar heterocyclic bases and maintaining acac as coligand329 or by replacing gly with other amino acids such as L-val,330 L-phe,331,332 L-tyr,333 and L-trp334 in combination with several diimines other research groups overall confirmed that these complexes bound and (photo)cleaved DNA via ROS generation. In these latter studies a peculiar structural feature was the expansion of the copper coordination sphere to a square-pyramidal geometry by insertion of a water molecule in the apical position. Metal coordination was further assisted by the orientation toward the inner core of the aromatic ring of tyrosine (see complex 114) or tryptophan, respectively, as illustrated in Figure 77a.

Figure 75. Structures of representative Casiopeinas-like complexes (Cas II-gly, 111, and Cas III-ia, 112).

Quantitative structure−activity relationship (QSAR) studies on these ternary complexes320 indicated that (i) the presence of the central fused aromatic ring in the phen-containing complexes was necessary to preserve the antiproliferative activity, (ii) there was a strong relationship between IC50 and E1/2, the most active species being the weaker oxidants, (iii) the nature of the O,O and O,N coligand had a poor influence on biological activity. Concerning the superior antiproliferative activity shown by phen-containing complexes compared to bipy ones, it has to be highlighted that this is a general behavior encountered for several classes of diimine-containing copper compounds, likely due to the better interaction of the planar polycyclic phen system with DNA. By means of computational studies the authors found that the stacking mechanism between Casiopeinas and DNA bases was due to an electron density deficiency of the ligands of Casiopeinas which was compensated for by an electron transfer from adenines by a π−π interaction.321,322 The additional X-ray diffraction study established that the molecular assembly was stabilized by the network of hydrogen bonds binding the adenines with the water molecules that occupy the apical position of the copper coordination compound.322 The interaction described at the molecular level had a direct impact in the DNA fragmentation observed in either pUC19 plasmid and in HeLa t cells.323 The authors reported that DNA fragmentation was accomplished with generation of ROS after copper reduction. The antiproliferative effects of Casiopeinas also correlated to intracellular GSH levels.324 In a translational study Cas III-ia, 112, was found to induce apoptosis in HCT-15 cells in vitro through caspase-dependent mechanisms and in HCT-15 cells transplanted to nude mice was found to retain remarkable in vivo antitumor activity.325,326 Chitosan (CS) was then selected for developing a based-nanoparticle drug delivery system for Cas III-ia, 112. No interactions affecting both stability or modification of the cytotoxic effectiveness of the drug were evidenced in this study pointing to a possible use of

Figure 77. Structure of (a) [Cu(L-tyr)(L114)(H2O)](ClO4), 114 (L114 = 5,6-dimethyl-1,10-phenantroline), and (b) [Cu2(L114)2(L-PDI-Ala)(H2O)2](ClO4)2, 115.

A strictly similar stereochemistry was adopted in the dinuclear complex including phen and N,N′-(p-xylylene)dialanine acid (H2PDI-Ala)331 (Figure 77b) and in two ternary complexes in which the amine function of L-val and L-leu had been coupled with 7-hydroxy-4-methyl-8-coumarin335 to increase the biocompatibility of the copper complex and 841

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enhance the affinity for DNA through formation of hydrogen bonds between coumarin and DNA double helix. Another approach aimed at increasing the bioavailability of these ternary complexes was pursued by preparing their watersoluble polyethyleneimine adducts.330,332 Physicochemical characterization of these polymeric species evidenced retention of DNA binding and cytotoxic activity but without selectivity toward cancer cells compared to normal ones.330 The distorted square-pyramidal ternary complexes [Cu(Lorn)(N-N)Cl] (L-orn = L-ornithine, N-N = bipy or phen) showed antiproliferative activity in vitro. In particular, the phen derivative had a IC50 value of 2.4 μM against A-549 cells and 1.2 μM against Hep-2 cells.336 Several fluoroquinolones and quinolones have been coordinated to the [Cu(N-N)]2+ moiety aiming at broadening the spectrum of action of Casiopeina-like complexes. Examples included (i) norfloxacin337,338 and N-propyl-norfloxacin339 with the corresponding complex showing in vitro antileukemic potential as well as an independent nuclease activity by inducing nicking of supercoiled pUC19 plasmid, (ii) moxifloxacin340,341 (antiproliferative and apoptosis-inducing activity against multiple human breast and lung cells), (iii) ciprofloxacin,337,338 (iv) levofloxacin,342 and (v) 2-phenyl-3-hydroxy4(1H)-quinolinone343 (cytotoxic activity against HOS and MCF-7 human cancer cell lines, binding with CT-DNA and ability to cleave pUC19 plasmid). In another study a barbiturate derivative (H4barb) was reacted with the [Cu(bipy)]2+ platform affording different species, among which a deprotonated form of the ligand (H3barb) or fragments of the ligand (e.g., barb*) completed the coordination sphere of the metal.344 Two complexes, [Cu(H3barb)2(H2O)2]·4H2O and [Cu(bipy)(barb*)]·3H2O,344 116 (Figure 78a), were found to cleave supercoiled plasmid

Figure 79. Structures of complexes 118 and 119.

cleaved DNA without any exogenous additive. The anticancer activity against MCF-7, HeLa, HL-60, and MCF-12A cells revealed a potent effectiveness with IC50 values in the microand submicromolar range.346 Other similar ternary complexes including maltolate and various diimines, as outlined in Figure 79 for the representative complex [Cu(L119)(maltolate)(NO3)], 119 (L119 = bipyridylglycoluril), confirmed the DNA binding of these metal assemblies, indicating partial intercalation of the planar polypyridyl ligands into DNA and plasmid pBR22 DNA cleavage by a hydrolytic mechanism. The cytotoxicity of these complexes against HeLa cell lines showed that synergy between the metal and the ligands resulted in a significant enhancement in the cell death with IC50 values in the submicromolar range.347 Ternary copper complexes containing an acetate or a salicylate group and phen or bipy exhibited high SOD mimetic activity. Both phen derivatives [Cu(CH3COO)2(phen)] and [Cu(sal)(phen)] were approximately seven times more active than cisplatin against HepG2, A-498, and A-549 cancer cells.348 Taking into account the pharmacological properties of salicylic acid (Hsal) and its derivatives (H2dips = 3,5-diisopropylsalicylic acid; H23-MeOsal = 3-methoxysalicylic acid), series of homoleptic and heteroleptic ternary copper compounds [Cu(salH)2(H2O)], [Cu(dipsH)2(H2O)], {[Cu(3-MeOsal)(H 2 O) 0.75 } n , [Cu(dipsH) 2 (BZDH) 2 ], [Cu(dipsH) 2 (2MeOHBZDH)2], [Cu(sal)(phen)], [Cu(dips)(phen)]·H2O, and [Cu(3-MeOsal)(phen)]·H2O, 120 (Figura 80a) (BZDH

Figure 78. Structures of (a) [Cu(bipy)(barb*)]·3H2O (barb* = 5hydroxyhydurilic acid), 116, and (b) complex 117.

Figure 80. Structures of (a) complex 120 and (b) monomeric complex 121.

DNA to nicked circular and linear DNA and showed significant cytotoxic activity (IC50 values in the nanomolar range) against T-cell lymphoma. Analogously, the ternary complex [Cu(phen)Cl(L117)], 117, containing the fluorescent curcuminoid ligand (HL117 = 1,7(di-9-anthracene-1,6-heptadiene-3,5-dione)) showed a weaktype interaction with CT-DNA, and fluorescence microscopy studies suggested that its action seemed to occur outside the nuclei in human osteosarcoma cells, providing valuable information over the cellular process (Figure 78b).345 In the square-planar fluorophore-labeled copper(II) complex [Cu(L118)(acac)]+ (L118 = 2-(naphthalen-1-yl)-1H-imidazo[4,5-f ][1,10]phenanthroline) 118 (Figure 79), an intercalating mode of DNA binding has been proposed. 118 oxidatively

= benzimidazole; 2-MeOHBZDH = 2-methanolbenzimidazole), have been synthetised.349 Ternary complexes [Cu(sal)(phen)], [Cu(dips)(phen)]·H2O, and [Cu(3-MeOsal)(phen)]· H2O, 120, displayed rapid cytotoxicity (in the low micromolar range) against cisplatin-sensitive MCF-7, DU145, and HT29 cells and cisplatin-resistant SKOV-3 cells. They also exhibited potent in vitro DNA binding and cleavage capabilities. Copper−phen complexes including indole-3-acetate or indole-3-propionate were found to inhibit proteasome activity and induce apoptosis in MDA-MB-231 cells but not in nontumorigenic MCF-10A cells.350 The dicopper(II) cation, [Cu2(l-terephthalate)(phen)4]2+, was found to be a powerful, nonsequence-specific, minorgroove oxidizer of duplex DNA which, unlike [Cu(phen)2]Cl2, 842

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benzamide ligand.360 Conventional DNA binding and cleavage was evidenced in all cases. In the latter study the involvement of coordinated diimine in hydrophobic interaction increased both DNA binding affinity and cytotoxic activity. Again, binding and cleavage of DNA was observed by action of tetrameric [Cu4(phen)4(H2O)2]·py·3H2O361 and dimeric [Cu2(phen)2(apopoxd)][ClO4] (apopoxd = N-(2-aminopropyl)-N′-(2-oxido-phenyl)oxamidate(3−)) 362 and [Cu 2 (μOH)(μ-CH3COO)(μ-OH2)(phen)2][ClO4]2363 complexes. Besides DNA binding and cleavage, the latter complex was found to inhibit lactate dehydrogenase enzyme as well as growth of MCF-7 cells lines at the submicromolar level. The biological properties of the resulting complexes (DNA binding and cytotoxic activity) were not substantially modified when the N,O- and O,O-bidentate systems of Casiopeinas-like complexes was replaced by chelating N,N,O- and N,N,Ntridentate systems maintaining intact the [Cu(N-N)]2+ building block. The resulting complexes displayed a distorted squarepyramidal geometry with an elongated metal−N-diimine bond at the apex of the pyramid when the roughly planar N,N,Otridentate 3,5-di-tert-butyl-2-hydroxybenzyl)(2-pyridylmethyl)imine (Hpyrmeim) was employed (Figure 82a).364 The

operated independently of exogenous reagents. The agent displayed excellent in vitro cytoxicity toward cisplatin-resistant SKOV-3 cells, producing intracellular ROS upon nanomolar exposure.351 Another interesting class of Casiopeina-like complexes is that including O,O-pyrophosphate (H4Pyroph) ligands. Both monomeric and dimeric complexes {[Cu(phen)(OH2)][H2Pyroph]}, 121 (Figure 80b), and {[Cu(phen)(OH2)]2[μPyroph}·8H2O displayed cytotoxic activity in the micro- to nanomolar range in adriamycin-resistant A2780/AD cells.352,353 The mechanism of action of these species was investigated focusing on DNA interactions, Topo I enzyme inhibition, and oxidative stress. In addition, the role of hydrolysis vs toxicity was also explored, indicating that these complexes worked as pro-drugs.353 Combination of the o-phthalate dianion with phen or bipy gave rise to square-planar Cu(II) N2O2 complexes with a broad chemotherapeutic potential against MCF-7, DU145, HT29, and cisplatin-resistant SKOV-3 cells (IC50 values in the low micromolar range) likely due to endogenous ROS generation.354 The binuclear copper(II) complexes bridged by N-(5-chloro2-hydroxyphenyl)-N′-[3-(dimethylamino)propyl]oxamide (H3hdpox) and end capped with bipy,355 4,4′-dimethyl-2,2′bipyridine,356 phen, and 5-nitro-1,10-phenanthroline (L122), 122, have been synthesized (Figure 81a), and their cytotoxic

Figure 82. Structures of (a) the mixed complex [Cu(Hpyrmeim)(L124)]ClO4 (L124 = pyrazino[2,3-f][1,10]phen) and (b) [Cu(phen)(bepyrmeam)(H2O)][ClO4]2·1/2H2O. Figure 81. Structures of (a) binuclear complex 122 and (b) polymeric complex [Cu2(bhpox)(phen)]n(ClO4)n·nH2O, 123.

coordination sphere expanded to a distorted octahedron with additional insertion of a water molecule or a perchlorate oxygen when the more flexible N-benzyldi(pyridylmethyl)amine ligand (bepyrmeam)365 (Figure 82b) or other strictly similar N,N,Ntripodal derivatives366−368 were utilized. 2.9.2. Clip-phen Systems. [Cu(phen)2]-type complexes are redox-active chemical nucleases that are known to irreversibly damage DNA. Together with Fe−bleomycin and Fe−edta systems,369 they are able to oxidize the deoxyribose unit of DNA in the presence of dioxygen or dihydrogen peroxide. In the case of the copper system, the low binding constant of the second phen limits its applicability, since copper complexes with only one coordinated phen are less efficient DNA cleaving agents. Trying to prevail over this problem, the two phen ligands have been coupled via their C2 or C3 atom by means of a serinol bridge (Clip-phen chelate system). The optimal length of the bridge linking phens has been estimated

activities against two cancer cell lines, human hepatocellular carcinoma cell line SMMC-7721 and human lung adenocarcinoma cell line A549, were investigated (IC50 values in the 9−18 μg/mL range).357 Also, a new one-dimensional polymeric copper(II) complex, [Cu2(bhpox)(phen)]n(ClO4)n·nH2O, 123 (bhpox = N-benzoate-N′-[3-(2-hydroxyethylammino)propyl]oxamide), has been synthesized (Figure 81b) and tested against the same two cancer cell lines SMMC-7721 and A549 (IC50 values in the 19−27 μM range).358 Oxygens of the hydroxylate and amide groups at ring A of doxycycline and tetracycline were found to coordinate on the equatorial plane trans to phen in a distorted tetragonal geometry filled by axially arranged water and perchlorate groups.359 A similar arrangement was shown in a dimeric complex in which tetracycline was replaced by a hydroxy843

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Cu(II) complexes containing one or two phen units together with N,N′-substituted imidazolidine-2-thione (ith) were synthesized, and the cytotoxic activity of [Cu(phen)2(ith)](ClO4)2 against CCRF-CEM and CCRF-SB and solid tumorderived cells K-MES-1 and DU-145 was investigated. The antiproliferative activities (IC50 in the 1−3 μM range) were comparable in both leukemia and carcinoma cells.382 2.9.4. (terpy)(N-N) and (terpy)2 Systems. Series of mixed-ligand complexes including both bidentate and tridentate diimine have been prepared and tested for their biological activities. 2,2′:6′,2″-Terpyridine (terpy) represents the simplest version of tridentate diimines. These copper(II) complexes mostly included derivatized terpy and derivatized phen usually arranged in a distorted square-pyramidal geometry, as illustrated in Figure 84a for the complex [Cu(Fc-terpy)(L127)](PF6)2·3CH3CN, 127 (L127 = dipyridophenazine, Fc-terpy = ferrocenyl-terpy).383−387 127 showed moderate cytotoxicity against HeLa cells.

by theoretical calculations to three carbon atoms, generating the class of copper(3-Clip-phen) complexes showing superior DNA cleavage activity.369 The bridge length was found to be critical for the geometry adopted by these metal complexes inducing a more planar conformation of the two distal phen fragments that favored van der Waals interactions with DNA via minor-groove binding preferred over intercalation and majorgroove binding.370 The versatile serinol bridge has been further coupled at the central amine function with distamycin-like minor-groove binders and cisplatin derivatives, generating classes of bifunctional DNA cleaving agents.371 In the case of heteronuclear Pt− Cu complexes based on the 3-Clip-phen framework, it was found that each complex exerted its antitumor activity through a distinct mechanism of action. The three heteronuclear Pt−Cu complexes showed excellent DNA-cleavage activity and significant cytotoxic activity against Hs-683, U373MG, HCT15, LoVo, MCF-7, and A549 cell lines (IC50 in the 0.4−2.7 μM range). 2.9.3. (N-N)2(X) Systems. A number of complexes adopting a twisted [Cu(N-N)2] configuration (twisted means that the planes defined by the two diimine ligands are virtually orthogonal) have been proposed as metal-based synthetic nucleases able to bind and cleave DNA with or without addition of redox cofactors. The coordination sphere of these complexes is usually completed by an additional neutral or charged ligand (O-water,372,373 S- imidazolidine-2-thione,374 Ohyppurate(1−),375 O-phtalate(1−),376 O-octanedioate(2−) (oda),377 N-purine(2−)),378 resulting in distorted squarepyramidal arrangements. Unprecedented nanomolar in vitro cytotoxicity against human-derived colorectal cancer cell lines (HT29, SW480, and SW620) was exhibited by water-soluble [Cu2(μ2-oda)(phen)4] Cu(II) complex 126 (Figure 83).377 This remarkable

Figure 84. Structures of the cationic portion of (a) complex 127 and (b) complex 128.

The coordination sphere is expanded to a distorted octahedron when two terpy-like ligands are bonded to the Cu(II) ion. Representative complexes comprising two anthracenyl-terpy,388 two ferrocenyl-terpy,389 and two pyrenyl-terpy390 frameworks all exhibited DNA binding and photocleavage activity. Complex [Cu(L128)2](ClO4)2, 128 (L128 = 4′-(9-anthryl)-2,2′:6′,2″-terpyridine), outlined in Figure 84b, bound CT-DNA through a partial intercalation mode and showed remarkable antiproliferative activity against several cancer cell lines (HeLa, SiHa, CaSki, MCF-7, HepG2, and H1299 cells with IC50 values in the 0.7−6.3 μM range).388

Figure 83. Structure of the cationic portion of complex 126.

property was further accomplished with less cytotoxicity toward normal HaCaT cells and greater in vivo drug tolerance compared to cisplatin when examined using the insect Galleria mellonella. This compound was a generator of ROS in HT29 cells, displayed avid DNA binding, and induced oxygendependent cleavage of supercoiled pUC18 DNA. Another attempt to make more hydrophilic the [Cu(NN)2]2+ moiety has been pursued using a branched polyethyleneimine (BPEI).379,380 The resulting water-soluble polymer species have shown DNA binding and antitumor activity on NCI-H460 cells. A similar approach generated the mixed [Cu(phen)(phendione)Cl]Cl complex381 that induced cleavage in pUC18 plasmid DNA and antitumor activity against K562 and Jurkat T cells.

3. MECHANISTIC APPROACHES AND PROPOSED BIOLOGICAL TARGETS Copper species have been shown to possess a broader spectrum of activity and a lower toxicity than platinum drugs and are suggested to be able to overcome inherited and/or acquired resistance to cisplatin. These features are consistent with the hypothesis that copper complexes possess mechanism(s) of action different from platinum drugs that covalently bind to DNA. However, little information is available on the molecular basis for the mode of action of copper complexes. At present, most investigations still focus on the ability of these complexes, 844

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or fragments thereof, to interact with DNA. However, other cellular constituents such as topoisomerases or the proteasome multiprotein complex are emerging as new putative targets (Table 1).

This binding was dependent on copper complex size, electron affinity, and geometry of the formed adduct, inducing an irreversible modification of the DNA conformational structure. According to these observations, a high number of copper complexes has been and is still being tested as DNA-targeting metallodrugs. For some classes of copper derivatives, the ability to bind DNA has been well established and documented. Copper derivatives have been found capable of noncovalently interact with DNA double helix rather than forming coordinated covalent adducts with DNA. The noncovalent DNA interactions included intercalative, electrostatic, and groove binding of metal complexes along the major or minor DNA groove. In most cases, the metal acted as an inorganic modifier of the organic backbone of the bioactive molecule and ligands granted DNA affinity and specificity. In this frame, particular attention has been focused on copper(II) complexes including N-donor ligands due to their high DNA interaction ability and in vitro antitumor efficiency. Copper derivatives containing 1,10-phen and related diimine chelates have been described as potent cytotoxic agents, eliciting IC50 values in the submicromolar range. In this respect, many recent papers reported on ternary copper(II) complexes based on the combination of a bidentate diimine ligand (N-N = phen, bipy, or their substituted derivatives) and other coligands (e.g., salicylic acid,349 tetracycline,359 terpyridine,387,394 imidazolidine-2-thiones,374 oxamidobenzoate,280 quinoline,395 oxamide,355 sulphonamide,378 antracene,345 amine,367 cumarine,335 and phthalate376). Overall, it has been demonstrated that physicochemical features, such as the planarity, hydrophobicity, and size of the diimine, the nature of the coligand, as well as the coordination geometry of the metal complex all played important roles in determining the binding/intercalating mode of copper complexes to DNA. For example, Selvakumar and co-workers gained insight on the structure−DNA binding relationships of some iminodiacetic copper(II) derivatives containing different diimine ligands: [Cu(imda)(phen)(H2O)], 129a (H2imda = iminodiacetic acid), [Cu(imda)(5,6-dmp)], 129b (5,6-dmp = 5,6dimethyl-1,10-phen), and [Cu(imda)(dpq)], 129c. All complexes showed significant DNA binding abilities, and derivatives 129a and 129c were capable to bind DNA through partial intercalation of the heterocycle ring with DNA base stack, whereas for 129b a predominance of DNA groove binding was indicated. It has been underlined that introduction of methyl groups on the phen ring, besides hindering the partial intercalation of the phen ring, allowed stronger hydrogenbonding interactions with the DNA surface and led to bending (kinking) of the DNA chain.396 Similar results have been reported in several studies comprised in this review262,323,329,343,355,367,395,397 (see section 2.9), thus strengthening the hypothesis that planar and unsubstituted diimine ligands could interact with DNA through an intercalation mode and that extended conjugated planar rings promoted deeper insertion within the DNA base stack,262,343,397,398 whereas the nonplanar aromatic heterocyclic ring ligand drastically weakened the intercalation properties of copper complexes.362,365 Conversely, copper derivatives containing substituted diimines favored formation of noncovalent DNA groove interaction and were able to partially modify the electronic distribution over the DNA polynucleotide chain.301,323,343,360

Table 1. Proposed Mechanisms of Action for Copper Complexes as Anticancer Agents mechanisms of action

class of ligands

DNA interaction intercalation (N-N)/amino acids

groove binding

oxidative cleavage hydrolytic cleavage

section

(N-N) diimines (N-N) diimines (N-N) diimines (N-N) diimines (N-N) diimines (N-N)/phosphines salphen κ2O,O flavonoids κ2O,O isoeuxanthones κ3N,N′,O Schiff bases κ3N,N′,O Schiff bases κ3N,O,O′ Schiff bases aminophosphines

2.9.3 2.9.4 3.1 2.6.2 2.5.8 2.7 3.1 2.2.2 2.2.2

323, 329, 335, 343, 345, 349, 355, 359, 360, 367 376, 378 387 396, 397, 436 280 262 301 399 135, 142−144 145, 146

2.5.5 2.5.6 2.5.7.2 2.7

236, 240 244, 246 255 301

substituted (N-N) diimines (N-N) diimines

2.9.1

323, 343, 437

2.9.3

343, 378, 436, 438

TACN

3.1

408

2.5.7.2

255

2.9.1 2.9.4

347, 363 384, 385

3.1 3.1 2.1.1 2.9.1

439 410 105, 413, 414, 439 353

2.4.6

210

3.1 2.6.1

417 273

2.2.2 2.1.3 and 3.3 2.5.5 and 3.3 2.7 2.4.4 2.9.1

130 426

semicarbazone systems (N-N) diimines (terpy)(N-N) and (terpy)2 systems Topoisomerase inhibition TOPO II salicylaldoxime 2-furaldehyde oxime thiosemicarbazones TOPO I (N-N)/ pyrophosphate (N-N)/ ethylendiamine (N-N)/glycine glycylglycine/ piperazine κ2O,O plumbagin Proteasome dithiocarbamates inhibition methylpyridinaminomethylphenol phosphines tioxotriazoles (N,N) diimines

2.9.1

refs

243, 429 292, 293, 295 203 350

3.1. Copper Complexes as DNA Targeting Drugs

Since 1969 copper has been found to possess high DNA binding affinity.391 Analogously to what has been widely illustrated for cisplatin,392 a crystal structure describing formation of an adduct between CuCl2 and DNA was published in 1991, in which copper bound to the guanine N7 residue.393 845

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More recently, copper complexes bearing ligands other than heterocyclic diimines have been tested for their DNA binding properties. Among them, salphen,399 isoeuxanthone145,146 (see section 2.2.2), flavonoids135,142,144 (see section 2.2.2), and several Schiff base ligands236,240,244,250,255 (see sections 2.5.5−2.5.7) deserved attention. In all of these studies it emerged that the ligand planarity played a pivotal role in inducing DNA binding affinity. Moreover, DNA-binding affinities of copper complexes can be finely tuned by introducing in the intercalative ligand substituents capable of π−π stacking.354 In many cases, DNA intercalation led to deformation of DNA structure, favoring DNA cleavage processes. Actually, these new putative antineoplastic copper metallodrugs behaved as “chemical nucleases” through several pathways, namely, (i) nucleobase oxidation, (ii) phosphate ester hydrolysis, and (iii) deoxyribose sugar oxidation. Because of their redox properties, Cu(II) complexes have been frequently used in development of agents for DNA oxidative cleavage. Since 1986, Zue et al. demonstrated that copper complexes could bind DNA with high affinity and functioned as redox catalysts.400 Later, many studies revealed that copper complexes promoted plasmid DNA cleavage at physiological conditions via an oxidative pathway343,346,378,395,401 (see section 2.9.3). DNA degradation promoted by copper complexes is believed to take place through a Fenton-type reaction. This reaction is a source of ROS, such as hydroxyl radical402 or different metal-based intermediates (CuOH2+ or CuO+ species),403 which, in turn, cause both direct oxidation and cleavage of DNA polynucleotide chains.404 In general, it has been assumed that the copper(II) species may be in equilibrium with the corresponding copper(I) species. The latter intercalate into the DNA base pairs due to ligand planarity. Electrostatic interactions between copper(I) and the phosphate diester backbone may further ensure a strong DNA binding. Copper−oxo species usually attack the C1′−H site of the deoxyribose residue, causing strand scission in DNA.395 However, the definite site of “metalation” on the DNA strand remains still unclear. On the other hand, there are several examples of Cu(II) complexes able to cleave DNA with a hydrolytic mechanism.255,347,363,384,385,405 Burstyn and co-workers reported the first example in 1996.406 The Cu(II)−TACN complex (TACN = 1,4,7-triazacyclononane) cleaved supercoiled DNA in both aerobic and anaerobic conditions, indicating a predominantly hydrolytic cleavage mechanism. In this frame, it is important to emphasize that oxidative DNA-cleaving agents produce fragments that, differently than those produced by natural hydrolases, cannot be enzymatically religated.407 Therefore, in view of a future development of metallonuclease as a chemotherapeutic drug, synthetic hydrolytic DNA-cleaving agents should be preferred over oxidative-cleaving agents. Other copper complexes defined by the authors as “molecular scissors” (classical chemical nucleases) can cleave DNA either by single- or by double-strand breaks. The cellular response following DNA damage (breaks) comprises the activation of diverse repairing mechanisms, and if repair fails cells undergo cell death. Double-strand breaks in duplex DNA are more significant sources of cell lethality than are singlestrand breaks, as they are less readily repaired by DNA repair mechanisms.408

Depending on the type of damage induced on DNA by copper complexes, cellular processing can drive the cell to activation of apoptosis signal transduction pathways. Despite many copper complexes being found to trigger apoptotic cell death as a consequence of DNA damage, very few papers report elucidations on signal transduction molecular determinants activated in copper complexes treated cells. In some cases, copper complexes determined an upregulation of proapoptotic proteins or a downregulation of antiapoptotic proteins, which were consistent with induction of apoptosis. ́ For example, Garcia-Gimé nez et al. described that apoptosis induced in Caco-2 cells by [Cu(N9-ABS)(phen)2] (H2N9-ABS = N-(9H-purin-6-yl)benzenesulfonamide) was associated with an increase in p53 protein level and a decrease of Bcl-2 expression378 (see section 2.9.3). Also, involvement of caspase activation in copper complex mediated cell death has not been fully elucidated. Very few copper derivatives have been reported to induce apoptosis in cancer cells through involvement of caspase-3144,232 and/or caspase-9 activation237 (see sections 2.2.2, 2.5.4, and 2.5.5). 3.2. Copper Complexes as Topoisomerase I,II Inhibitors

Recent research into the ability of copper complexes to inhibit topoisomerases (topos) has served not only to reinforce the significant potential of this class of metal complexes in cancer research but also to expand the array of possible biochemical targets for these molecules. Topos are essential nuclear enzymes that regulate the overwinding or underwinding of DNA, and so they play essential functions in DNA replication and transcription. Topos create transient nicks (Topo I) or breaks (Topo II) in the double-stranded DNA polymer, allowing DNA to be converted between topological isomers.409 Nuclear Topo I and Topo II have been identified as clinically important targets for cancer chemotherapy, and their inhibitors are central components in many therapeutic regimens. These topo-targeting agents are broadly classified in two groups, viz. topo poisons and catalytic inhibitors. Topo poisons are able to stabilize the reversible covalent topo−DNA complex termed the cleavage complex, whereas catalytic inhibitors, most of which target Topo II, act on the other steps in the catalytic cycle without trapping the covalent complex. Currently there is still increasing interest focusing on development of new kinds of drugs targeting human topoisomerases, and development of metal complexes as Topo I,II inhibitors fits just in this therapeutic niche. However, unlike that involving DNA, interaction of copper complexes with topos is a relatively new field of research. The first observations regarded oxime copper complexes as Topo II poisons.410 In particular, a copper complex of 2-furaldehyde oxime was found to poison Topo II activity in a manner similar to etoposide (VP-16) and showed better activity than this drug by blocking the phosphorylation activation of Topo II. More recently, a copper salicylaldoxime, which effectively inhibited the L1210 leukemia cell proliferation, blocked Topo II, disrupting Topo II dimer formation with consequent induction of enzyme-linked single-strand breaks in the DNA.411 A small number of publications indicated that α-heterocyclic TSCs and their Cu(II) complexes were capable of in vivo and in vitro inhibition of Topo II at IC50 below that of the widely employed Topo II poison VP-16103,412,413 (see section 2.1.1.2). Despite these encouraging results, little has been reported on the role that metalation played in the ability of TSCs to inhibit Topo II. Very recently, a series of α-heterocyclic-N-4846

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compounds targeting topos. The selectivity of all [Cu(phen)(aa)(H2O)]+ copper(II) complexes against HK1 cancer than NP69 normal cells has been explained in terms of Topo I inhibition.417 The dinuclear copper(II) dipeptide ppz-bridged complex 92 (section 2.6.1, Figure 68) capable of recognizing a specific sequence in DNA minor groove to inhibit the expression of Topo I and thereby control cancer cell replication has been recently designed.273 92 was able to oxidatively cleave DNA, bind to the DNA minor groove, and inhibit Topo I activity at very low concentration (IC50 =12.5 μM) and to be a SOD mimic (IC50 0.086 μM). Molecular docking studies revealed that 92 intercalated between the base pairs in the minor groove without having hydrogen bonds with the enzyme. Copper complex occupying the Topo I binding site suppressed the association of the enzyme with DNA, thus influencing the Topo I ability to form cleavable complexes. Also, in this case, selective growth inhibition against cancer cells (A498, A549, and Mia PaCa-2) provoked by copper complex has been correlated to Topo I inhibition. The potent cytotoxicity of two plumbagine (HL20) copper complexes toward selected cancer cells has been related to their ability to inhibit Topo I. [Cu(L20)2]·2H2O, 20a, and [Cu(L20)(bipy)(H2O)]2(NO3)2, 20b, inhibited the Topo Imediated relaxation of supercoiled DNA at very low concentrations. Given that the interactions of plumbagin complexes with CT-DNA revealed that they intercalated the neighboring base pairs of DNA, the authors claimed a dualtargeting mechanism responsible for cancer cell killing ability130 (see section 2.2.2, Figure 18).

substituted TSCs and their Cu(II) complexes were investigated for their ability to inhibit Topo II and promote antiproliferative effects against breast cancer cells expressing different levels of Topo II105 (see section 2.1.1.2). The results showed that this class of [Cu(TSC)Cl] complexes was a more potent Topo II inhibitor than the TSC ligands alone, with IC50 values, in most cases, lower by an order of magnitude. A similar discrepancy in the Topo II inhibitory activity of metalated vs free TSCs has been reported for 1,2-naphthoquinone TSC and its Cu(II), Pd(II), and Ni(II) complexes.413 It has been proposed that copper complexes containing α-heterocyclic-N4-substituted TSCs acted as catalytic inhibitors rather than poisons of Topo II, likely by binding to the ATP hydrolysis domain of Topo II, thus interferring with ATP hydrolysis of the enzyme in a manner similar to that described for 2-quinoneline carboxaldehyde-4,4-dimethyl TSC.414 Quinolinone derivatives have been reported to possess proapoptotic characteristics,415 and many quinolinone-, quinolineand coumarin-based compounds have been shown to be potent Topo II inhibitors.412 Recently, a series of novel quinolinone Schiff bases and their corresponding copper(II) complexes were tested for their Topo II inhibitory potential and anticancer activity against HepG2 cells. Results indicated that complexation of quinolinone Schiff bases with copper served to significantly enhance cytotoxicity but also somehow prevented inhibition of Topo II induced by the ligands alone.416 Copper complexes have also been studied for their ability to inhibit Topo I. Copper(II) chloride was found to inhibit Topo I extracted from shrimp at millimolar concentration.417 Among a series of metal(II) pyrophosphate-bridged complexes, {[M(phen)x]2(μ-P2O7)} (where x = 1 or 2), the copper complex 121 (see section 2.9.1, Figure 80) inhibited Topo I at micromolar concentrations. This mechanism coupled with DNA interaction and oxidative stress had been proposed to account for the exceptional cytotoxicity (IC50 values in the low nanomolar range) of {[Cu(phen)(H2O)]2(μ-P2O7)}·8H2O in adriamycin-resistant cancer cells.353 A heterobimetallic CuII−Sn2IV complex containing 1,10-phen and ethylenendiamine (see section 2.4.6, Figure 42b) was found to be a catalytic inhibitor of human Topo I (IC50 value of 20 μM), similarly to the Topo I targeted drug camptothecin. Molecular docking studies revealed that planar heterocyclic phen rings approaching toward the DNA cleavage site in the topo−DNA complex formed a stable complex through π−π stacking interactions parallel to the plane of base pairs without having hydrogen bonds with Topo I. Chlorine atoms instead acted as hydrogen-bond acceptors, forming a H bond with Asn 722 residue, a catalytically important amino acid residue. This Topo I inhibitory activity was accompanied by a marked cytotoxicity toward cancer cells.210 Once more, among copper complexes containing the pharmacophoric planar heterocyclic phen, a series of mixed copper(II)−phen complexes with glycine and methylated glycine (aa) has been developed with the aim to investigate the effect of the position and number of methyl substituent(s) in the auxiliary ligand on the biological activity, including inhibition of Topo I. It has been found that replacement of metal-coordinated glycine with methylated glycine affected the DNA binding properties of the ternary complexes, whereas there was no significant difference in the antiproliferative activity promoted against HK1 cancer cells as well as in the degree of Topo I inhibition. The Topo I inhibitory property was very similar to that induced by some anticancer organic

3.3. Copper Complexes as Proteasome Inhibitors

The proteasome is a large multiprotein complex located in both the nucleus and the cytoplasm that selectively modulates and degrades intracellular proteins. The eukaryotic 26S proteasome contains one 20S core particle structure and two 19S regulatory caps. The core is hollow and provides an enclosed cavity in which proteins are degraded. Each end of the core particle associates with a 19S regulatory subunit that contains multiple ATPase active sites and ubiquitin binding sites. In order to be recognized and processed by the proteasome a protein substrate needs to be linked to ubiquitin.418 After polyubiquitinated proteins have been recognized, they are transferred into the 20S core that contains multiple peptidase activities, including the chymotrypsin-like (cleavage after hydrophobic residues, CT-L), trypsin-like (cleavage after basic residues, TL), and caspase-like (cleavage after acidic residues, C-L) activities.419 The proteasome is part of a major mechanism by which cells regulate the concentration and stability of particular proteins (e.g., cyclins, bcl-2 family members, and p53) and decompose unfolded proteins. The ubiquitin proteasomedependent degradation system is essential for many cellular functions, including processes of primary importance for carcinogenesis such as proliferation, apoptosis, angiogenesis, and metastasis formation.420 It has been shown that cancer cells are more sensitive to proteasome inhibition than normal cells. Thus, targeting the ubiquitin−proteasome pathway has emerged as a favorable anticancer strategy,421 and currently, development of proteasome inhibitors as novel anticancer agents is under intensive investigation. The first case of copper complexes inhibiting proteasome function has been reported by Dou and co-workers.70 In 2004 847

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Figure 85. Schematic diagrams of cellular pathways involved in proteasome inhibition induced by copper compounds.( a) Apoptosis triggered by DTC copper(II) complexes. (b) Paraptosis caused by phosphine copper(I) and thioxotriazole copper(II) complexes.

they described some “copper mixtures”, derived from mixtures of copper(II) salts (CuCl2 or CuBr2) and bidentate ligands (the family of 8-OHQ including CQ, phen, and the family of DTCs) as potent inhibitors of the CT-L proteasome activity.422 Owing to proteasome inhibitory activity, these copper mixtures could selectively induce apoptotic cell death in cancer cells but not in nontransformed cells and were effective in in vivo tumor models.423 These studies established that elevated proteasome activity and high concentration of copper are unique features in human tumor cells that can be used as targets by copper mixtures that act as potent tumor cell killers162,163,424−427 (see section 2.3.1). Interestingly, all these studies suggested that copper ion played a fundamental role in the mixture for conferring the proteasome inhibitory activity, but limited information was available about the composition of the coordination species generated. Copper-mediated proteasome-inhibitory activity could be enhanced by the choice of appropriate bidentate ligands but blocked by stronger copper polydentate chelators such as EDTA. This feature denoted that substitution-inert copper complexes, in which copper was totally sequestered by the ligand framework, could not act as proteasome inhibitors because the metal was likely incapable to interact with cell substrates at the molecular level.11 Furthermore, Xiao and coworkers recently investigated the effect of the oxidation status of copper Cu(I) and Cu(II) on inhibition of proteasome activity.428 Mixing neocuproine (NC), a copper-binding compound, with Cu(I) or Cu(II), both copper mixtures could inhibit proteasome CT-L activity and induce apoptosis in tumor cells even if Cu(I) mixture was more potent. Actually, purified 20S proteasome protein was able to directly reduce Cu(II) to Cu(I), suggesting that Cu(I) is the oxidation state of copper that directly reacts with proteasome. However, little is known about the mode of interaction/inhibition of these copper derivatives with the catalytic subunits of 26S proteasome. More recently, Dou et al. investigated the effects of discrete copper complexes of the type [Cu(PyDTC)2], 14b, and [Cu(EtDTC)2], 15b (PyDTC = pyrrolidinedithiocarbamate, EtDTC = diethyldithiocarbamate; Figure 13). Biological studies performed in human cancer cells, while confirming the

proteasome inhibition activity of the discrete complexes, tried to gain insights on the proteasome inhibition mechanism. 14b was found to inhibit the CT-L activity of cellular 26S with much less inhibition of the 20S proteasome. The structural JAB1/MPN/Mov34 (JAMM) domain in the 19S proteasome has been proposed as a putative target for these copper compounds426 (Figure 85a). A series of copper(II) complexes with distinct stoichiometries, protonation states, and nature of the ligand containing the methylpyridin-amino-methylphenol moiety was designed considering that proteasome inbibition could occur via bonding of the metal complex to the N-terminal threonine present in the beta sites of the 20S core243,429 (see section 2.5.5). When these complexes were tested in C4−2B and PC3 cultured prostate cancer cells a significant proteasome inhibition associated with higher levels of ubiquitinated proteins and massive apoptosis was apparent. It has been suggested that these copper complexes served as a way to carry the metal ion across the cell membrane and avoid (or decrease) nonspecific intracellular interactions. Moreover, the iodo-derivatized complex or, likely, some related solvated species was described as the pharmacophore. This entity would have the vacant n coordination sites necessary to promote interaction and bonding with available amino acids such as the N-terminal threonine present in each beta active site with high affinity for copper. Proteasome has been identified as the main molecular target for a series of copper(I) complexes with hydrophilic phosphine ligands.293 The monocationic copper(I) complex [Cu(thp)4][PF6], 102 (thp = trishydroxymethylphosphine; see section 2.7; Figure 72a), highly soluble and stable in water solution, gained special attention because of its strong antiproliferative effects selectively directed toward human cancer cells.292 102 was found to inhibit both in vitro and in human colon cancer cells, CT-L, T-L, and C-L catalytic activities of 26S proteasome causing intracellular accumulation of polyubiquitinated proteins and functional suppression of the ubiquitin−proteasome pathway, thus triggering endoplasmic reticulum (ER) stress. The latter was paralleled by a strong increase in the levels of phosphorilated ER sensors, PERK and IRE1, proving the concomitant induction of unfolded protein response (UPR). 848

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Table 2. Copper Complexes Recently Tested in in Vivo Experiments

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Table 2. continued

cyano-dithiolato complexes (see section 2.1.5, Figure 15) studying the influence of lipophilicity on their antiproliferative activity by varying nitrogenous bases coligands. The in vivo investigations on leukemia P388 bearing mice treated with a single ip LD10 dose of tested compounds revealed that the thiazole/dithiolate complex 17 was the most effective derivative, yielding a treated/control (T/C) value of 164% and increasing the lifespan of treated animals by 64%. The enhanced antitumor activity had been related to factors such as the high polarity of the complex due to the distorted tetrahedral or square-planar geometry and electrostatic interactions and not with lipophilicity. Copper−TSC species represent one of the most widely investigated classes of copper complexes, but very few reports have been published looking at their in vivo activity. Hancock et al.106 described the antitumor activity of a copper chelate of the pyridine 2-carbaldehyde TSC, HL5 (Figure 6b) (see section 2.1.1.2), in an HL60 human xenograft model. Nude mice harboring HL60 xenografts receiving complex 5 whether given once or twice a day ip (3 mg/kg) for 5 days had statistically significant reductions in tumor size compared to controls, even if there was not a statistically significant difference between complex 5 and the corresponding free ligand. 5 was well tolerated; actually no animals were lost to toxicity, and the weight loss in all groups was less than 20% of their starting body weights. The assessment of transcripts and pathways altered by 5 revealed in treated cells the activation of pathways involved in oxidative and ER stress/UPR responses. Among copper(II) complexes bearing tetradentate κ4N,N′,S,S′-TSC ligands (H2L12a−c see section 2.1.1.4; Figure 10b), Raman et al. showed that 12a significantly extended the lifespan of Ehrlich Ascites Carcinoma (EAC) bearing mice.113 Compared to control animals, copper complex, administered po for 9 days at a dose of 100 mg/kg/die 24 h after tumor inoculation, was able to approximately double the lifespan of tumor-bearing mice. These antitumor effects were less pronounced than those obtained with the standard drug 5FU and almost comparable to those obtained more recently by the same authors testing copper(II) complexes N,N-bidentate Schiff base and benzenedithiolate (see below).215 As stated above, Casiopeinas represent a series of patented Cu(II) mixed-chelate compounds (see section 2.9.1; Figure 75). Promising in vivo activity has been described for Casiopeina III-ia, 112, against HCT-15 colorectal cancer cell line xenografts.325 The relative tumor volume (RTV) of tumors in nude mice bearing HCT-15 cells treated with Casiopeina IIIia showed slow growth compared with control animals. In particular, Casiopeina III-ia (6.0 mg/kg, each 4 days, 6 doses) showed about 5-fold reduction of tumor volume and 3-fold enhancement of tumor doubling size days. Additionally,

The irreversible ER stress was accompanied with a massive cytoplasmatic vacuolization and a programmed cell death (PCD) termed paraptosis.295 Paraptosis, a PCD morphologically and biochemically different from apoptosis, had been observed in cancer cells treated with another class of copper complexes.189 In particular, the thioxotriazole copper(II) complex [Cu(L49)Cl2], 49 (see section 2.4.4, Figure 40a), induced paraptotic-like cell death in a wide panel of human cancer cell lines. 49 was found to inhibit the CT-L activity of proteasomes, thus preventing degradation of misfolded proteins and committing the cell to death through the pro-death arm of the UPR203 (Figure 85b). More recently, it has been found that coordination of phen as the third ligand to dinuclear copper(II) complexes in which Cu(II) coordinated two molecules of indole 3-acetic or 3propionic acid (see section 2.9.1) gave novel proteasome inhibitors and apoptosis inducers in human cancer cells. It has been proposed that phen played a key role in carrying copper into the cancer cell, leading to direct proteasome interaction/ inhibition and/or through oxidation of the proteasome by copper, which consequently caused deactivation of the multiprotein complex.350

4. IN VIVO ANTITUMOR STUDIES Although many different in vitro assays, both cell based and molecular-target driven, have been used to identify lead compounds, the most common step following in vitro assays is efficacy assessments in animal tumor models. Actually, there are series of reports in the literature describing in vitro cytotoxic activity investigations as no predictive assays of in vivo antitumor efficacy.430 Animal models have several advantages over in vitro cell cultures as tumors develop vasculature and interact with the stroma; therefore, they allow evaluation of toxicity and provide pharmacokinetic data of the agent. The typical development plan for a cancer agent also requires studies on preclinical models in which critically important measures of antitumor effectiveness (i.e., the increase in the lifetime and/or tumor growth delay in tumor bearing mice) can be monitored according to the standard protocols of the experimental evaluation of antitumor drugs (NCI, USA). Despite huge interest in the development of copper-based compounds that are poorly toxic and highly active as antitumor drugs, nowadays there is still a paucity of studies investigating the in vivo antitumor activity of copper(I,II) complexes. Actually, although several classes of copper(I,II) complexes have been proposed as very promising cytotoxic agents, for very few of them a remarkable in vivo activity has been demonstrated so far (Table 2). Bolos et al.122 investigated the antileukemic activity of a series of neutral mixed-ligand Cu(II) cyano- and substituted 850

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5. CONCLUDING REMARKS The research on copper(I,II) coordination compounds as antiproliferative agents has boosted dramatically in the last few years as demonstrated by the high number of papers published in this field in the period 2008−2012 and surveyed in this review. The first consideration which stems from the presented data concerns the large variety of ligands used to synthesize potentially active copper drugs. The reported copper complexes (mostly copper(II)) comprised ligands of different hapticity, from monodentate to hexadentate, and characterized by different donor atoms (O, N, S, P, and C) which gave rise to different geometrical arrangements (tetrahedral, square pyramidal, trigonal bipyramidal, octahedral) and, in some cases, dimeric and polymeric species. The choice of the ligand was generally determined by different approaches. In many studies, the criterion laid on using already known bioactive molecules including anti-inflammatory drugs, natural medicines, and antitumor agents, all mainly DNA-targeting species, pointing to a synergistic “metal + ligand” effect. However, biological tests revealed that this approach was not straightforward. In other reports, the choice of the ligands was based on their ability to aim at specific targets other than DNA, to mimic biological sites, to stabilize copper in a particular framework or oxidation state, and to confer a peculiar lipophilicity. Despite the large number of compounds which exerted a remarkable cytotoxicity (sometimes at nanomolar level) against cultured cancer cells, few systematic attempts to correlate the in vitro antitumor activity of these complexes with oxidation state, coordination number, or geometry and to understand the role of the metal and of the ligands have been reported. Overall, a rational design of a copper-based antitumor drug is far to be attained, and the absence of a distinct “copper lead compound”, as it happened in the past with cisplatin among Pt(II) antitumor drugs, does not drive research toward a well-defined chemical scaffold. Nevertheless, from a critical analysis of the huge number of complexes considered in this survey, it is possible to extrapolate few basic concepts useful to direct future research in this area. Considering the coordination number of the complex, four- and five-coordinate species appear to be more cytotoxic than sixcoordinate ones. Often, more active compounds comprise labile group(s) (water, halogens, and other weakly coordinated solvents or counteranions) in the metal coordination sphere. Therefore, ligand(s) coordinating the copper ion should not seek the metal in a markedly stable arrangement, as the complex should be stable enough to shuttle the metal to the cancer cell without irreversible interactions with physiological entities but sufficiently labile to allow the metal to directly interact with the binding site once it has reached the target substrate. Regarding the copper oxidation state, there is no direct correlation between the antiproliferative activity and reduced or oxidized forms of the metal. However, the few reported copper(I) complexes, featured by phosphine or heterocyclic carbene ligands (species again displaying low coordination numbers of four and two, respectively), generally showed a potent cytotoxic activity. Also, in these series of complexes the presence of bulky and/or chelating groups wrapping the metal in a shielded environment diminished the antiproliferative action. Trying to mimic DNA−metal interactions typical of the workhorse antiproliferative drug cisplatin, most of the studies with copper complexes continue to consider DNA as the main biological target. In these routine investigations, novel copper

Casiopeina III-ia treatment resulted in induction of apoptotic cell death morphology. Unfortunately, histological analysis revealed a chronic irritative effect induced by the complex to the peritoneal serose. Nevertheless, no statistical differences were observed between loss of weight (as a toxicity indicator) by Casiopeina III-ia-treated and control groups. Chakraborty et al.232 performed a study on N-methyl-Nnitroso urea (MNU) treated rat breast tumor model to test the efficacy of complex 68 (see section 2.5.4, Figure 50) in the in vivo system. This compound was picked up among a series of mononuclear copper complexes having a Schiff base ligand containing two pyridine donors, one imine donor, and various monodentate ligands. The results on rat breast tumors revealed, after 1 month of 68 treatment (1 mg/kg, twice a week), a 2.5fold decrease in tumor growth rate and 2-fold increase in tumor doubling time with respect to cisplatin, tested under similar conditions. 68 induced apoptosis in breast tumors mainly through involvement of the caspase pathways. Interestingly, the prominent anticancer properties of 68 appeared more relevant due to its marginal systemic toxicity. Actually, 68 did not show any hemotoxic effect and clinical toxicity like lethargy or weight loss, and histological analysis of liver and kidney showed no signs of toxicity. The antitumor properties of a series of copper complexes containing as Schiff base ligand the bis(3-acetyl-coumarin)thiocarbohydrazone (see section 2.5.2, Figure 46) have been investigated using the EAC model.223 Copper complexes significantly prolonged the mean survival times with respect to controls; however, they were much less efficacious than cisplatin, used as standard drug. More recently, the same authors examined the antitumor effects induced by a novel Dglucopyranose-4-phenylthiosemicarbazide copper(II) complex 13 (see section 2.1.2; Figure 12) using the same in vivo EAC tumor model. 13 Exerted a significant activity against the EAC model. With respect to control animals, 13 (administered at 50 mg/kg, every 2 days after tumor transplantation) reversed the tumor-induced changes in the parameters monitored, viz. percentage increase in lifespan, tumor viable count, and hematological parameters. These effects were almost comparable but always less pronounced than those obtained with cisplatin administered at 3.5 mg/kg every 2 days after tumor transplantation.116 Copper(II) complexes comprising a N,N-bidentate Schiff base and benzenedithiolate (see section 2.5.1) distinguished themselves as more interesting derivatives against the EAC model.215 In particular, complex 61b (Figure 44) tested at a dose of 100 mg/kg/day, po, doubled the median survival time of EAC bearing mice with respect to controls. Moreover, analysis of the hematological parameters showed minimum toxic effects in copper complex-treated mice. Fourteen days after transplantation, copper complexes were all able to reverse the changes in the hematological parameters consequent to tumor inoculation. Finally, the inhibitory effect against a MNU-induced rat mammary carcinoma for a series of supramolecular Cu/Sn heterometallic polymers has been recently described (see section 2.4.6; Figure 42a).209 55b administered daily (5 days) at the maximum tolerated dose of 4.3 mg/kg of body weight suppressed tumor growth by 52.3% compared to vehicletreated control. However, this inhibition rate was lower than that induced by etoposide (71.8% inhibition with a 30 mg/kg dose on days 1, 5, 10, and 15), which was used as a reference clinical anti-breast cancer agent. 851

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complexes are thoroughly characterized and preliminarily tested by in vitro screening on several human cancer cell lines and/or DNA binding studies. In this frame, particular attention has been focused on Cu(II) complexes including N,N-diimine ligands (and other extended aromatic planar systems comprised in thiosemicarbazone or Schiff base assemblies) due to their efficient DNA binding/intercalating action that often induces cytotoxicity at the nanomolar level. Among the factors that influence the cytotoxic activity, the planarity of N,N-diimine ligands plays a determinant role, as demonstrated by the higher efficacy shown, for example, by phen derivatives compared to bipy ones. Although the ability to induce DNA damage is the primary mechanism by which these copper complexes (and many other conventional chemotherapeutic agents) act, this antiproliferative process does not always guarantee selective cytotoxicity to cancer cells. Furthermore, compounds that can attack cancer intefering with biological processes other than DNA replication should represent good alternatives for treating tumors refractory/resistant to conventional platinum drugs. Therefore, the search for intracellular targets other than DNA and possibly cancer specific is a major challenge. Only a few studies focused on identification of potential novel targets and/ or on delineation of alternative mechanism(s) underlying the cytotoxic action of copper drugs, but cellular constituents such as topoisomerases or the proteasome multiprotein complex are emerging as new putative targets. The molecular basis of these new metal−target interactions are still elusive, but several studies have demonstrated that the antiproliferative effects of copper compounds rely on the impairment of topo (I,II) or proteasome activity. A better understanding of these mechanisms should enable the rational design of new anticancer copper complexes more specific and useful in overcoming drug resistance. Several copper complexes such as those containing (i) N,Odonor systems (carboxylate174 and phenol analogues to 8hydroxyquinoline162,164), (ii) κ2S,N Shiff base systems,229 and (iii) P-donor phosphine systems295 exhibited good selectivity against tumor vs nontumor cells. In addition, various copper(I,II) derivatives efficiently overcome cisplatin resistance. Examples include complexes containing TSCs,87 DTCs,120 pyrazoles,188 indoles,207,208 and pyridine-236 and pyrazolebased240 ligands. Noteworthy, several phosphine copper(I) complexes, besides not showing cross-resistance with first- and second-generation platinum drugs, overcome multidrug resistance.11,12,295 In spite of these encouraging perspectives, the transfer of in vitro studies into in vivo models remains poorly practiced. It is well recognized that a pure in vitro screening methodology is not sufficient to delineate clinical activity, particularly because pharmacokinetics have a major impact on pharmacodynamic activity. Data derived from in vivo model systems are necessary to ensure that drug concentrations inhibiting target and cancer cell proliferation can be reached. Moreover, in the few in vivo reports, the tumor models were uncharacterized (syngenic/ xenografts models) and therefore not really clinically relevant and molecularly characterized. To the best of our knowledge, there are no copper(I,II) coordination compounds entering phase I clinical trials.431 Currently, there is an ongoing clinical trial (phase I) of a copper mixture based on coadministration of disulfiram and copper gluconate for treatment of refractory solid malignancies, carried out by the Huntsman Cancer Institute, Utah (US).432

Comparing the extensive literature regarding the use of existing clinical drugs and development of novel chemical entities based on platinum, the field of anticancer copper complexes seems only at an infancy stage, even though it shows much promise for future development. Actually, copper complexes offer the potential over platinum(II) complexes of reduced toxicity, a novel mechanism of action, a different spectrum of activity, and the prospect of non-cross-resistance. On the other hand, numerous challenges and hurdles at different stages of development exist before a new drug can reach the clinic. Just think that even though over the last 40 years more than 10 000 platinum complexes have been prepared, these efforts have brought only five drugs into clinical use and 10 more complexes are currently under clinical trial investigation.433−435 In the authors’ opinion, in light of the above-mentioned chemical and biological properties, copper complexes containing S-donor systems (e.g., DTCs, TSCs, κ2-S,N-Schiff bases) or phosphine ligands seem to be the most promising derivatives that should deserve further investigation in in vivo experiments followed eventually by clinical trials. Moreover, integration of empirical screening approaches with novel knowledge emerging from genome and proteome research as well as bioinformation technologies might be the most efficient way forward in order to identify other promising targets and gain molecular insights into the mechanism of action of copper species. This information may hopefully allow a move away from the mere synthesis of cytotoxic agents, with unknown mechanisms of actions, to rational design of copperbased anticancer therapeutics.

AUTHOR INFORMATION Corresponding Authors

*E-mail: [email protected] *E-mail: [email protected] Author Contributions

This manuscript was written through contributions of all authors. All authors contributed equally, and all authors have given approval to the final version of the manuscript. Notes

The authors declare no competing financial interest. Biographies

Carlo Santini was born in 1967 in Roccafluvione, Ascoli Piceno, Italy. He obtained his degree in Chemistry with full marks and honours in 1993 and received his Ph.D. degree in Chemical Sciences from the University of Camerino in 1997. In 1999 he was appointed Researcher, 852

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and in 2006 he became Associate Professor of General and Inorganic Chemistry at the University of Camerino, School of Science and Technology. Currently, he serves as Coordinator of the Doctoral Course in Chemical and Pharmaceutical Sciences and Biotechnologies of the School of Advanced Studies of the University of Camerino. His major research interests are in synthetic inorganic and organometallic chemistry, including coordination chemistry, molecular chemistry, reactive intermediates, metal-based drugs, metals in medicine, and biological processes. His current research interest focuses on development of novel group 11 metal-based drugs acting as anticancer agents.

activity as a recipient of two postdoctoral fellowship grants. Part of her research has been developed at the Department of Laboratory Medicine, Pathology Division of Karolinska Institutet Hospital, in Stockholm under the direction of Professor M. Björnstedt. From 2012 she has been Assistant Professor at the Department of Pharmaceutical and Pharmacological Sciences of Padova University. She is a member of the Interuniversity Society for Research on Metal Chemistry in Biological Systems (Bari, Italy). Her research interests are focused on development of target-specific metal-based antitumor agents and aim at evaluation of cytotoxic/genotoxic activity, in vivo anticancer effects, and elucidation of their mechanism of action.

Maura Pellei was born in 1969 in Ascoli Piceno, Italy. In 1993 she obtained her degree in Biological Sciences with full marks and honour at the University of L’Aquila; in 2003 she obtained her degree in Chemistry, with full marks and honour, and in 2009 she obtained her Ph.D. degree in Chemical Sciences at the University of Camerino. From 1993 to 1994 she worked in the Organic Chemistry research group at the University of L’Aquila, being a recipient of a fellowship from CNR. From 1995 she continued her research activity in the Inorganic Chemistry research group at the University of Camerino. Since 2007 she is Lecturer in General and Inorganic Chemistry and Bioinorganic Chemistry, and since 2011 she is working as Assistant Professor of General and Inorganic Chemistry at the School of Science and Technology, University of Camerino. Currently, she is Rector’s Delegate in Life Long Learning. Her research has been mainly focused on the synthesis of organometallic and coordination compounds. At present her main research efforts involve the synthesis of group 11 metal complexes and their biological evaluation as potential anticancer compounds.

Marina Porchia was born in 1958 in Venice, Italy. She studied Industrial Chemistry at the University of Venice, where she graduated in 1983. In 1984 she joined the Italian National Research Council (CNR) as a researcher in the field of organometallic chemistry of uranium and thorium. In 1988 she did postdoctoral work at Northwestern University under the direction of Professor Tobin J. Marks. Currently, she is Senior Researcher at the Institute for Energetics and Interphases of CNR in Padua. Her research has been mainly focused on synthesis of organometallic and coordination compounds as precursors in material sciences (Ga, In, Ti, and Zr derivatives) or diagnostic or therapeutic agents (Re and Tc derivatives). At present her main research interests include design, synthesis, and biological evaluation of metal-based complexes, in particular, copper and silver compounds, as potential anticancer drugs.

Francesco Tisato was born in 1955 in Padova, Italy. In 1981 he graduated in Chemistry at the University of Padova. In 1984 he joined the public research agency Consiglio Nazionale delle Ricerche (CNR) in Padova as a researcher working in the field of coordination chemistry. He did postdoctoral work at the Massachusetts Institute of Technology in 1986 and at the University of Cincinnati in 1990 studying the coordination chemistry of technetium and rhenium and their application in Nuclear Medicine as radiodiagnostic and

Valentina Gandin was born in 1980 in Padova, Italy. In 2005 she obtained her degree in Pharmaceutical Chemistry and Technology, and in 2009 she obtained her Ph.D. degree in Molecular Sciences at Padova University. From 2009 to 2012 she continued her research 853

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BEL-7404 BT-20 C13 or C13* C6 Caco-2 Capan-1 CaSki CCRF-CEM CCRF-SB CH1 CNE2 DLD-1 DU145 EAC Eca-109 EVSAT GLC4 H1299 H226 H460 HCT-116 HCT-15 HCT-8 HeLa Hep-2 HepG2 HL-60 HOS Hs-683 HT1080 HT29 IGROV Jurkat T K562 KBM-5 K-MES-1 L1210 LMS LoVo M19 MCF-7 MDAH-2774 MDA-468 MDA-MB-231 MDA-MB-435 Mia PaCa-2 MOLT-4 NALM-6 NCI-H23 NCI-H460 OCI-AML2 OVCAR-3 P388 PC3 REH SKOV-3 SF295 SGC-7901 SH-SY5Y SiHa SK-BR-3 SK-II SK-N-DZ

radiotheraupetic agents. He currently works as Senior Researcher at IENI-CNR Institute in Padova, Italy, in the research group “Metal ions in life sciences”. His research interests comprise drug design in the field of copper-based antitumor agents and radiopharmaceuticals (99mTc, 188Re, 64Cu, and 68Ga).

Cristina Marzano was born in 1966 in Venice, Italy. In 1991 she obtained her degree in Pharmacy (magna cum laude), and in 1995 she obtained her Ph.D. degree in Pharmaceutical Sciences from the University of Padua, Italy. In 1994 she worked as a visiting research scientist at the Centre de Recherches Contre le Cancer of the Institute Curie (Paris, France) under the direction of Professor D. Averbeck focusing on the study of furocoumarin analogues as anticancer agents. From 1995 to 1997 she continued her research activity as the recipient of a 3-year grant from AIRC (Associazione Italiana per la Ricerca sul Cancro, Milano, Italy), studying the antitumor properties of novel topoisomerase II inhibitors. Since 1997 she has been working as Assistant Professor of Toxicological Chemistry at the Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Italy. Her research interests include drug design and discovery, medicinal and toxicological chemistry, and molecular and cellular biology. Her recent research has focused on development of novel metal-based drugs (in particular, copper complexes) acting as anticancer agents.

ACKNOWLEDGMENTS This work was financially supported by the University of Camerino (Fondo di Ateneo per la Ricerca 2011-2012) and University of Padova (Progetto di Ateneo CPDA121973/12). We are grateful to CIRCMSB (Consorzio Interuniversitario di Ricerca in Chimica dei Metalli nei Sistemi Biologici). ABBREVIATIONS Acronyms of Cancer Cell Lines Cited in This Review

2008 41M 786-0 8MGBA A2780 A2780R A375 A431 A431/Pt A498 A549 B16 BEL-7402

human ovarian carcinoma human ovarian carcinoma human renal carcinoma human glioblastoma multiforme human ovarian carcinoma human cisplatin-resistant ovarian carcinoma human melanoma human epidermoid carcinoma human cisplatin-resistant epidermoid carcinoma human kidney carcinoma human nonsmall cell lung carcinoma mouse melanoma human hepatocellular carcinoma 854

human hepatocellular carcinoma human breast carcinoma human cisplatin-resistant ovarian carcinoma rat glioma human colon carcinoma human pancreatic carcinoma human cervical carcinoma human acute lymphoblastic leukemia human acute lymphoblastic leukemia human ovarian carcinoma human nasopharyngeal carcinoma human colon carcinoma human prostate carcinoma mouse Ehrlich ascites carcinoma human esophageal carcinoma human breast carcinoma human small cell lung carcinoma human nonsmall cell lung carcinoma human nonsmall cell lung carcinoma human nonsmall cell lung carcinoma human colon carcinoma human colon carcinoma human colon carcinoma human cervical carcinoma human larynx carcinoma human hepatocellular carcinoma human promyelocytic leukemia human osteosarcoma human glioma human fibrosarcoma human colon carcinoma human ovarian cancer human acute T-cell leukemia human chronic myelogenous leukemia human chronic myelogenous leukemia human squamous lung carcinoma mouse leukemia human leiomyosarcoma human colon carcinoma human melanoma human breast carcinoma human ovarian cancer human breast cancer human breast carcinoma human breast carcinoma human pancreatic carcinoma human acute lymphoblastic leukemia human pre-B cell leukemia human nonsmall cell lung carcinoma human nonsmall cell lung carcinoma human acute myeloid leukemia human ovarian carcinoma mouse leukemia human prostatic carcinoma human lymphocytic leukemia human ovarian carcinoma human glioblastoma human gastric carcinoma human neuroblastoma human cervical cancer human breast carcinoma human skin carcinoma human neuroblastoma dx.doi.org/10.1021/cr400135x | Chem. Rev. 2014, 114, 815−862

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human nonsmall cell lung cancer human hepatocellular carcinoma human colon carcinoma human colon carcinoma human colon carcinoma human bladder carcinoma human colon carcinoma (Caco-2 subclone) human osteosarcoma human glioma human glioma rat osteosarcoma human colon carcinoma human melanoma human breast carcinoma

Acronyms of Nonmalignant Cell Lines Cited in This Review

Balb/c 3T3 Chang GM05757 HaCaT HEK 293T HEK293 L929 MC3T3-E1 MCF-10A MCF-12A MDBK NIH 3T3 V79

mouse embryonic fibroblasts human liver epithelial cells human fibroblasts human keratinocytes human embryonic kidney cells human embryonic kidney cells mouse fibroblasts mouse preosteoblasts human mammary gland epithelial cells human mammary gland epithelial cells Madin−Darby bovine kidney cells mouse embryonic fibroblasts Chinese hamster lung fibroblasts

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