Contemporary Challenges in the Design of Topoisomerase II Inhibitors

Review pubs.acs.org/CR

Contemporary Challenges in the Design of Topoisomerase II Inhibitors for Cancer Chemotherapy Christian Bailly* Centre de Recherche et Développement, Institut de Recherche Pierre Fabre, 3 Avenue Hubert Curien, BP 13562, 31035 Toulouse cedex 1, France 1. INTRODUCTION The length of straightened-out DNA in a single cell is nearly 2 m. In mammalian cells, the nucleus has a diameter of approximately 6 μm and occupies about 10% of the total cell volume. Therefore, DNA must be packaged into cells in a highly compacted state to fit inside the small space of the cell nucleus. To do this, cells wrap their DNA strands around scaffolding proteins to form a coiled condensed structure: chromatin, which is further folded into higher orders of structure, the chromosomes. Cells exert control over the compactness of the chromatin structure as a mean to regulate gene expression. Genes in tightly condensed regions (heterochromatin) are not as accessible for gene expression. In CONTENTS contrast, genes in more accessible, lightly packed chromatin 1. Introduction 3611 regions (euchromatin) are actively transcribed. Euchromatin 2. Novel Synthetic Topoisomerase II Inhibitors 3613 and heterochromatin are functional compartments of the 3. Novel Naturally Occurring Topoisomerase II genome, distributed in many different territories within the Inhibitors 3617 nucleus. In humans, regions surrounding centromeres and 4. Epipodophyllotoxins Forever 3622 telomeres are heterochromatic whereas large parts of the 4.1. Forty Years of Etoposide Therapy 3622 chromosome arms consist of transcriptionally competent 4.2. Recent Epipodophyllotoxin Derivatives: euchromatin. In each compartment, heavily crowded with From Research to the Clinic with New proteins and with a fractal-like organization,1 the genome is not Epipodophyllotoxins 3623 static but constantly manipulated and read. Despite the 4.2.1. Research 3623 enormous degree of compaction, DNA must be rapidly 4.2.2. Clinic 3624 accessible to permit its interaction with protein machineries 5. New Topoisomerase II Poisons in Clinical Develthat regulate the different functions of chromatin, such as opment 3625 replication, repair, and recombination. Many proteins are 5.1. Vosaroxin (Formerly SNS-595, AG-7352, ATinvolved in the control of DNA accessibility. The prominent 3639, or Voreloxin) 3625 class is that of topoisomerases, a family of enzymes that 5.1.1. Chemistry 3625 manipulate DNA topology, such as knots, tangles, and 5.1.2. Pharmacology 3626 catenanes, remaining on DNA after replication or transcription. 5.1.3. Clinical Development 3626 Topoisomerase II is arguably the second most abundant 5.2. C-1311 (Symadex) 3627 chromatin protein after histones.2 5.2.1. Chemistry 3627 DNA topoisomerases are classified into two categories. 5.2.2. Pharmacology 3627 Monomeric type I enzymes catalyze the formation of DNA 5.2.3. Clinical Development 3628 single-strand breaks. Multimeric type II enzymes engender 5.3. R(+)XK469 (NSC 698215) 3629 DNA double-strand breaks (DSBs). In both cases, enzymes are 5.3.1. Chemistry 3629 subclassified into two groups, IA/B and IIA/B, according to 5.3.2. Pharmacology 3629 their specific structures and mechanisms of action. There are 5.3.3. Clinical Development 3629 several recent comprehensive reviews detailing the molecular 6. Conclusion and Perspectives 3630 architecture of these enzymes and the protein regulators of Author Information 3633 their activity on DNA in cells.3−5 Structural studies based on XCorresponding Author 3633 ray crystallography data have greatly helped to understand the Notes 3633 intrinsic mechanism of the topoisomerase machinery and Biography 3633 provided a structural basis for understanding drug action, for Acknowledgments 3633 both antibacterial drugs targeting DNA gyrase or topReferences

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Received: August 20, 2011 Published: March 8, 2012 © 2012 American Chemical Society

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dx.doi.org/10.1021/cr200325f | Chem. Rev. 2012, 112, 3611−3640

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Figure 1. Structures of the three clinically used prototypic topoisomerase II inhibitors (top) and three inhibitors currently in clinical development (bottom).

oisomerase IV (two bacterial type IIA topoisomerases) and anticancer drugs targeting human topoisomerase II.6−9 The chirality and dynamics of the cleavage reaction are also better understood, with the help of in silico methods and miniaturized techniques.10−12 In particular, the repertoire of biological functions covered by DNA topoisomerase II has been analyzed in detail, providing a relatively precise knowledge of its many roles in cancer cells and its abundant protein partners.13,14 In this review, I will not focus on the enzymes per se but on their small molecule inhibitors, with a specific interest in topoisomerase II modulators as anticancer agents. The search for selective inhibitors of this enzyme was initiated a long time ago and led to the development and use of four major chemical families of anticancer drugs:15 (i) Epipodopodophyllotoxins, with etoposide (VP16, Figure 1) as the major representative of the group. Etoposide has been approved for the treatment of lung cancer, choriocarcinoma, ovarian and testicular cancers, lymphoma, and acute myeloid leukemia. The other member of this group, teniposide (VM-26), is approved for central nervous system tumors, malignant lymphoma, and bladder cancer.16 (ii) Anthracyclines, which represent a rich family of natural products isolated from microorganisms. The prominent members of this group include doxorubicin (Figure 1), daunorubicin, and idarubicin, used for the treatment of a variety of solid tumors and hematologic cancers. Novel generation of anthracyclines is continuously studied and tested in humans: valrubicin, pirarubicin, amrubicin, sabarubicin, berubicin, .... The anthracycline saga continues. (iii) Anthraquinones, typified by the blue drug mitoxantrone (Figure 1) used for the treatment of advanced prostate cancer and certain forms of leukemia, for example (and for the treatment of multiple sclerosis). Novel mitoxantrone derivatives with reduced cardiotoxicity have been proposed17 as well as modern anthracenediones with a reinforced capacity to form stable, covalent complexes with DNA.18,19

(iv) Acridines, represented by the drug amsacrine, which is now less frequently used in oncology but still available for the treatment of leukemia essentially. These four categories of molecules are classified as topoisomerase II poisons in the sense that they lead to the accumulation of DNA double-strand breaks. They disrupt the normal catalytic cycle of the enzyme by stabilizing the intermediate state of the enzyme−DNA complex (the so-called “cleavable” or cleavage complex) where the topoisomerase II enzyme is covalently linked to the cleaved two strands of the DNA through phosphor−tyrosine linkages. By inhibiting the religation reaction or by increasing the forward cleavage reaction, these poisons enhance the level of topoisomerase II−DNA covalent complexes and then the level of DNA double-strand breaks in cells. If they are not repaired, these breaks are rapidly lethal as cells replicate their DNA. Activation of the DNA damage response pathway leads, in most cases, to drug-induced apoptosis and/or to cell cycle arrest in the G1, S, and G2 phases. Depletion of the two isoforms of mammalian topoisomerase II (α and β) increases the duration of the cell cycle and mitosis, interferes with chromosome condensation and sister chromatid segregation, and leads to frequent failure of cell division, ending in either cell death or restitution of polyploid cells.20 Here again, there are recent well-documented reviews on these aspects of enzyme regulation and topoisomerase II-mediated cell death that I will not detail here.21 Along with the topoisomerase II poisons, there are also small molecules that can regulate the activity of topoisomerase II without interfering directly with the cleavable complex. They act by preventing binding of topoisomerase II to DNA (aclarubicin, suramin), blocking the ATP-binding site of the enzyme (novobiocin, salvicine), or inhibiting the cleavage reaction (merbarone, bisdioxopiperazines). These molecules are generally designated as catalytic inhibitors of topoisomerase II. This latter heterogeneous category of products includes very common drugs such as sodium salicylate22 and a very few approved anticancer drugs, such as the cardioprotective agent dexrazoxane (ICRF-187), which antagonizes doxorubicininduced DNA damage via a complex mechanism implicating 3612


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Figure 2. Synthetic topoisomerase II inhibitors.

better tolerated. Fifth, novel strategies to target topoisomerase II could represent an efficient approach to the treatment of certain forms of cancers. Sixth, via the design of novel molecules, these pharmacological studies contribute to a better understanding of the mode of action of the known topoisomerase II inhibitors and then a more rational clinical use of topoisomerase II-targeted approved drugs, via the design of safer drug combinations, for example, or newer treatment modalities (new treatment schemes, oral formulations). For all these reasons, the search for novel small molecules directed against topoisomerase II remains an active domain in oncopharmacology, and it is the objective of this paper to review the different types of molecules recently described as topoisomerase II-interfering anticancer agents. As illustrated below, topoisomerase II remains an attractive target for drug development.

iron chelation (involved in the production of anthracyclinedependent reactive oxygen species) and a direct trapping of the topoisomerase IIβ isoenzyme predominantly present in nonproliferating cells such as cardiac cells and neurons.23,24 However, this compound is not frequently used in the clinic, even if it is clearly demonstrated that dexrazoxane provides long-term cardioprotection without compromising oncological efficacy in doxorubicin-treated children with high-risk leukemia.25 Several potent and approved topoisomerase II inhibitors are thus available for the treatment of cancers. These drugs were essentially discovered in the 1960s and 1970s, and their clinical use tends to decrease with the advance of newer anticancer drugs more specificat least at the cellular leveltoward cancer cells. Targeted therapeutic agents, principally kinase inhibitors and monoclonal antibodies, are now the leading classes of antitumor agents, and they contribute to limiting the prescription of conventional cytotoxic agents, including topoisomerase II inhibitors. Therefore, do we need today new drugs targeting topoisomerases? The question is even broader: do we need novel cytotoxic agents? This question is regularly discussed.26 Again today the answer remains a definitive yes, for several reasons briefly evoked here. First, many forms of cancers are still devastating, and the use of potent cytotoxic agents is frequently the only remedy to limit rapid tumor growth, progression, and metastasis. Second, targeted therapeutics are essentially used in combination with cytotoxics, especially for the treatment of advanced solid tumors. Third, the unfortunately frequent development of clinical drug resistance leads to the use of drug cocktails and the change of drug regimens during a prolonged treatment. Fourth, approved topoisomerase II inhibitors, essentially topoisomerase II poisons, are efficient but produce detrimental secondary effects (myelosuppression, leucopoenia, gastrointestinal toxicities, alopecia, and even secondary leukemia in some cases). It would be useful to design newer products more potent and

2. NOVEL SYNTHETIC TOPOISOMERASE II INHIBITORS A large diversity of natural compounds and synthetic products interfering with topoisomerase II functions have been described as topoisomerase II inhibitors. Following is an update of the molecules recently reported in the literature. For the sake of convenience, I will first refer to synthetic molecules, prior to discussing the natural products. I selected 16 series of compounds to illustrate the diversity of synthetic topoisomerase II inhibitors proposed in recent years: (i) Benzoxanthone derivatives27 with a linear or curved tetracyclic core equipped with one or two epoxy- or thioepoxy-containing side chains to anchor to DNA. A representative example of the series is presented in Figure 2: compound 1 is a topoisomerase II inhibitor, whereas the equivalent bisepoxy derivative is a DNA cross-linker (and it is more cytotoxic than compound 1). Similar xanthone derivatives supporting a halohydrin group have been reported to function as both DNA 3613


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oisomerase II with an IC50 of 1.7 μM, whereas an N9methyl analogue proved to be inactive, supporting the idea that the N9 position is engaged in a direct hydrogen bond with the enzyme (Asn120 residue). The N-terminal ATP-binding domain of human topoisomerase II is conserved evolutionally and belongs to the GHKL (gyrase, HSP90, histidine kinase, MutL) family.44 Although no biological activity was reported for this compound, the study illustrates the utility of a structurebased drug design strategy to identify novel topoisomerase II regulators. The mode of action of compound 5 is comparable to that of the purine derivative 8-chloroadenosine triphosphate (8-Cl-Ado), which prevents the catalytic activity of topoisomerase II in K562 leukemia cells by inhibiting ATP hydrolysis and stabilizing the closed clamp form of the enzyme.45 This ribosyl nucleoside analogue is currently in phase I testing for the treatment of chronic lymphocytic leukemia (CLL).46 A close analogue of compound 5, designated QAP 1, also incorporating a purine scaffold substituted with a quinoline residue (Figure 2), functions as a catalytic inhibitor of both topoisomerases IIα and IIβ in a cell-free assay and in a cellular context. Interestingly, BRCA1 mutant cells display increased sensitivity to the drug.47 Such a catalytic inhibitor may exhibit less side effects compared to topoisomerase II poisons. (v) Anilinothiazoloquinolines.48 Structurally, these molecules derive from the reference topoisomerase II poison amsacrine, with a similar planar tricyclic nucleus for DNA binding and an orthogonal aniline moiety possibly contacting the enzyme. A modest inhibition of kinetoplast DNA decatenation was observed with some compounds, such as compound 6 (Figure 2), which is also poorly cytotoxic. (vi) Benzophenanthridines are classical topoisomerase inhibitors, interfering with topoisomerase I or more rarely topoisomerase II, in addition to binding to DNA. The most potent topoisomerase II poison in the series is certainly the benzo[c]phenanthridine derivative NK314 (Figure 2), which robustly stabilizes topoisomerase II− DNA cleavable complexes.49,50 This molecule has revealed potent anticancer activities in vitro and in vivo and was advanced to human clinical trials in Japan. It produces extensive DNA damage in tumor cells, with an efficacy superior to that of etoposide and doxorubicin. NK314 specifically targets the α isoform of topoisomerase II51 and activates certain serine proteases and nucleases to degrade cellular DNA extensively. It is in fact a dual inhibitor of topoisomerase IIα and DNAdependent protein kinase (DNA-PK), particularly active in adult T-cell leukemia and lymphoma.52 Both DNA-PK and ataxia telangiectasia mutated (ATM) contribute to cell survival in response to NK-314.53 This is perhaps why NK314 showed an antitumor activity in xenograft models (e.g., ovarian tumor OC-09-JCK) insensitive to etoposide and doxorubicin. This superior therapeutic efficiency, coupled with its satisfactory pharmaceutical properties, makes NK314 an interesting drug candidate for human clinical trials. (vii) Nitrofurans.54 In the course of a screening campaign aimed at identifying modulators of the estrogen signaling pathway, different nitrofuran derivatives were selected. Additional studies revealed that these molecules were

alkylators and topoisomerase II inhibitors.28,29 In a similar design strategy, retrochalcone derivatives equipped with bisthioepoxide functions were described as moderately potent topoisomerase II inhibitors.30 (ii) Trisubstituted pyridines.31,32 Unfused tetracyclic molecules with a central pyridine ring substituted with three distinct branches were designed as topoisomerasetargeted anticancer agents. Among a group of 60 molecules synthesized, many were found to interfere with topoisomerase II activity, such as compound 2 (Figure 2), which inhibited topoisomerase II-mediated DNA relaxation by 50% at 20 μM. These propellershaped molecules also exert cytotoxic activities toward different cancer cell types, but no direct correlation could be determined between inhibition of topoisomerase II activity and cell proliferation. Additional side chains to reinforce the interaction with the DNA and/or the enzyme (and to increase water solubility) would certainly be useful. Other series of pyridine analogues have been recently described,33,34 including dual inhibitors of topoisomerases I and II such as compound 3 (Figure 2).35 The most recent series includes 2,4-diarylchromenopyridines, such as compound 4 (Figure 2),36 and 2,4diaryl-5,6-dihydrothienoquinoline derivatives,37 which exhibited a significant but globally modest inhibitory activity against topoisomerase II. (iii) Thiosemicarbazones.38 The lead compound in a series of thiosemicarbazone derivatives bearing condensed heterocyclic carboxaldehyde moieties is the quinoline-containing compound TSC24 (Figure 2), which functions both as an iron chelator and a topoisomerase IIα catalytic inhibitor. The molecule directly interacts with the ATPase domain of the enzyme to block ATP hydrolysis. The dual activity translates into a potent antiproliferative activity toward tumor cells, with IC50 in the range of 20− 90 nM. TSC24 is not cell type selective but has the capacity to overcome multidrug resistance (MDR). Binding of TCS24 to the ATPase domain of topoisomerase II, as judged from surface plasmon resonance measurements, provides a novel route to the rational design of a selective catalytic inhibitor. The same mechanism of action was invoked with the thiosemicarbazone derivative Dp44mT (Figure 2). This ironchelating agent induces DNA double-strand breaks in tumor cells via a selective poisoning of topoisomerase IIα. Interestingly, Dp44mT exacerbates the cytotoxicity of doxorubicin via a distinct action on the cell cycle. A dual mode of action, iron chelation and topoisomerase II inhibition, may turn out to be clinically useful.39 Its antitumor activity is apparently mediated by formation of a redox-active copper complex that accumulates in lysosomes.40 This molecule is not a cardioprotectant against doxorubicin-induced toxicity but is of a potential interest for inhibiting the growth of a broad range of malignant cell types while exhibiting very low intrinsic toxicity to healthy tissues.41 A more potent antitumor analogue, Bp44mT active orally, has been recently designed and characterized.42 (iv) Purine analogues.43 A structure-based approach to discover small molecules binding to the ATP-binding site of topoisomerase II led to the identification of purine derivatives, such as compound 5 in Figure 2. This synthetic ligand inhibits the ATPase activity of top3614


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Figure 3. Naphthalimide-based topoisomerase II inhibitors.

• Second, with derivatives targeting the ATPase domain of topoisomerase IIα, such as the pentacyclic amonafide derivative R16 (Figure 3). R16 induces G2 cell cycle arrest and apoptosis in a topoisomerase II-dependent manner 64 and through the ATM-activated Chk2-executed pathway.65 This R16 compound bears a structural resemblance to the tetracyclic derivative ethonafide (AMP-53 or 6-ethoxyazonafide, Amplizone), which has been characterized as a topoisomerase IIα-specific inhibitor in a prostate cancer cell line,66 potentiated by the proteasome inhibitor bortezomib.67 Ethonafide, which is less cardiotoxic than mitoxantrone, also exhibits immunosuppressive properties and has shown activity in an animal model of multiple sclerosis.68 • Third, via the design of agents that have the features of both DNA intercalators and lysosomotropic detergents. This has been achieved by attaching to the naphthalimide ring at the 2- and 6positions long alkyl side chains acting as lysosomal membrane permeabilizers. For example, compound 7 of this series (Figure 3) revealed an inhibitory effect on topoisomerase II-mediated decatenation of kinetoplast DNA, coupled with an induction of lysosomal membrane permeability. This dual action concurs to marked proapoptotic and cytotoxic effects.69 This strategy may be profitable providing that a selective action on cancer cells versus normal cells can be induced. A related compound, designated 7-b (Figure 3), incorporating a dodecylamino side chain on the benzo[de]isoquinoline chromophore, was found to cause inhibition of growth and apoptosis of Raji lymphoma cells via a reactive oxygen species (ROS)-mediated mitochondrial pathway.70 • Fourth, by screening series of amonafide analogues capable of overcoming chemoresistance. In this program, the aminothiazonaphthalimide B1 (Fig-

also capable of inhibiting topoisomerase II, without inducing DNA double-strand breaks in contrast to etoposide. These molecules, designated Thanatops (from the Greek work thanatos (death) and top for topoisomerase) and in particular the lead molecule EMBL153441 (Figure 2), induce cell cycle arrest in the G0−G1 phase of the cell cycle and are not substrates for the MDR export system. The anticancer activity in vivo was found to be marginal, at least when using a xenograft model of lung cancer, but nevertheless this family of molecules warrants further studies to better appreciate their potential as therapeutic agents. (viii) Naphthalimides represent an important chemical class of DNA-intercalating topoisomerase II inhibitors.55,56 The most active drugs in this series were amonafide and mitonafide, both tested in humans as anticancer agents. In particular, amonafide (AS-1413, xanafide, Figure 3) showed encouraging properties as an antileukemia drug candidate, unaffected by P-glycoprotein-mediated efflux, which is a common mechanism of drug resistance encountered in the treatment of patients with acute myeloid leukemia (AML).57 An improved antileukemic activity has been observed when amonafide is associated with cytarabine, with a complete remission rate of 40% in a recent phase II trial in secondary AML,58 but apparently, its clinical development has been terminated, on account of central neurotoxicity and/or limited efficacy. However, the search for more efficient and better tolerated analogues continues in at least five directions. • First, via derivatives with higher DNA-binding affinity, for example, by attaching a homospermidine motif to the naphthalimide nucleus.59−61 The 3-nitronaphthalimide−norspermine conjugate NPC-16 (Figure 3) triggers both apoptosis and autophagy in hepatocecllular carcinoma HepG2 cells.62 Attachment of a photosensitive phenyltriazolyl side chain has also been described as a means to trigger DNA photocleavage.63 3615


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Figure 4. Additional synthetic topoisomerase II inhibitors.

than doxorubicin, presumably because, in contrast to doxorubicin, it does not generate reactive oxygen species at the heart level.80 The mechanism of action of HU-331 is still unclear. It may function by thiol depletion via conjugation with glutathione,81 but its primary target seems to be topoisomerase II. Indeed, this compound is a highly potent topoisomerase II catalytic inhibitor, even at nanomolar concentrations.82 HU-331 inhibits tumor cell proliferation and exerts antiangiogenic properties by targeting vascular endothelial cells.83 Cannabidiol has revealed promising properties for the treatment of breast cancer metastasis.84 It may be of interest to further exploit the cannabinoid scaffold as a platform for the design of a specific catalytic inhibitor of topoisomerase II. (x) Benzofuroquinolinediones are tetracyclic compounds bearing a structural analogy with ellipticine. Some of the derivatives reported in this series were found to potently inhibit topoisomerase II with submicromolar IC50. This is a classical series of coplanar annulated polycyclic compounds, exhibiting robust antiproliferative properties.85 Similarly, different pyridophenazinediones have been characterized as topoisomerase II inhibitors,86 as well as triazolophthalazines87 and naphtothiophenediones.88 They all contain a planar chromophore with a quinone function and generally an appended cationic side chain. In general, they exhibit little or no tumor cell line selectivity, but interestingly, in the case of aminonaphtho[2,3-b]thiophenediones, the authors identified DNA-intercalating agents potently active against topoisomerase II, such as compound 9 (Figure 4), showing a greater cytotoxic potency than doxorubicin against chemo-resistant cancer cell lines, including melanoma and glioblastoma cells.88 (xi) Acridines represent a long-established class of DNAintercalating agents and include robust topoisomerase II poisons such as the antitumor drug amsacrine and the

ure 3) was selected on account of its capacity to cause DNA damage and inhibit cancer cell growth.71 B1 induces cell cycle arrest and apoptosis in HeLa cells via p53 activation72 and overcomes the resistance conferred by Bcl-2 in leukemia HL60 cells, via a drug-induced downregulation of the 14−3−3σ protein associated with the MBD2 signaling pathway.73 This topoisomerase II inhibitor also induces apoptosis and cell cycle G1 arrest in lung adenocarcinoma A549 cells.74 • Fifth, via the design of naphthalimide dimers. For many years, bisnaphthalimide derivatives susceptible to bisintercalate into DNA have been synthesized and evaluated as anticancer agents. This strategy has generated tumor-active compounds, and at least two of them, LU79553 (elinafide)75 and DMP-840 (bisnafide),76 were tested clinically, but without a marked success. However, this is still an option to design anticancer agents. Recently, a new bisnaphthalimide incorporating a long polyamine linker (compound 8 in Figure 3) was shown to exert potent cytotoxic activities coupled with topoisomerase II inhibitory effects.77 (ix) Cannabinoids are essentially known for their psychoactivities, but some of them also exhibit antiproliferative activities that might be exploited for the design of anticancer agents.78 Starting from cannabinol and cannabidiol (the most abundant nonpsychoactive cannabinoid in Cannabis sativa), p-quinone derivatives have been synthesized, and compounds endowed with potent cytotoxic and antitumor activities were obtained.79 The lead compound in the series is HU-331 (Figure 4), which is more potent and less cardiotoxic 3616


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small molecule quinacrine.89 Interestingly, the 9-aminoacridine chromophore can be diversely substituted to generate either topoisomerase II poisons or catalytic inhibitors. Series of cytotoxic and proapoptotic monoacridines capable of inducing topoisomerase II-dependent DNA breaks have been synthesized,90,91 but closely related series have produced catalytic inhibitors that also showed promising antiproliferative activities against cancer cell lines, in particular pancreatic and mesothelioma cell lines.92,93 Recently, acriflavine was described as a dual topoisomerase I and II inhibitor, active against colorectal cancer tumor cells,94 and other acridine-based catalytic inhibitors of human topoisomerase II were shown to suppress mesothelioma cell proliferation and induce apoptosis.93 Polysubstituted tetraacridine derivatives interfering with topoisomerase II as well as the proteasome have also been described,95 but in the acridine series, the reference compounds remain amsacrine mentioned above and its acridine-4-carboxamide cousin DACA (XR5000), which is a potent topoisomerase IIα inhibitor and has undergone phase I and II clinical trials in ovarian and non-small-cell lung cancers (NSCLC) but found essentially inactive.96,97 On the basis of the same design strategy to identify compounds incorporating a DNA-binding chromophore and a sequence-selective side chain, Baguley and coworkers recently proposed a related series of benzonaphthyridine derivatives, with the compound SN28049 (Figure 4) as the lead compound and potential clinical candidate. The cytotoxic properties of SN28049 are dependent on the expression of topoisomerase IIα. Its action is however complex, implicating poisoning of topoisomerase IIα, suppression of topoisomerase I, and inhibition of SP-1-regulated genes.98 This topoisomerase II poison has shown excellent antitumor activities in a melanoma xenograft model99 and in a murine model of colon adenocarcinoma, with a superior activity when compared to etoposide.100 A selective uptake and retention of SN28049 in the tumor was recently characterized.101 Platinum complexes can also interfere with topoisomerase II. The most recent exemple is that of a cyclometalated platinum(II) derivative capable of stabilizing the covalent topoisomerase IIα−DNA cleavage complex and inducing cancer cell death.102 Other platinum complexes acting on topoisomerase II have been described.103−105 Synthetic flavonoids such as the epoxy derivative MHY336 (Figure 4) active against prostate cancer cells, capable of inducing G2/M or S phase cell cycle arrest via a topoisomerase II-dependent mechanism.106 N-fused aminoimidazoles include a large series of bicyclic scaffolds, synthesized by multicomponent reactions, characterized as catalytic inhibitors of topoisomerase II, blocking the ATP-binding site. These molecules, such as compound 10 (Figure 4), exert cytotoxic and proapoptotic effects, and to a certain extent, they restrict cancer cell motility, at relatively high drug concentrations however.107 The coumarin derivative BNS-22 (Figure 4) characterized by an elegant proteomic approach as an antagonist of topoisomerase II-mediated DNA damage and which thus functions as a catalytic inhibitor.108 This

synthetic bicylic coumarin derives from the natural product GUT-70, a tricyclic coumarin isolated from the stem bark of the plant Calophyllum brasiliense (Guttiferae) collected in Brazil.109 GUT-70 was initially evidenced as a potent antileukemic and proapoptotic molecule and was recently shown to bind to the heat-shock protein 90 (hsp90) and to inhibit the proliferation of mantle lymphoma cells,110 but unlike GUT-70, BNS-22 bears a tetrahydroquinoline group appended to the coumarin moiety, and this group is essential for topoisomerase II inhibition. Analogues of BNS-22 with a modified tetrahydroquinoline group all failed to inhibit kinetoplast DNA decatenation by topoisomerase II. In cells, BNS-22 induces mitotic abnormalities causing polyploidy, a signature reminiscent of the catalytic inhibitor ICRF193.108 (xvi) The indole derivative BPR1H0101 (Figure 4), initially synthesized as a peroxisome proliferator-activator receptor (PPAR) agonist (dual PPARα/γ agonist) and which was shown to prevent the cytotoxic effects of etoposide in cancer cells. This bidentate molecule behaves as a catalytic inhibitor of topoisomerase II, inhibiting etoposide-induced cleavable complex stabilization, possibly via a direct interaction with the enzyme before the DNA cleavage reaction occurs.111 Antibacterial bisindole derivatives targeting topoisomerase II have also been described.112 These compounds are selected recent examples of topoisomerase II-interfering synthetic products. We could also cite ruthenium complexes,113−115 different mono- and bimetallic complexes,116−118 synthetic derivatives of the sesquiterpene lactone parthenin (compound 11, Figure 4),119 different indenoisoquinolindiones,120 benzimidazoles,121 pyridocarbazoles,122 carbazolyldihydro-β-carbolines such as compound 12 (Figure 4) derived from the β-carboline marine alkaloid manzamine A and considered as a DNA minor groove binding inhibitor of topoisomerase II,123 N-phenylmaleimides,124 βcarbolines derived from arborescidine alkaloids,125 anthracenediones such as compound M2 (Figure 4), which stabilizes the topoisomerase II cleavage complex and elicits a strong DNA damage response,126 furocarbazoles such as compound 13 (Figure 4),127 epoxyanthraquinones,128 C60 fullerene,129 cholesterol derivatives,130 propargylic enol ethers,131 bisanthrapyrazoles,132 and, to complete the list, the naphthoquinone adduct TU100 (Figure 4) characterized as a dual inhibitor of topoisomerases I and II, capable of targeting the enzyme in the absence of DNA,133 but all these compounds are essentially laboratory tools, not drug candidates. In addition, it is worth referring to synthetic derivatives of the marine alkaloid makaluvamines, in particular pyrroloquinoline derivatives described as topoisomerase II-interfering agents.134−136 A makaluvamine derivative, designated FBA-TPQ, is considered as a potential clinical candidate, but its antitumor action does not seem to depend on topoisomerase II inhibition.137,138 FBATPQ is suspected to exert its activity through ROS-associated activation of the death receptor, p53-MDM2, and PI3K-Akt pathways in ovarian cancer cells.139

3. NOVEL NATURALLY OCCURRING TOPOISOMERASE II INHIBITORS Over the past 3 years, a variety of natural products isolated from plants or microorganisms have been characterized as 3617


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Figure 5. Naturally occurring topoisomerase II inhibitors.

cell lines. It also displays significant antitumor activities in vivo.141 This triterpene glycoside has also been isolated from the sea cucumber Holothuria scabra and characterized as an antifungal agent.142 (iii) Glycosylated diphyllins, which are structurally similar to the podophyllotoxins. The diphyllin derivative D11 with an acetylated D-quinovose residue (Figure 5) was recently found to inhibit topoisomerase IIα but not topoisomerase I.143 The parent product diphyllin, a lignan isolated from Cleistanthus collinus, functions as a V-ATPase inhibitor, affecting the Wnt/β-catenin signaling pathway so as to inhibit the proliferation and induce apoptosis of human gastric cancer cells.144 Structure− activity relationships have been recently investigated in this series to show in particular that the sugar moiety is essential for the anticancer activity.145 (iv) Eleutherin (Figure 5) and derivatives.146 From a series of pyranonaphthoquinone compounds, a few inhibitors of human topoisomerase IIα were identified, such as ventoliquinone L and thysanone (Figure 5), both structurally close to eleutherin, which was previously characterized as a relatively potent inhibitor of the enzyme.147,148 No clear correlation could be established between topoisomerase II inhibition and toxicity toward cancer cells for this series of compounds, but this quinone archetype remains interesting for drug design. Important structure−activity relationships have been delineated. Interestingly, in this series dimeric compounds revealed potent antitopoisomerase II activity but possessed little or no cytotoxicity against the yeast Saccharomyces cerevisiae. Along the same lines, derivatives of the naphthoquinone lapachol and its tumor-active derivative α-lapachone have been synthesized as topoisomerase II inhibitors.149 α-Lapachone (Figure 5) is an effective antitopoisomerase II agent, and the design of

topoisomerase II inhibitors. In most cases, the inhibitory process was preliminarily characterized using a simple direct assay to evidence inhibition of either relaxation of a supercoiled plasmid DNA or decatenation of kinetoplast DNA by the purified enzyme in the test tube in the presence of the test compound. Less frequently, the effect was robustly evidenced using complementary assays based on the induction of DNA double-strand breaks in cells. Among naturally occurring compounds recently identified as topoisomerase II inhibitors, I chose 16 compounds or series, particularly potent or innovative or structurally new: (i) Albanol A (Figure 5).140 This polycyclic compound, also known as mulberrofuran G, has been isolated from the root bark of the plant mulberry (Morus alba L., Moraceae) cultivated in China and Japan. Leaves of this plant are used as food for silkworms. The compound displays potent cytotoxic activities against a variety of tumor cell lines, including leukemia and melanoma cells. Albanol triggers apoptosis in HL60 leukemia cells via both the death receptor and mitochondrial pathways. It is plausible that at least a part of this proapoptotic effect results from an inhibition of topoisomerases. Albanol modestly inhibits DNA relaxation by topoisomerase II (IC50 = 23 μM). (ii) Echinoside A (Figure 5), a saponin derivative isolated from the sea cucumber Holothuria nobilis Selenka, which inhibits the noncovalent binding of topoisomerase IIα. The drug interferes with the binding of topoisomerase II to DNA, so as to impair the prestrand passage cleavage/ religation equilibrium. This effect results in DNA doublestrand breaks (perhaps not only by interfering with topoisomerase II) and subsequent apoptosis. This natural compound exerts potent cytotoxic properties toward a variety of tumor cell lines, including multi-drug-resistant 3618


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Figure 6. Additional naturally occurring topoisomerase II inhibitors.

ties. It possesses anti-MDR activities and in vivo efficacy.164 Using a yeast genetic system, the authors demonstrated that topoisomerase II is the primary cellular target of MFTZ-1, but in a more recent study, they reported that the macrolide elicits additional propertiesreduction of hypoxia-inducible factor-1α (HIF-1α) accumulation and vascular endothelial growth factor (VEGF) secretion, leading to an antiangiogenic effectindependently of its topoisomerase II inhibition.165 (vii) Riccardin D (Figure 5), a macrocyclic bisbenzyl derivative extracted from the Chinese liverwort plant Dumortiera hirsute.166 The drug is proapoptotic and cytotoxic toward HL60 promyelocytic leukemia cells but showed no effect on the topoisomerase II-deficient counterpart HL60/MX2. In a DNA relaxation assay, riccardin D was found more active than etoposide, suppressing topoisomerase II (but not topoisomerase I) activity, but at relatively high concentrations. This is a novel archetype for topoisomerase II inhibition. Inhibition of angiogenesis is also involved in the anticancer activity of riccardin D.167 (viii) Simocyclinone D8 (Figure 6), a bifunctional angucyclinone antibiotic isolated from Streptomyces antibioticus Tu6010, is primarily referred to as an antibacterial agent, acting as a potent catalytic inhibitor of bacterial DNA gyrase, the prokaryotic homologue of human topoisomerase II. SD8 prevents DNA binding to the enzyme by placing its aminocoumarin and polyketide moieties in two juxtaposed binding pockets of gyrase A.168 An additional binding site has also been mapped on gyrase B.169 Anticancer properties have been reported as well.170 The drug blocks topoisomerase II binding to DNA, thus preventing the generation of DNA strand breaks. This molecular activity leads to a relatively modest inhibition of tumor cell proliferation (IC50 = 75−

lactone-containing derivatives may improve the bioactivity. The pyranonaphthoquinone derivatives α- and β-lapachone induce abortive dissociation of topoisomerase II from the DNA, leading to an irreversible accumulation of high molecular weight DNA fragments.148 (v) Different flavonoids endowed with topoisomerase II inhibition properties have been reported, including (1) various dietary polyphenols,150 (2) the tea flavanol (−)-epigallocatechin-3-gallate (EGCG, Figure 6), which is a redox-dependent topoisomerase II poison,151,152 (3) isoliquiritigenin (Figure 6) found in many vegetables (shallots and bean sprouts in particular), which causes cell cycle arrest through topoisomerase II poisoning,153 (4) myritecin and fisetin (Figure 5), two dietary flavonoids acting as dual inhibitors of topoisomerases I and II in cells,154,155 and (v) flavonoids and triterpenes from the Korean tree Ulmus davidiana var. japonica.156 They may represent useful starting points for drug design, but it is important also to mention that some widely consumed dietary flavonoids (quercetin, genistein, curcumin, and kaempferol),157−159 at biologically relevant concentrations, can induce abnormalities of the mixed-lineage leukemia (MLL) gene in primary hematopoietic progenitor cells.160,161 As for the therapeutic inhibitors, the genotoxicity of these dietary toposomerase II inhibitors (e.g., genistein) is correlated to prolongation of enzyme−DNA residence, more than enzyme-mediated DNA cleavage.162 In this category, cocoa-derived flavanols also exert effects on topoisomerase II and cellular proliferation in cancer cell lines.163 (vi) The macrolide compound MFTZ-1 (Figure 5) isolated from an endophyte Streptomyces sp. Ls9131 of Magnolia hookeri. This dimeric dinactin (cyclotetralactone derived from nonactic acid) triggers topoisomerase II-dependent DNA strand breaks and displays wide cytotoxic proper3619


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Figure 7. More naturally occurring topoisomerase II inhibitors.

125 μM), but thanks to the precise knowledge of the architecture of the drug−enzyme complex, more potent analogues may be rationally designed. (ix) Taspine (or thaspine) (Figure 6) is a tetracyclic alkaloid initially isolated from the Chinese herb Radix et Rhizoma Leonticis and also found in the cortex of the South American tree Croton lechleri. It was characterized as an antiangiogenic molecule capable of down-regulating VEGF and βFGF secretion in human cancer cells and endothelial cells.171 More recently, this alkaloid was shown to function as a dual topoisomerase I and II inhibitor, active in tumor cells overexpressing the transporters PgP and MRP.172 These observations have encouraged the design of ring-opened derivatives.173,174 (x) 4-Hydroxyderricin (Figure 6), a prenylated chalcone isolated from the roots of Angelica keiskei, which is a perrenial herb growing mainly along the Japanese Pacific coast. This phenolic compound exhibits significant antiprofilerative activities toward different cancer cell lines, as well as antitumor and antimetastatic activities in vivo,175 and inhibits relaxation of DNA by topoisomerase II, not topoisomerase I.176 As for the related chalcone xanthoangelol also characterized from A. keiskei as a proapoptotic agent, 4-hydroxyderricin is able to modulate inflammatory pathways.177 (xi) Gambogic acid (Figure 6), the major ingredient from the gamboges resin, secreted by the Garcinia hanburyi tree in Southeast Asia, used in traditional Chinese medicine. Gambogic acid exerts its antiproliferative effects by inhibiting the catalytic activity of topoisomerase IIα, preventing DNA damage and ATP hydrolysis. In fact, this natural product binds to the ATPase domain of the enzyme.178 Binding to Hsp90 has also been recently evidenced179 as well as inhibition of STAT3 phosphorylation through activation of protein tyrosine phosphatase SHP-1.180 Its capacities to induce cell cycle arrest

and apoptosis have been extensively characterized, using a variety of tumor cell systems.181,182 Interestingly, simplified analogues maintaining antiproliferative activities comparable to that of gambogic acid have now been synthesized, and a caged pharmacophore has been described.183 (xii) Wedelolactone (Figure 6), a coumestan isolated from different herbal medicines used in Taiwan and southern China (Wedelia chinensis, Eclipta prostrata). It was previously reported that an herbal extract of W. chinensis attenuates androgen receptor activity and orthotopic growth of prostate cancer in nude mice.184 More recently, one of the major constituents of this extract, wedelolactone, was shown to inhibit DNA relaxation and decatenation mediated by topoisomerase IIα.185 This naturally occurring coumestan is also an inhibitor of RNA-dependent RNA polymerase from the hepatitis C virus.186 (xiii) Mansonone F (Figure 6), a naturally occurring sesquiterpene o-quinone found in plants such as Mansonia altissima, Thespesia populnea, and Ulmus pumila. It displays antibacterial and cytotoxic activities likely linked to inhibition of topoisomerase II. Mansonone F and derivatives were recently characterized as inhibitors of topoisomerase II-mediated DNA relaxation.187 Mansonone F bears a structural analogy to the diterpenoid o-quinone salvicine (Figure 6) derived from a natural product extracted from the Chinese medicinal herb Salvia prionitis Hance (Labiatae) and previously identified as a binder of the ATP pocket of topoisomerase II188 capable of inducing DNA strand breaks.189 As for salvicine,190 ROS likely play a dominant role in the mechanism of action of mansonone F. ROS modulate DNA damage and repair and elicit apoptosis by concurrently disrupting topoisomerase II.191 3620


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Figure 8. Additional naturally occurring topoisomerase II inhibitors.

enhanced topoisomerase IIα activity.195 Metnase is a double-strand break repair factor that interacts with topoisomerase IIα so as to promote tumor cell growth in the presence of topoisomerase II poisons. The close analogue amphimedine is biologically inactive, and deoxyamphimedine damages DNA in vitro independent of topoisomerase enzymes through the generation of reactive oxygen species.196 Other natural products (or NP-derived molecules) have been described as topoisomerase II inhibitors, such as the shikonin derivative SH-7 (Figure 7),197 the plant/fungi anthraquinone emodin (Figure 7),198 marinactinones isolated from the actinomycete Marinactinospora thermotolerans,199 pericosine A (Figure 7) isolated from a strain of Periconia byssoides separated from a sea hare,200 a propionyloxy derivative of the pentacyclic triterpene 11-keto-β-boswellic acid, designated PKBA (Figure 7) or HKBA,201,202 the acetogenin pyranicin (Figure 7) inhibitor of several DNA metabolic enzymes including polymerases and topoisomerases,203 plumbagin (Figure 7) derived from the plant Plumbago zeylanica, which inhibits topoisomerase II through the generation of reactive oxygen species 204 and/or via a mechanism involving protein thiolation,205 20-O-decadienoylingenol (Figure 8) from the plant Euphoria kansui characterized as a catalytic inhibitor,206 the chalcone trimer pauferrol A (Figure 8) isolated from the stems of the Brazilian plant Pau ferro (Caesalpinia ferrea Mart, Leguminosae),207 certain flavonoids, flavanols, and isoflavones (genistein, Figure 8),208,209 lignans from Saururus chinensis,210 lanostane-type triterpenoids isolated from Pinus luchensis,211 the lignan-related naphthodioxolone compound 4-MTDND (Figure 8) from the Jamaican plant Hyptis verticillata jacq,212 the phenanthridine alkaloid ungeremine (Figure 8) isolated from the methanol extract of the bulbs of Pancratium illyricum L.,213 kaempherol glycoside (Figure 8) derived from a unique variety of Leguminosae,214 pimarane-type terpenoids from the bark of

(xiv) Tricitrinol B (Figure 7) extracted from a volcano ash isolate of the fungus Penicillium citrinum HGY1-5.192 This citrinin trimer is equally cytotoxic toward two multidrug-resistant cell lines overexpressing PgP compared to the parental cell lines. It induces cell cycle arrest in the G2/M phase and stimulates apoptosis, via the induction of DNA fragmentation and caspase activation. On the basis of topoisomerase-mediated plasmid DNA rexalation experiments and molecular modeling, it has been suggested that the drug intercalates between DNA base pairs, but further evidence is certainly needed. At the topoisomerase II level, tricitrinol B can enhance topoisomerase IIα-mediated DNA cleavage and suppress the DNA religation step. It thus affects the cleavage/ religation equilibria, so as to increase the amount of broken DNA in cells. (xv) Rotenoid analogues of 6-deoxyclitoriacetal (Figure 7) extracted from the roots of Stemona collinsae Craib (Stemonaceae), Clitoria fairchildiana, and Clitoria macrophylla Wall. (Papilionaceae). This naturally occurring rotenoid with a four-fused tetrahydrochromeno[3,4b]chromene ring core exhibits cytotoxic properties against certain cancer cell lines and has been shown recently to inhibit plasmid DNA relaxation by topoisomerase II.193 Various derivatives bearing functional groups at the C11-OH position were also described, including some potent topoisomerase IIα inhibitors endowed with modest cytotoxic properties.193 (xvi) Neoamphimedine (Figure 7), a marine pyridoacridine from Xestospongia sp. This pentacyclic alkaloid is known to inhibit topoisomerase II and is as effective as etoposide at inhibiting the growth of xenograft tumors in mice.194 Interestingly, it was shown recently that neoamphimedine is an ATP-competitive inhibitor of topoisomerase IIα and is able to inhibit Metnase3621


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Figure 9. Topoisomerase II inhibitors in the epipodophyllotoxin series.

Macaranga tanarius,215 or the stilbenoid nepalensinol from Kobresia nepalensis (Cyperaceae),216 but these molecules structurally complex and/or modestly active against topoisomerase II are of little interest as anticancer drug candidates. Lunacridine (Figure 7) from the plant Lunasia amara Blanco (Rutaceae)217 and diverse diterpenes isolated from the roots of the plant Euphorbia kansui218 have been described as well, but the extent of activity was limited and/or superficially documented mechanistically. Despite their highly complex structures, the case of nepalensinols A, B, and C is interesting to mention because these compounds are oligomers of the trihydroxystilbene resveratrol, which is a well-known polyphenol synthesized by a large variety of plant species in response to injury, UV irradiation, and fungal attack. Nepalensinol B (Figure 5) is considerably more active at inhibiting decatenation of kinetoplast DNA by topoisomerase II than nepalensinols A and C and also much more potent than the reference drug etoposide in this assay.216 It would be useful to investigate further the bioactivity of this symmetric molecule. Unlike resveratrol (Figure 8), which acts as a topoisomerase IIα poison in cancer cells,219,220 one may speculate that nepalensinol B functions as a catalytic inhibitor of topoisomerase II, blocking the DNA−enzyme interface so as to increase the lifetime of the cleavage complexes. This hypothesis is conceivable with the large molecular surface of this complex natural product. Topoisomerase II inhibition has been described with alkylhydroquinones isolated from the sap of the laquer tree Rhus succedanea L.221 Similarly, a series of modestly potent alkyl coumarates isolated from the plant Artemisia annua L. were reported, including docosyl p-coumarate (Figure 8) as the most potent topoisomerase II inhibitor in this series.222 This plant also produces the sesquiterpene artemisinin, which is used in traditional Chinese medicine for the treatment of fever and chills. Synthetic derivatives of artemisinin have been developed, such as artesunate used for the treatment of malaria, but in

addition to its antimalarial effect, artesunate also exerts a cytotoxic action toward cancer cell lines. This latter activity certainly derives from the capacity of the molecule to interfere with topoisomerase II. Indeed, gene expression profiling and biochemical studies demonstrated that artesunate (Figure 8) is a topoisomerase IIα inhibitor.223 Much more recently, the heavy metal cadmium chloride has also been described as a catalytic inhibitor of topoisomerase IIα through reaction with critical cysteine thiols.224 Similarly, dietary isothiocyanates can induce apoptosis of oncogene-transformed cells via thiol modification of DNA topoisomerase II. Selenocysteine, which is thiol-reactive, but not the nonthiol-reactive selenomethionine, induces topoisomerase IIα cleavage complexes.225 Natural product inhibitors of topoisomerase II are regularly described. We could not conclude this section without raising the case of the epipodophyllotoxins, which are the reference topoisomerase II inhibitors. They are specifically referred to in the next section.

4. EPIPODOPHYLLOTOXINS FOREVER 4.1. Forty Years of Etoposide Therapy

Since its introduction in the clinic in 1971,226 etoposide (Figure 1) remains routinely used in chemotherapy for a large variety of solid and hematological tumors, in particular in second-line therapy for acute myeloid leukemia in combination with cytarabine and/or mitoxantrone,227 in association with rituximab for CLL,228 and with cisplatin for small-cell lung cancer (SCLC),229 and many other tumor types, including rare tumors and pediatric malignancies, such as infantile fibrosarcoma, ependymoma, seminoma, and germ-cell tumors, choroid carcinoma, adrenocortical carcinoma, esophageal carcinoma, and carcinoma of the bladder. However, undesirable effects are observed upon treatment with etoposide, including, at short term, myelosuppression and neurotoxicity and, at longer term, risk of secondary leukemia.230 The susceptibility to etoposideinduced cytotoxicity is supposed to be heritable,231 but 3622


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Figure 10. Additional topoisomerase II inhibitors in the epipodophyllotoxin series.

Naturally occurring podophyllotoxin derivatives continue to be isolated. This is the case recently for 4′-DPG (4demethylepipodophyllotoxin 7′-O-β-glucopyranoside, Figure 9) isolated from the rhizomes of Sinopodophyllum emodi (Wall.) Ying. This plant belongs to the traditional Chinese medicine and is used to treat cancer and various types of verrucosis. Like etoposide, 4′-DPG has prominent cytotoxic activity and induces apoptosis.252 Another example of an etoposide-related natural product is daurinol (Figure 9), an arylnaphthalene lignan isolated from the ethnopharmacological plant Haplophyllum dauricum.253 Unlike etoposide, daurinol is a catalytic inhibitor of human topoisomerase IIα and induces S phase cell cycle arrest (not G2/M arrest) and does not cause DNA damage or nuclear enlargement in vitro. This natural product has a potent antitumor effect in mice, with lower adverse effects compared to etoposide. These characteristics suggest that daurinol might be a safer anticancer drug than etoposide, but the vast majority of topoisomerase II-targeting podophyllotoxin derivatives are (hemi)synthetic products. The trans-lactone form of etoposide is essential to preserve the topoisomerase II inhibitory activity, but the C4-glycoside moiety is dispensable. Etoposide−topoisomerase II binding is driven by interactions with the A- and B-rings and potentially by stacking interactions with the E-ring.254 The sugar moiety is not involved in the topoisomerase II−DNA complex.255,256 4βAmino-4′-demethylepipodophyllotoxin (4β-NH2-4′-DMEP, Figure 9), which can be prepared stereoselectively from podophyllotoxin,257 can therefore serve as a platform to incorporate various substituents on the 4-amino position, without reducing bioactivity. The binding of epipodophyllotoxin to human topoisomerase IIα has been predicted by flexible docking simulations, using docking and molecular mechanics. This model positions the 4β-NH2-4′-DMEP in the active site, with the phenyl group interacting with the catalytic tyrosine 804 residue, and surrounding contacts with the Asp-737, Lys738, and Gln-784 amino acids. The amino group points into an open cavity, leaving room for a diversity of substituents.258 In

epipodophyllotoxin-mediated leukemogenesis is apparently not directly linked to drug cytotoxicity.232 It is now well established that etoposide-induced cleavage of DNA by topoisomerase II can mediate the formation of chromosomal translocation break points (11q23 translocation with rearrangements of the MLL oncogene in particular), leading to the expression of oncogenic factors responsible for secondary leukemia.233−235 A total of 2− 3% of patients treated with etoposide develop treatment-related leukemias characterized by 11q23 chromosomal rearrangements. Etoposide quinone, formed upon metabolization of etoposide by CYP3A4 into a catechol form which can be further oxidized to the quinone form, contributes to etoposiderelated leukemogenesis.236 It has been hypothesized that etoposide-induced carcinogenesis involves mainly the β rather than the α isoform of topoisomerase II, pointing therefore to the importance of developing topoisomerase IIα-specific anticancer drugs for effective chemotherapy.237 Anthracyclines, such as epirubicin, have also been implicated in the induction of chromosomal translocations (in particular t(15;17)) at the origin of certain leukemias.238,239 Therapy-related leukemias are becoming an increasing healthcare problem as more patients survive their primary cancers.240,241 4.2. Recent Epipodophyllotoxin Derivatives: From Research to the Clinic with New Epipodophyllotoxins

4.2.1. Research. Over the past two decades, many podophyllotoxin derivatives have been designed as topoisomerase II inhibitors,242,243 and several of them have been tested clinically, such as TOP-53,244−246 GL331, 247,248 NK611,249 and tafluposide,250,251 but none of these drug candidates ever reached the market. In all cases the development was halted at an early stage due to dose-limiting toxicities or lack of efficacy. Despite these failures, oncologists and medicinal chemists continue to pay a large interest to this class of compounds with respect to their anticancer potential. Today, the podophyllotoxin story is pursued, with novel candidates and novel strategies, as discussed below. 3623


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recent years, 11 new series of amino-substituted 4′-DMEP have been presented: (i) Triazolyl derivatives, such as compound 14 (Figure 9), which is more cytotoxic than etoposide in a panel of tumor cell lines.259−261 A series of (alkyltriazolyl)epipodophyllotoxins have been reported with a satisfactory correlation between interaction with topoisomerase II (docking study in silico) and drug-induced cytotoxicity.262 (ii) Selenopodophyllotoxin derivatives, typified by the 4seleno-β-peltatin derivative CPZ (Figure 9), which is a more potent cytotoxic and proapoptotic agent than etoposide when tested in the hepatoma SMMC-7721 cell line.263 The exact role of the selenium atom is unknown, but it may play a role in the mechanism of action. Indeed, it is known that selenite induces topoisomerase II−DNA complexes in cells, with a potential link to the induction of apoptosis.264 (iii) Nitroxide-free radical to generate spin-labeled probes.265−268 Different series of spin-labeled etoposides have been described, including compounds with immunosuppressive properties and, recently, molecules such as the antioxidant cytotoxic derivative 15 (Figure 9)268 and GP-7 characterized as a proapoptotic agent capable of down-regulating PgP.269 (iv) Aroylthiourea derivatives, able to interfere with both tyrosine kinases and topoisomerases. In this series, compound 16 (Figure 9) was found to inhibit topoisomerase II-mediated decatenation of DNA coupled with marked cytotoxic properties.270,271 (v) Diazirine-containing molecules. The 3-(trifluoromethyl)3-aryldiazirine derivative 17 depicted in Figure 9 is a selective photoaffinity probe for the labeling of topoisomerase II. Upon photoirradiation, the probe forms a covalent adduct with topoisomerase IIα, thus providing a tool for localizing the drug-binding site on the enzyme.272 (vi) Pyrrolidine- and piperidine-containing derivatives. Compound 18 (Figure 10) with a pyrrolidine substituent on the 4-amino position has revealed higher antitumor activity than etoposide in a KB/VCR MDR tumor xenograft model that overexpresses PgP. Compound 16 inhibits topoisomerase II and generates DNA doublestrand breaks. At low doses, the drug activates the ATM/ ATR (ATR = ATM- and Rad3-related) checkpoint and the downstream targets Chk1 and Chk2 leading to cell cycle arrest in the G2 phase.273 G2/M arrest is an important determinant in the cytostatic action of etoposide.274 At higher doses, the drug triggers apoptosis via a mitochondrial pathway, with caspase activation.273 Its analogue, the aniline−piperidine derivative 19 (Figure 10), has also shown a marked antitumor activity in vivo and potent proapoptotic functions. It is considered as a potential drug candidate for cancer chemotherapy.275 These compounds bear a structural resemblance to the nitroanilino derivative GL-331, tested clinically 10 years ago. (vii) Indolylglyoxyl derivatives, such as compounds L1EPO276 and YB-1EPN,277 which are endowed with potent antitumor activity, at least in vitro (Figure 10). These compounds can overcome PgP-mediated multidrug resistance. They likely function as tubulin poisons, not

topoisomerase II inhibitors, because they derive from podophyllotoxin (with a 4′-methoxy group). (viii) Polyaromatic (chrycenyl, pyrenyl, fluorenyl, anthranyl) derivatives recently described as topoisomerase II inhibitors and proapoptotic agents.278 The same group of authors also recently reported a series of benzothiazolyl-4β-anilino derivatives, such as compound 20 (Figure 10), and 4β-carbamoyl derivatives, endowed with marked cytotoxic activities.279 (ix) 4β-Anilino derivatives substituted with amidoalkylamino or amidoaryl groups.280 In the latter series, the acetoxy derivative 21 (Figure 10), administered intragastrically, revealed in vivo antitumor activity in a xenograft model of metastatic human lung cancer 95D in nude mice. (x) Compound QS-ZYX-1-61 (Figure 10) recently presented as potent DNA damaging and a proapoptotic agent. In A549 cancer cells, QS-ZYX-1-61 triggers the DNA damage response, leading to accumulation of p53 protein, increased expression of p53 target genes (puma and p21), and induction of apoptosis signaling pathways.281 (xi) Polyamine derivatives, designed to reinforce DNA interaction and selectively target tumor cells with an active polyamine transport system.282 The lead molecule in this class, F14512 (Figure 10), will be discussed in more detail below. This compound is currently developed by Pierre Fabre Médicament. 4.2.2. Clinic. The lack of tumor cell selectivity is the most frequent criterion evoked to explain the limited antitumor activity of topoisomerase II inhibitors at the clinical level. Highly potent poisons have been designed, such as the aforementioned drug DACA (XR5000), but in most cases the clinical responses were somewhat disappointing. It is therefore essential to develop novel strategies to target these molecules primarily to cancer cells. Several approaches have been proposed, such as the coupling of tumor-specific or receptorspecific peptides. A recent example is the linkage of a 19-mer peptide with a high affinity for the LRP-1 receptor to permit crossing of the blood−brain barrier by a transcytosis mechanism and thus to facilitate drug accumulation in brain tumors. This peptide, designated Angiopep-2, has been coupled to paclitaxel and more recently to the topoisomerase II poisons doxorubicin and etoposide. In both cases, a facilitated brain passage was demonstrated.283 Another option to drive a topoisomerase II inhibitor selectively to tumor cells consists of attaching the drug to a polyamine, so as to facilitate the uptake of the drug by cells overexpressing the polyamine transport system (PTS). Polyamine transport is positively correlated with the rate of cellular proliferation. This is the concept underlying the design of the molecule F41512 (Figure 9) discussed below. Exploiting the PTS as a Trojan horse approach for drug delivery has been highlighted recently as a particularly promising approach in cancer chemotherapy.284,285 However, one must admit that the PTS refers to a process still poorly understood at the molecular level. Polyamine transporters have thus far been isolated from unicellular species exclusively; the molecular identity of a PTS in human cells remains largely unknown, even if recently a first polyamine transporter (CCC9A) may have been uncovered for the first time in animal cells.286 The drug candidate F14512 (Figure 9) is composed of an epipodophyllotoxin core coupled to a spermine side chain via a 3624


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cells treated with F14512 are less prone to undergo apoptosis or autophagy but preferentially entered into senescence.294 In P388 leukemia cells, the F14512-induced DNA damage signaling pathway resulted in greater senescence-like growth arrest and delayed apoptosis; inhibition of survivin (by an siRNA) resulted in a switch from senescence-like growth arrest to apoptosis.295 The superiority of F14512 over etoposide is not restricted to its preferential uptake by cancer cells, but is also due to unique effects on topoisomerase II interactions with DNA. Using a Drosophila melanogaster model system, it was recently shown that the drug specifically targets a select and limited subset of genomic sequences. Feeding F14512 to developing mutant Drosophila larvae led to the recovery of flies expressing a strinking phenotype, designated “eye wide shut”, where one eye is replaced by a first thoracic segment. Other F14512-induced gain- and loss-of-function phenotypes similarly correspond to precise genetic dysfunctions. These complex in vivo observations illustrate the occurrence of specific alterations of gene expression upon treatment with F14512. Here again, the spermine−drug core linkage is critical for these attributes.296 The clinical development of F14512 has been initiated. A phase I study in AML is in progress to determine the maximal tolerated dose and optimize the treatment schedule. This makes F14512 the most recent clinically tested topoisomerase II inhibitor and conceptually the most promising drug in the category. Polyamine conjugates, as well as antitumor polyamine derivatives (e.g., PG11047, from Progen Pharmaceuticals Ltd., which is currently undergoing early clinical development),297,298 are the focus of considerable scientific interest. For F14512 as for PG11047 and other polyamine-related drug candidates, the current challenge is to determine the most promising indications, via appropriate translational studies. Such compounds have the potential to provide a first-in-class oncology product. To complete this section, we should also refer to the drug Adva-27a, a difluoroetoposide derivative for which Sunshine Biopharma Inc. (Montreal, Canada) recently announced the beginning of drug development activities (http:// sunshinebiopharma.com), but no information about this drug could be obtained.

glycine linker. Each part of the molecule has been rationally designed. The epipodophyllotoxin moiety is responsible for the interference with topoisomerase II. An intact tetracyclic lactone core has been preserved as it is essential to the stability of the ternary enzyme−drug−DNA complex.287 The pendant E-ring at position C1 has also been preserved, but the glycosidic portion at C4 has been replaced with a polyamine chain. The spermine chain serves, on one hand, as a cell delivery system to facilitate the uptake and accumulation of the drug in tumor cells expressing the PTS. On the other hand, this polyamine tail, positively charged, contributes to reinforce the interaction with DNA. The target interaction is thus reinforced, as well as the cell selectivity. The glycyl connector has been selected to link the two active parts, without reducing their intrinsic properties. As described for similar polyamine-containing fluorescent probes,288 not all polyamines and linkers can be introduced. Recognition by the PTS is dependent on the nature of the polyamine, and the nature of the linker can significantly alter the extent of topoisomerase II inhibition and/or DNA binding. In a large series of epipodophyllotoxin−polyamine conjugates, F14512 was selected as the most promising molecule, combining efficacy, stability, facilitated chemical access, and minimal toxicity. Etoposide does not appreciably bind to DNA in the absence of topoisomerase II. In sharp contrast, F14512 interacts with DNA via its polyamine tail and stabilizes the two strands of the double helix. The enhanced activity of F14512 correlates with a tighter binding and an increased stability of the ternary topoisomerase II−drug−DNA complex. Moreoer, unlike other structurally similar drugs (etoposide and TOP53), F14512 maintains robust activity in the absence of ATP.289 The preferential uptake of the drug in PTS-positive tumor cells, coupled with the reinforced topoisomerase II inhibition, confers marked cytotoxic properties to F14512, which is about 10 times more potent than etoposide at inhibiting cell proliferation (average IC50 values of 0.18 and 1.4 μM for F14512 and etoposide, respectively). Its antitumor efficacy in vivo is also markedly superior to that of etoposide.282 A detailed evaluation of its activity using a panel of 18 xenograft models revealed that F14512 provided significant tumor responses in 67% of the models, with tumor regressions in 33% of the responsive models. This is the signature of a promising new drug, supporting a novel concept in oncology.290 Recently, an investigation of the antiproliferative activity of F14512 against 13 leukemia cell lines demonstrated a significant correlation with the level of PTS activity, measured in cells with a fluorescent probe specifically designed to measure the PTS. This dedicated probe and the corresponding labeling protocol adapted for clinical applications for blood, bone marrow, and AML samples are now used clinically to try to guide patients’ selection for ongoing enrollment in F14512 clinical trials in oncohematology.291 A functional procedure using fresh samples to select patients with AML prior to treatment with this novel targeted cytotoxic agent has been designed.292 A (99m)TcHYNIC-spermine scintigraphic probe to evaluate F14512 uptake in cancer cells expressing the PTS has also been developed.293 At the cellular level, F14512 triggers less but unrecoverable DNA damage than the parent drug etoposide lacking the polyamine tail, and this translates into a much higher cytotoxicity. The cytotoxic action of F14512 is extremely rapid and does not lead to a marked accumulation in the S phase of the cell cycle, unlike etoposide. Interestingly, A549

5. NEW TOPOISOMERASE II POISONS IN CLINICAL DEVELOPMENT In addition to F14512 cited above, three other topoisomerase II poisons are currently subject to clinical development: vosaroxin, C-1311, and R(+)XK469 (Figure 1). They will be discussed in turn. 5.1. Vosaroxin (Formerly SNS-595, AG-7352, AT-3639, or Voreloxin)

The drug originated from Dainippon Sumitomo Pharma Co. Ltd. (formerly Dainippon Pharmaceutical Co. Ltd., prior to the merger of Dainippon and Sumitomo in October 2005) in Japan and later on was licensed to Sunesis Pharmaceuticals Inc. in California in October 2003. Since this date, the clinical development of vosaroxin has been under the guidance of Sunesis. On Feb 23, 2011, the U.S. Food and Drug Administration granted fast track designation to vosaroxin for the potential treatment of relapsed or refractory AML in combination with cytarabine. 5.1.1. Chemistry. The drug contains a 1,8-naphthyridine core, and its structure (Figure 1) derives from that of 3625


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micromolar range depending on the cell type. An average IC50 of 0.5 μM was measured using a panel of 15 cell lines.306 With leukemia cell lines such as HL-60 (acute promyelocytic leukemia) and MV4-11 (acute myeloid leukemia), the combination of vosaroxin and cytarabine was found to be synergistic, with combination indexes of 0.58 and 0.68 for the two cell lines, respectively. This combination was also effective in vivo. Vosaroxin and cytarabine at their respective maximal tolerated doses (MTDs) reduced bone marrow cellularity, measured in femurs of drug-treated mice, by 80% and 42%, respectively. When combined, the reduction in bone marrow cellularity reached 91% with diminished doses of vosaroxin (50% MTD) and cytarabine (33% MTD) and returned to normal after 1 week. Cells exiting the S phase and entering the G2 phase with cytarabine-induced DNA damage are then subjected to DNA double-strand breaks upon action of vosaroxin. In parallel, the repair of vosaroxin-induced DSBs is impaired by the blockade of DNA synthesis induced by cytarabine. This combined action stimulates drug-induced cancer cell death.307 These preclinical data support the ongoing AML clinical program. The dose-dependent antitumor activity of vosaroxin has been demonstrated in various in vivo xenograft models, including lung adenocarcinoma (Calu-6, NCI-H460), ovarian carcinoma (PA-1), breast adenocarcinoma (MDA-MB231), lymphoma (LM3 Jck), and gastric cancer (Hs746T). A strong antitumor effect was also reported with tumors resistant to etoposide (SBC-3/ETP, SCL cancer) or doxorubicin (MESSA/Dx5, uterine cancer). In a panel of 13 human tumor xenografts, the drug revealed potent antitumor activity in 12 models, with a global effect comparable to that of irinotecan and paclitaxel and superior to that of the two reference topoisomerase II inhibitors doxorubicin and etoposide. Tumor distribution of vosaroxin is high, reaching tumor drug levels in excess of the average cellular IC90 value of 3.9 μM.306 Vosaroxin acts synergistically with cytarabine to induce cell death of primary acute myeloid leukemia blasts. A dosedependent induction of apoptosis has been observed.308 Apparently, the action of vosaroxin is not affected by the p53 status. The drug is not a substrate for the P-glycoprotein (P-gp) efflux pump. The P-gp resistance mechanism is of particular relevance to AML, as older and relapsed patients often express higher levels of this efflux pump. An interesting observation306 was the activity of vosaroxin in the drug-resistant PC-14 NSCLC xenograft tumor model, which is resistant to cytotoxic drugs as diverse as cisplatin, doxorubicin, etoposide, irinotecan, and paclitaxel, agents widely used to treat lung cancer. Multidrug resistance does not comprise the anticancer activity of the molecule, suggesting that vosaroxin has the potential to remain active in tumors that are refractory to commonly used anticancer drugs. 5.1.3. Clinical Development. The drug is currently tested in several tumor indications, primarily acute myeloid leukemia in oncohematology and platinum-resistant ovarian cancer for the solid tumor aspect. From the pharmacokinetics point of view, the molecule is well behaved in humans, with a dose linear increase in exposure, low clearance, and a long half-life. The metabolic pathways for vosaroxin include glucuronide conjugation, oxidation, N-dealkylation, and O-dealkylation.309 Four primary metabolites have been identified in rats, with a low level of circulating metabolites. In humans and other species, the predominant metabolite, and the only one detected in plasma, is N-desmethylvosaroxin, which is probably mediated by the

antibacterial quinolones, such as ciprofloxacin and norfloxacin, which poison bacterial DNA gyrase and topoisomerase IV enzymes. The 2-thiazolyl and aminopyrrolidinyl substituents on the naphthyridine nucleus abolish the antibacterial activity but confer a potent cytotoxic potential toward cancer cells.299 The molecule is enantiomerically pure and exists as a switterionic form containing carboxylic and amine groups. The structure− activity relationships in this chemical series have been delineated. The 3-aminopyrrolidine substituent contributes to reinforce the antitumor activity and provides a better water solubility. Vosaroxin is water-soluble (23.7 mg/mL in a pH 7.2 buffer). The bioactivity of the racemate and the two optical isomers R,R and S,S are roughly equivalent, but the S,S isomer as a free base was selected as a drug candidate for clinical development due to its slightly higher solubility and cytotoxicity.300 5.1.2. Pharmacology. Vosaroxin is a DNA-damaging agent. The drug intercalates into DNA and inhibits topoisomerase II so as to generate DNA double-strand breaks. The relative role of each submechanism, intercalation vs topoisomerase inhibition, remains to be determined. They are obviously associated but not correlated. Intercalation into DNA is not sufficient to engender topoisomerase II inhibition in general, but in the present case, intercalation between DNA base pairs is required for vosaroxin’s activity. Enhancement or reduction of the capacity of the molecule to intercalate into DNA, via the use of a more planar (tetracyclic fused phenyl analogue) or a bulkier substituent in place of the thiazole ring (phenyl analogue), manifested in a more potent or reduced cytotoxicity.301 The DNA-intercalative property of vosaroxin seems to be greater than that of the quinolone antibacterials. At the cellular level, the drug induces replication-dependent DNA damage in the S phase of the cell cycle, causing irreversible arrests in the G2 phase and a rapid apoptosis. This action principally manifests toward proliferating cells. Vosaroxin exhibits a very high cytotoxic potential, superior to that of the reference drug etoposide. Intercalation into DNA and topoisomerase II inhibition both contribute to the bioactivity, thus providing a dual action that persists when the topoisomerase II enzyme is knocked out. The drug is less dependent on topoisomerase II for its cytotoxicity than etoposide or doxorubicin. Unlike other DNA double-strand breaking agents, vosaroxin-mediated damage is repaired by the DNA-PK and nonhomologous end-joining (NHEJ) pathway.302 The homologous recombination repair is also essential for repair of vosaroxin-induced DNA double-strand breaks.303 Interestingly, the drug is a poor topoisomerase II poison but a potent DNA-damaging agent, although it induces less overall DNA fragmentation than doxorubicin. In vitro, it induces little global DNA cleavage in the presence of either the α or β isoform of topoisomerase II, but the drug promotes cleavage at selective sites in DNA. Vosaroxin-induced DNA damage occurs essentially at GC-rich regions similar to those mediated by gyrase in the presence of quinolone antibacterial drugs. This GC selectivity likely derives from a facilitated access of the drug to adjacent GC/CG base pairs. Many years ago, it was shown that the related compound norfloxacin, an antibacterial fluoroquinolone, interacts preferentially with poly(dGC)2 rather than with other polynucleotides.304 However, binding to double-stranded DNA should also be considered and investigated, as is the case for antibacterial quinolones.305 In vitro, the drug exhibits potent cytotoxic effects toward a variety of cancer cell lines with IC50 values in the sub3626


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vosaroxin (90 mg/m2) on days 1 and 4 in combination with cytarabine (1 g/m2) daily for 5 days or placebo in combination with cytarabine. The FDA’s fast track designation for vosaroxin is reflective of its potency and mechanistic features and the need for novel anticancer drugs that demonstrate the potential to provide better clinical outcomes and improved tolerability for individuals suffering from acute myeloid leukemia. It has been a long time since a new topoisomerase II inhibitor entered a phase III clinical trial.

P450 cytochrome system. This metabolite maintains a cytotoxic potential roughly equal to that of vosaroxin, at least toward the human colon carcinoma cell line HCT116. Elimination of vosaroxin occurs via the renal and hepatic routes as well as by direct intestinal secretion.309 No drug accumulation was reported, even upon repeated administration. In clinical trials, the pharmacokinetic profile of vosaroxin does not seem to be dependent on the schedule. Several phases I and II have been conducted, in patients with solid tumors or hematological malignancies.310 A recent phase I study evaluating two dosing schedules of vosaroxin given intravenously to patients with relapsed/refractory solid tumors showed an acceptable safety profile and signs of clinical activity (about 50% of the overall response of the stabilized disease). The primary dose-limiting toxicity was neutropenia, which was noncumulative. The initial recommended phase II single-agent dose of vosaroxin is 48 mg/ m2 administered every 3 weeks in all patients with advanced solid tumors. This dose would be sufficient to reach a clinically active plasma concentration of 1 μM in cancer patients. In this trial, the drug exhibited low clearance (2 (L/h)/m2) and a long terminal half-life (22 h). Encouraging preliminary clinical activity of vosaroxin has been noted in patients with platinumresistant relapsed or refractory ovarian cancer on the basis of radiographic response and measurement of the serum CA-125 level. The observations of a good tolerability and antitumor activity augur well for the development of this compound. Other phase II studies have been completed in lung cancers, both NSCLC and SCLC. In relapsed SCLC, vosaroxin showed minimal activity (11% response rate based on intent to treat) when administered at 48 mg/m on a 3 week schedule.311 Interesting data have been reported also with vosaroxin in AML, either as a single-agent therapy or in combination with cytarabine.312 In the case of hematological malignancies, the dose-limiting toxicity was reversible oral mucositis. In monotherapy, the drug induced complete remissions in elderly AML patients. From May 2008 to October 2009, 113 patients were enrolled in the REVEAL-1 (response evaluation of voreloxin in AML) trial, a phase II dose regimen optimization trial of single agent vosaroxin in newly diagnosed elderly AML patients who are unlikely to benefit from standard induction chemotherapy. Patients enrolled in the trial were treated with vosaroxin according to one of three dosing schedules: 72 mg/ m2 vosaroxin dosed weekly for 3 weeks, 72 mg/m2 vosaroxin dosed weekly for 2 weeks, or 72 or 90 mg/m2 vosaroxin dosed on days 1 and 4. In parallel, a second phase II study was conducted of vosaroxin combination with cytarabine for refractory/relapsed AML. Mechanism-based pharmacodynamic activity of the drug was evidenced in the combination study, with the detection of a DNA damage response in peripheral blood mononuclear cells (PBMCs) from vosaroxin-treated AML patients. The detection of drug-induced DNA damage in patient samples provides proof of the mechanism of action. These data prompted the U.S. Food and Drug Administration (FDA) to grant vosaroxin orphan drug designation for the treatment of AML in November 2009. Next, a multinational, randomized, double-blind, placebo-controlled, pivotal phase III trial of vosaroxin in combination with cytarabine was engaged. This VALOR (vosaroxin and Ara-C combination evaluating overall survival in relapsed/refractory AML) trial recently initiated is expected to enroll 450 evaluable patients with first relapsed or refractory AML, at leading sites in the United States, Canada, Europe, Australia, and New Zealand. Patients are expected to be randomized one-to-one to receive either

5.2. C-1311 (Symadex)

C-1311 was initially developed by Xanthus Pharmaceuticals, Inc. (Boston, MA, and Montreal, Canada) before this company was acquired by Antisoma Research Ltd. (London, U.K., and Cambridge, MA) in June 2008. 5.2.1. Chemistry. This compound belongs to a large series of fluorescent imidazoacridinone derivatives initially synthesized by Konopa and co-workers at the University of Gdansk (Poland) in the early 1990s.313−315 The 8-hydroxy substituent is a key element of the bioactivity, and the 5-alkylamino side chain contributes to both target interaction and water solubility. C-1311 was freely soluble in water and relatively stable in solution. For clinical use, the drug is formulated as a lyophilized product containing 100 mg of anhydrous free base of C-1311 per dosage unit.316 The global molecular architecture of the molecule resembles that of anthracyclines (e.g., doxorubicin), anthracenediones (e.g., mitoxantrone), or anthrapyrazoles (e.g., oxantrazole). A quantitative structure−activity relationship (QSAR) study showed that lipophilic properties significantly influence cytotoxicity and antileukemic potency in this series.317 The imidazole ring condensed with the acridinone backbone increases the electron density of the π system, making the molecule more resistant to enzymatic reduction into oxygen free radicals, which are implicated in the doselimiting cardiotoxicity of anthacyclines. 5.2.2. Pharmacology. C-1311 (Figure 1) is a typical DNAintercalating agent. The planar tetracyclic chromophore inserts between two consecutive base pairs of the DNA so as to unwind the double helix. Upon intercalation, a peroxidasemediated activation of the drug occurs under oxidative enzymatic conditions, to generate a DNA-alkylating agent. The resulting activated molecule covalently binds to DNA.318 This oxidative process explains the key role of the 8-hydroxy group, evidenced in the structure−activity relationships, but both the native molecule and the oxidized iminoquinone product contribute to the cytotoxic action, via topoisomerase II poisoning and DNA alkylation, respectively. At the in vivo level, the DNA alkylation process is likely responsible for the potent antitumor effect of the drug, but certainly for its toxicity as well. Both C-1311 and doxorubicin intercalate into DNA, and their extents of binding to DNA are roughly equivalent. Using spectrophotometry, Burger et al.319 measured association constants for the formation of bound ligand−calf thymus DNA complex of 3.1 × 106 and 2.36 × 106 M−1 for C-1311 and doxorubicin, respectively. In a more recent study, a weaker binding affinity was measured, with a Ki of 1.2 × 105 M−1, and the authors concluded that the ability of imidazoacridinones to noncovalently bind to DNA is not crucial for their biological activity.320 Binding per se may not be important, but the effect on DNA structure might play a role. A close analogue of C1311, designated C-1305 and containing a triazole in place of the imidazole ring, induces very unusual DNA structural changes in DNA sequences containing guanine triplets. Unlike 3627


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doxorubicin or 22 other DNA-intercalating agents or topoisomerase inhibitors tested, C-1305 was found to perturb the major groove geometry in DNA regions containing triplets of guanines.321 This property is unique among anticancer compounds that bind to DNA. Structural changes in guanine triplets might lead to preferential stabilization of cleavable complexes in these regions. However, studies are required to determine if C-1311 behaves as C-1305 in terms of DNA binding and triple-G recognition. C-1311 was shown to inhibit the catalytic activity of purified topoisomerase II in vitro. In cells, significant levels of DNA complexes were observed when DC-3F fibrosarcoma cells were treated with C-1311, whereas DC-3F/9-OHE cells, which are resistant to other topoisomerase II inhibitors, are markedly (30−125-fold) cross-resistant to the drug. This observation, and others, clearly underlines that DNA topoisomerase II is a major cellular target of this imidazoacridinone derivative,322 but topoisomerase II is probably not the exclusive target of the drug, which was shown more recently to function also as a kinase inhibitor. In a meeting abstract, C-1311 was described as a potent and selective inhibitor of the FMS-like tyrosine kinase 3 (FLT3),323 but this preliminary information was never confirmed in a full study. Interestingly, C-1311 also seems to be an effective inhibitor of HIF-1α, VEGF, and angiogenesis. C1311 significantly affects angiogenesis in vivo, as measured by vascularization of Matrigel plugs in mice.324 At the cellular level, the drug easily accumulates in the nuclear compartment, inhibits topoisomerase II, and triggers cell death.322 The mechanism of action has been thoroughly investigated with different cancer cell types and models. A potent drug-induced arrest of the cell cycle progression in the G2 phase has been reported in leukemia cells and in cells derived from solid tumors, in particular colon carcinoma, ovarian, and osteogenic sarcoma cell lines.225−227 However, the cytotoxic effect of C-1311 is not related to the extent of G2M accumulation in different cell lines.228,229 Interestingly, unlike other topoisomerase II inhibitors, C-1311 was found to be equally cytotoxic toward fast-growing monolayer cultures and cells growing in three dimensions as multicellular spheroids, which have a slower growth fraction.322 In combination with a taxane, the drug may be particularly interesting for the treatment of bladder cancers.330 The type of cell death observed upon drug treatment seems to vary from one cell to another, depending on the intrinsic cell machinery and possibly the drug concentration and/or incubation time. Both apoptosis and cell death by a process of mitotic catastrophe have been reported.327,328 C-1311-induced mitotic catastrophe may be considered as a step precipitating delayed apoptotic responses.331 A lysosomotropic effect has also been reported in colon cancer cells.332 A drug-induced cellular autolysis, with a profound lysosomal rupture, may be a key characteristic of this anticancer agent and clearly suggests a specific mechanism of action, distinct from that of conventional topoisomerase II poisons. C-1311 is active against a wide variety of cell lines288 and is a weak substrate for P-glycoprotein (ABCB1) in contrast to doxorubicin and paclitaxel. The drug may be used to reverse multidrug resistance in cancer cells.333 However, the drug seems to be a good substrate for the ABCG2 (BCRP) transporter, as is the case for other anticancer drugs such as mitoxantrone and the camptothecin derivative SN-38. It was shown that ABCG2-overexpressing lung cancer A549/K1.5 cells extrude C-1311 efficiently.334,335

The drug has been selected for clinical development on the basis of its atypical mechanism of action and its antitumor activity demonstrated in several xenograft models. C-1311 was found to significantly delay tumor growth of human colon cancer xenograft HT29, after a single-dose intraperitoneal (ip) bolus injection.319 The efficacy profile was completed by the European Organisation for Research and Treatment of Cancer and Screening and Pharmacology Group (EORTC-SPG) screening laboratories,332 but the complete data were apparently not published. Colon cancer cell lines seem to be particularly sensitive to C-1311 as judged from in vitro data and the hollow fiber assay in vivo.336 From the pharmacokinetic point of view, C-1311 is quickly cleared from the plasma and rapidly distributed into the tissues. The plasma pharmacokinetics are linear up to doses of 100 mg/kg. Concentrations of C-1311 are greater in the cellular fraction of the blood than in the plasma.337 A recent study with the analogue C-1305 revealed that this triazoloacridinone is an effective inhibitor of CYP1A2 and CYP3A4 and that flavin monooxygenases FMO1 and FMO3, not cytochrome P450 isoenzymes, contribute to its metabolism.338 Similarly, C-1311 is a good substrate for human recombinant FMO1 and FMO3 but not for FMO5. The microsomal metabolite of C-1311, which is also a specific substrate of UGT1A1, is an N-oxide derivative.339 5.2.3. Clinical Development. The clinical development of C-1311 was initiated at least 5 years ago.340 In a phase I study performed with patients with tumors refractory to conventional therapy, and using a dosing schedule with a 1 h infusion daily for 5 consecutive days every 3 weeks and then once every 3 weeks (q3w), anMTD of 950 mg/m2 was determined and a recommended dose (RD) of 850 mg/m2 was proposed. The safety profile of the drug was acceptable, with reversible doserelated neutropenia as the only dose-limiting toxicity (DLT). In this study, preliminary signs of clinical efficacy were noted.341 In another phase I study performed in two French cancer centers, a similar profile of tolerance was reported. The drug was given intravenously (iv) to 22 patients with advanced metastatic diseases (all with a very poor prognosis), once a week for 3 weeks with 1 week off. In this case, the MTD was 640 mg/m2 and the RD was 480 mg/m2. Grade 4 neutropaenia was the DLT, and no cardiac toxicity was observed. There was no complete or partial response, but a modest response to treatment (stabilized disease) was noted in six patients, especially two patients with a head and neck tumor.340,342 These two phase I studies indicated that the drug is safe and manageable. A phase II trial in advanced breast cancer was reported in 2008. A totat of 53 patients with breast cancer resistant to taxanes, anthracyclines, and other agents were enrolled, and a total of 163 cycles of therapy were administered, for a total cumulative dose of 3.9 g/patient. Neutropenia was the only serious toxicity. An overall therapeutic effect was observed in 40% of patients, with two partial responses lasting up to 9 months, and 36% of patients sustained stable disease,343 but despite these interesting data, the clinical development of C-1311 has been halted apparently. After the acquisition of Xanthus, Antisoma Plc announced that the Symadex program was placed on hold to concentrate on the development of other Antisoma products, including the topoisomerase II inhibitor Xanafide (AS1413, amonafide) currently in phase III development in secondary AML (http://www.citycomments.co.uk/ PDFS/as160508.pdf). Altogether, the data suggest that C-1311 is an atypical topoisomerase II poison and a potent antitumor agent. The 3628


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XK469.358 However, along with topoisomerase II inhibition, other factors may contribute to the cytotoxicity of the drug. Binding to the peripheral benzodiazepine receptor has been proposed, due to an observed correlation between the cytotoxic response to XK469 accompanied by apoptosis and the extent of drug binding to the receptor in cell culture.359 p53-dependent and -independent G2-M arrests via inactivation of cdc2-cyclin B1 kinase activity have also been evoked360 as well as the druginduced mitotic arrest, correlated with the inhibition of cyclin B1 ubiquitination.361,362 Additional studies showed that the antiproliferative effect of XK469 is mediated by inhibiting the mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK)/mitogen-activated protein kinase (MAPK) signaling pathways.363,364 Whatever the exact pathways, which is as usual cell-type-dependent and probably distinct in vitro and in vivo, it is clear that this drug exerts potent proapoptotic functions, 365 acts as an inductor of autophagy 366 or senescence367 depending on the cell type, and displays a high potential of antitumor activities in vivo.368 The drug has shown marked activity in several xenograft models of leukemia and solid tumors, including neuroblastoma to cite a very recent example.369 In an earlier study, XK469 was active against seven of seven murine tumors tested, including pancreatic ductal carcinomas and colon and mammary adenocarcinomas.344 XK469 has also revealed activity in Waldenstrom’s macroglobulinemia, which is a rare type of slow-growing, nonHodgkin lymphoma, inducing overproduction of immunoglobulin M antibody (IgM or macroglobulin). XK469 induces apoptosis in the Waldenstrom’s macroglobulinemia cell line WSU-WM,370 but topoisomerase IIβ inhibition by this drug is not sufficient for therapeutic effects in this xenograft model.371 However, it potentiates the activity of etoposide in this model,372 through an up-regulation of topoisomerase IIα levels, which consequently sensitizes indolent malignant B cells to the cytotoxic effect of etoposide in a schedule-dependent manner.373 It is interesting to note also that XK-469 is well tolerated by the oral route, requiring 35% higher dosages per os (po) to reach the same efficacy and toxicity as produced iv.368 According to bioavailability and pharmacokinetic studies in rats, an oral dosage form of R-XK469 could be developed in the clinic.374 5.3.3. Clinical Development. In 1998, a paper published by Corbett and co-workers concluded “the analog XK469 is in clinical development”.375 Thirteen years later, this drug is still in early phases of clinical development, which may not augur well for this compound. At least three phase I investigations have been published over the past 4 years. In patients with advanced solid tumors and with an alternate single-dose schedule of once every 21 days, a partial response was observed in a patient with nasopharyngeal carcinoma, but a significant interpatient pharmacokinetic variability in clearance was also noticed, prompting investigation into the presence of genetic polymorphism in relevant metabolizing enzymes.376 In another study with 21 evaluable patients, no antitumor activity was identified.377 In a third phase I study conducted in patients with refractory acute leukemia, 1 of 42 patients achieved a complete remission and 5 patients had hematologic improvement.378 XK469R was generally well-tolerated and induced reproducible and reversible bone marrow suppression at all dose levels evaluated. The authors concluded that further exploration of this drug, in combination with other established agents, is warranted in patients with refractory AML.378 Finally, in a recent note, a clinical response in a pediatric indication was

clinical development of the drug for the treatment of solid tumors may be pursued, but in addition to cancers, Symadex is undergoing testing for the treatment of non-neoplastic disorders, in particular autoimmune diseases such as multiple sclerosis and rheumatoid arthritis. In this context, the preclinical data also look interesting (http://www. medicalnewstoday.com/articles/104469.php). 5.3. R(+)XK469 (NSC 698215)

R(+)XK469 was developed by the National Cancer Institute (Bethesda, MD). 5.3.1. Chemistry. With a molecular weight of about 350, R(+)XK469 is a small molecule, and it is structurally simple and apparently easy to synthesize. The chloroquinoxaline moiety is appended to a phenoxy group substituted with a propanoic acid side chain (2-[4-[(7-chloro-2-quinoxalinyl)oxy)phenoxy]propanoic acid) (Figure 1). This compound derives from the herbicide quizalofop-ethyl (XK472, Assure, from Dupont). The acidic function provides water solubility and reinforces activity, compared to the acid-free analogue XB947 initially discovered.344 XK469 is easily formulatable.345 The racemate drug XK469 (NSC 656889 or NSC 697887) was characterized as the first topoisomerase IIβ-specific inhibitor,346 in contrast to the simplified analogue chloroquinoxalinesulfonamide (chlorosulfaquinoxaline, NSC 339004), which inhibits both isoforms of the enzyme.347 Both the R-(+) and S-(−) enantiomers are cytotoxic and active against topoisomerase II, but the R isomer is more potent. Unsurprisingly, many analogues have been synthesized in the past few years, with, for example, the bioisosteric replacements of the quinoxaline moiety of XK469 by quinazoline, benzotriazine, and quinoline ring systems,348 or naphthyridine, pyrrole, and imidazole,349 but the quinoxaline ring in XK469 is fundamental to the bioactivity against transplanted tumors in mice. Similarly, a chloro substituent350 and an intact 2oxypropionic acid moiety351 are prerequisites for maximum antitumor activity of XK469. A highly rigidified, polycyclic analogue of XK469 has also been synthesized, but this compound proved to be considerably less active than the parent drug.352 5.3.2. Pharmacology. Initial studies were conducted with the racemate form of XK469, and potent activities in vitro and in vivo were observed, but early on, the R-(+) enantiomer was selected. In fact, the S-(−) isomer is rapidly and almost completely converted to the R-(+) form in vivo, in rats, mice, and dogs.353,354 Moreover, the R-(+) form is the less toxic of the two. Several metabolites have been characterized in urine and plasma, but XK469 is the active principle, with a surprisingly long half-life (approximately 3 days). The drug has a low potential for active or toxic metabolites or for drug− drug interactions.355 Its interaction with cytochromes was investigated, and an inhibition of CYP2C9 has been noted in patients.356 The mechanism of action of XK469 is not totally clear. Initially, the drug was characterized as a specific inhibitor of topoisomerase IIβ,347 inducing DNA cleavage by the enzyme at specific sites in the double helix, distinct from those observed with chloroquinoxalinesulfonamide.357 In contrast to amsacrine, topoisomerase IIβ knockout mouse cells were found to be resistant to XK469 as compared to wild-type β+/+ cells. A slight inhibitory activity against topoisomerase I was also observed, but the effect is too weak to conclude that topoisomerase I contributes to the cytotoxic action of 3629


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Table 1. Topoisomerase II Inhibitors Cited in This Review

reported. A 14 year old patient with relapsed neruoblastoma experienced disease stabilization for 14 months while receiving R(+)XK469 monotherapy.379 This is an isolated case, consistent with the previously observed activity of this compound in neuroblastoma cell lines and an in vivo model, and attesting that the drug is still under investigation. However, the three mentioned clinical trials have now been completed, and no new clinical trial has been identified with this drug. Apparently, no pharmaceutical company is involved in its development. The clinical trials engaged with vosaroxin, C-1311, and XK469 illustrate the costly and long-horizon process that the pharmaceutical industry is facing, with more and more difficulties in identifying the “winner” (and eliminating the “losers” as soon as possible), a challenging research-driven innovation path, which has not been very successful in recent years. Efforts must continue to select the best drug, but perhaps most importantly to identify the most appropriate patient population to treat with these topoisomerase II inhibitors. In the same vein, we could also cite the antitumor antibiotic elsamitrucin (also known as elsamicin A379 or SPI 28090), developed by Spectrum Pharmaceuticals. The drug is apparently in phase I trial in combination with paclitaxel in patients with advanced solid tumors (http://www.sppirx.com/ elsamitrucin.html). A dose-escalating phase I study for the

treatment of malignant solid tumors in dogs has been recently published,380 15 years after the report of a human phase II study for the treatment of non-Hodgkin lymphoma.381

6. CONCLUSION AND PERSPECTIVES As illustrated here, there exists a large chemical and structural diversity of topoisomerase II modulators, acting as catalytic inhibitors or poisons of the enzyme−DNA complexes (Table 1). Many types of small molecules, synthetic products and natural substances, targeting this enzyme (or protein isoforms) have been described over the past few years. It is difficult to classify all these compounds, due to their very diverse structures, origins, and/or mechanisms of action. Broadly speaking, two main categories are considered (Table 1), but beyond this mechanistic distinction, one could also define groups in terms of DNA intercalation (doxorubicin, daunorubicin, amonafide, mitonafide, mitoxantrone, amsacrine, DACA, ellipticine, ...) vs binding to the ATPase domain of the enzyme, for example (thiosemicarbazones, neoamphimedine, gambogic acid, salvicine, purine analogues, ...). However, for many of the molecules cited here, the exact mode of interaction with the enzyme, the DNA, or the complex is not well-known, and thus, a more precise classification is not possible. Moreover, many of the topoisomerase II inhibitors listed here have effects at other biochemical loci, as is the case 3630


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invoked. First, topoisomerase II inhibitors such as etoposide and doxorubicin are clinically effective (as well as costeffective), are routinely used in the daily practice of oncology in many combination regimen, and have not been replaced with newer drugs. Second, the constant searches and discoveries of new topoisomerase II-interacting products attest to the need for such types of products. Third, broadly speaking, the search for new cytotoxic agents, interfering with topoisomerase II or other targets associated with tumor proliferation, remains an active field of reasearch, certainly controversial, but nevertheless always pursued. The recent approval of drugs such as vinflunine (Javlor), trabectedin (Yondelis), ixabepilone (Ixempra), or eribulin (Halaven), and the late-stage development of products such as patupilone,382 fosbretabulin (combretastatin-A4 phosphate, Zybrestat),383 and plitidepsin (Aplidin),384 can be taken as an indication that this domain of oncology is still active and valid, despite the excessively optimistic, somewhat pollyannaish view of “modern targeted therapeutics”. There are several successful examples of rationally based designed drugs (e.g., imatinib and trastuzumab), but there are also notorious examples of target-specific agents that only provide small gains in symptom control and/or survival.385 The frontier between cytotoxic agents, including topoisomerase II inhibitors, and the so-called targeted therapeutics (some of which are particularly cytotoxic!) is somewhat narrow and often questionable. We can refer here to two examples: First, etoposide, which is the archetype of topoisomerase II poison, exquisitely binds to the topoisomerase II−DNA complex, with a modest affinity for topoisomerase II alone and little or no affinity for free DNA; no other target has been identified thus far for this natural product. This is a true targeted compound. Second, the kinase inhibitor imatinib, which has pioneered the era of targeted therapeutics, has been recently reported to interfere with topoisomerases functions, suggesting that this activity may be a significant factor in imatinib-induced apoptosis in CML.386 After all, it is not just drugs against “princely targets” that can help to treat cancer, but also drugs acting at the level of “pauper targets” which bear the same potential for efficacy.385 It is also tempting to answer “no” to the question for several reasons as well. First, topoisomerase II is a ubiquitous enzyme, present in both tumoral and nontumoral cells, and therefore a strict cancer specificity cannot be achieved with this type of target; more cancer-selective targets are now preferred. Second, the available inhibitors, in particular etoposide, are extremelly potent in terms of target inhibition; there may be little room for improvement at this level. Third, and this is general to all cytotoxic agents, cytotoxic chemotherapy has only made a minor contribution to cancer survival. The overall contribution of curative and adjuvant cytotoxic chemotherapy to 5 year survival in adults has been estimated to be 2.1% in the United States.387 In fact, surgery and radiotherapy have certainly provided a greater contribution to treatment and survival in solid cancers than drug treatments and in particular cytotoxic agents, but cancer chemotherapy remains the only treatment modality with curative activity against multiple forms of metastatic malignancy.388 The future certainly resides in the wider use of genetic screening and biomarkers to identify subtypes which will respond more efficiently to these topoisomerase II inhibitors. Further research is suggested into areas such as genetic markers, chemotherapy regimens, patient and carer quality of life, and patient views on survival advantages vs treatment disadvantages. Pharmacogenomic and

for all types of drugs. For antitumor agents in particular, the “off-target” effects can be critical for effective antitumor activity, and this aspect, specific for any given structural chemical series, complicates the lives of medicinal chemists and pharmacologists. Rarely does 1 week go past without a new inhibitor described, adding to the already long corpus of literature in this domain. These compounds or their parts can be combined to create new molecules endowed with desired properties: from reinforced DNA damage to cancer cell delivery or metal complexation, for example (Figure 11). The topoisomerase II

Figure 11. Current challenges in the design of topoisomerase II inhibitors: (a) illustration of drug design to create new topoisomerase II inhibitors endowed with specific properties, (b) criteria taken into acount to optimize anticancer agents targeting topoisomerase II.

field can thus be considered as “alive and well” on the basis of the number of new inhibitors regularly described and several drug candidates currently in the clinic. However, this positive assessment must not be considered with blinders on to prevent from looking sideways. Volume (large number of inhibitors discovered and tested) does not necessarily go with innovation (new mechanisms, new pharmacological profiles). The situation is not as clear as it may seem because no new topoisomerase II inhibitor has been clinically approved over the past two decades or more. Much to our dismay, the recurrent hopes pronounced when a new inhibitor is discovered and characterized pharmacologically are rarely maintained at the clinical level. We are still waiting for a successor to etoposide or doxorubicin. Nevertheless, topoisomerase II, as a veteran or mature cancer target, is fundamentally alive and well. The lack of new approved topoisomerase II inhibitors over the past 20 years begs the following question: Nowaday, in the era of targeted therapy, is there still room for new topoisomerase II inhibitors in the anticancer arsenal? In light of the above catalog of new compounds identified, the first answer is a clear “yes”. At least three reasons can be 3631


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drugs are almost all topoisomerase II poisons that kill cells by generating enzyme-mediated DNA damage. The most cytotoxic compounds belong to this category. The design of catalytic inhibitors is another option, potentially leading to nonmutagenic compounds, but their antitumor activity remains to be established in the clinic. In this category, two complementary options seem to be encouraging: on one hand, the design of ATP competitive inhibitors, such as compounds TCS2438 and QAP-147 and, on the other hand, blockers of the DNA−topoisomerase II interface such as nepalensinol B216 and simocyclinone D8.170 However, at first sight topoisomerase II poisons seem to exhibit more potent antitumor activity in vivo. The future certainly resides in the design and development of topoisomerase II poisons specific for the α isoform, potentially less toxic to nontumor cells, and not inducing secondary malignancies, but the most important challenge resides at the cellular, not molecular, level. The objective is to design compounds targeting cancer cells specifically. Patient selection should become a priority for drug development. Focusing on the right patients should reduce the risk of product failure, as well as the length and size of clinical studies needed to show a statistically significant benefit. In this respect, the case of the epipodophyllotoxin− spermine conjugate F14512 is exemplary. The drug, currently tested in patients with acute myeloid leukemia, is accompanied by a functional biomarker to select patients with an active PTS, by means of a robust cytometry analysis using a fluorescent spermine conjugate.291 It is too early to judge the value of this selection procedure combining a new therapeutic product and a patient selection biomarker, but this is certainly the only topoisomerase II inhibitor to which the concept of personalized medicine is applied. The ultimate objective is to administer F14512 only to patients with PTS-positive cancers so as to maximize the level of response. The polyamine tail of F14512 serves to drive selectively the topoisomerase II poison to the PTS-efficient cancer cells, in addition to reinforcing the interaction with the topoisomerase II target. The spermine conjugation makes this new drug a robust candidate that is both molecularly targeted to the topoisomerase II enzyme and cellularly targeted to cancer cells. Speaking of molecular targeting, a drug such as etoposide is with no doubt far more addicted to its target than a broad- or narrow-spectrum kinase inhibitor. In the long term, the procedure implemented with F14512 and its functional biomarker will limit the patient population from which the new drug could receive marketing authorization, but the drug should also exhibit a superior efficacy or safety profile in the target AML patient population compared to a nonpreselected conventional population. Considering F14512 brings us to the family of epipodophyllotoxin derivatives which are “on the road again”, with the regular design and synthesis of new derivatives equipped with a variety of functional groups including alkylating, photoactive, or cell-delivery heads. This family of products also drives us to the field of natural products and hemisynthetic derivatives. As discussed in this review, natural products continue to provide a diverse and unique source of bioactive topoisomerase II inhibitors. Natural product research remains a viable and productive route to drug discovery, even if there are wellknown hurdles to overcome in any natural product development program (time-to-lead, supply, ownership, ...). Dual inhibition of topoisomerases I and II is another option. The emergence of resistance phenomena to topoisomerase I inhibitors is often accompanied by a concomitant rise in the

molecular markers should help us to better understand the mechanisms of the disease, predict toxicity, and refine therapies with topoisomerase II inhibitors. Appropriate combinations of DNA-damaging anticancer treatments, possibly combined with DNA-damage response (DDR) pathway regulators,389 should be encouraged. Over the past 30 years, since the discovery of topoisomerase II, extensive efforts have been devoted to elucidating the intimate mechanism of action of this enzyme and its role in cancer progression and metastasis. Nowadays, not only the molecular structures of type II enzymes are known (at least the ATP-binding domain for human topoisomerase IIα, not the full-size human enzyme) but also its many cellular roles are being better understood and appreciated. The past few years have seen en explosion in findings concerning the biochemistry and biology of type II topoisomerases.9,13,14 Structural insights have been enormous. Recently, the crystal structure of a large fragment of human topoisomerase IIβ complexed to DNA and to etoposide has revealed structural details of drug-induced stabilization of the cleavage complex, thus explaining the structure−activity relations of etoposide derivatives and the molecular basis of drug-resistant mutations.254 At the cellular level, advances have also been important.390 Key recent advances are, on one hand, the involvement of topoisomerase II in transcription and its requirement (redundantly with topoisomerase I) for optimal recruitment of RNA polymerase II at promoter regions391 and, on the other hand, the discovery of proteins that regulate the intrinsic DNA cleavage−religation reaction catalyzed by topoisomerase II, in particular TDP1 and TDP2 (TTRAP), two 5′-tyrosyl DNA phosphodiesterases that repair topoisomerase-mediated DNA damage.392 Cellular depletion of TDP2 increases the susceptibility and sensitivity to topoisomerase II-induced DNA double-strand breaks. TDP2-deleted cells are highly sensitive to etoposide, but not to the topoisomerase I poison camptothecin or a DNAalkylating agent.393 There are certainly other factors that control the topoisomerisation reaction, and these regulators could be considered as potential topoisomerase II-dependent targets of interest to limit tumor cell growth and/or to modulate the activity of topoisomerase II inhibitors. Topoisomerase II remains a challenging protein, and the principal difficulty at the pharmacological level has been, I believe, to target specifically one isoform over the other. A few isoformselective inhibitors have been described, such as the thiosemicarbazone derivative Dp44mT poisoning selectively topoisomerase IIα,41 but the search for potent and specific inhibitors of topoisomerase IIβ remains a major challenge. It is the C-terminal domain of topoisomerase II that distinguishes the two isoforms in terms of binding to DNA. Topoisomerase IIβ binds DNA with a higher affinity than topoisomerase IIα.394 The C-terminal domain is viewed as a negative regulator of DNA interaction, and this provides a rationale for isoformspecific functions in vivo.395 DNA topoisomerase II is a “molecular engineer” that unravels the DNA during replication and transcription. The human enzyme can be considered as the juxtaposition of three domains: (i) the N-terminal ATP-binding domain, which is conserved evolutionally (several catalytic inhibitors block ATP from its binding pocket in this domain, thereby attenuating the ATPase activity), (ii) the DNA-binding/cleaving domain, which contains the catalytic active site essential for covalent complex formation (this is the binding site for topoisomerase II poisons), and (iii) the C-terminal tail. The clinically active 3632


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Biography

level of topoisomerase II expression and vice versa, leading to the failure of clinical therapies. A single compound able to inhibit both enzymes may present the advantage of improving antitopoisomerase activity, with reduced toxic side effects.396 This is the theory; in practice, the vast majority of dual topoisomerase inhibitors act potently on one enzyme, while affecting much less efficiently the other. For example, the drug TAS-103 initially characterized as a dual inhibitor,397 and often referred to as such, functions in fact essentially as a topoisomerase II poison, with little effect on topoisomerase I in a cellular context.398,399 There are several examples of this type, and to the best of our knowledge, no true equipotent dual inhibitor has ever been made. Topoisomerase II inhibitors are useful for the treatment of cancers, but they are interesting as well to combat other pathologies, in particular certain bacterial or parasitic infections.400,401 Certain topoisomerase II poisons, such as idarubicin, display interesting antifungal activities.402 Bacterial type II topoisomerases are the targets for quinolones, the most important class of antibacterial in clinical use.403,404 Topoisomerase II is certainly not a target in disgrace, but the research has largely evolved over the past few years, and at least four levels of activity must be considered (Figure 11): (i) target interference, at the protein−DNA interface in the case of the topoisomerase II poisons or at the ATP-binding site as is frequently the case for catalytic inhibitors; (ii) in terms of enzyme selectivity, with a preference for targeting the α isoform to the β form; (iii) the signaling pathway(s) activated upon topoisomerase II inhibition, with a particular emphasis on DNA damage and repair, as well as on mechanisms of drug-induced cell death; (iv) the selectivity for cancer vs normal cells, which is a key aspect that translates at the clinical level in terms of safety/efficacy ratio (in addition to tissue distribution, pharmacokinetics/dynamics, etc.). Times have changed; marked topoisomerase II inhibition, whatever the molecular mechanism implicated, does not necessarily need to be coupled with a highly potent cytotoxic activity. A cytotoxic action is needed, but more important are the amplitudes of molecular and cellular selectivities. Useful topoisomerase II inhibitors will be those that best combine these aspects. A parallel with other popular therapeutic targets, such as protein kinases, can be established. The initial goal was to generate inhibitors with a high degree of potency, but experience has revealed that molecular and cellular selectivities are essential factors which greatly affect the safety/efficacy equilibrium. Novel generations of topoisomerase inhibitors capturing these criteria are being designed. A rebound of the topoisomerase II field can be anticipated in the near future.

Christian Bailly (born 1964, France) is Director of Research at the Pierre Fabre Research Institute (IRPF, Toulouse, France). He received his Ph.D. in life sciences in 1989 (University of Lille, France) for work on the synthesis and biological study of novel DNA-binding anticancer agents. He then joined the Department of Pharmacology, University of Cambridge (United Kingdom), for a postdoctoral period and held a research associate position (1990−1995) on the team of Prof. Michael J. Waring (University of Cambridge), studying drug−nucleic acid interactions. He then came back to France as Director of Research at the National Institute of Health and Medical Research (INSERM U524, Lille, France), working for 8 years on the mechanism of action of topoisomerase I and II inhibitors and DNA recognition. In 2001 he received the INSERM prize for Therapeutic Research. In 2003, he moved to the Pierre Fabre Research Institute as Director of Oncology Research, managing two research centers in immunology (CIPF, 2004−2010) and experimental oncology (2003−2010). He is now responsible for the research activities (drug discovery) of the IRPF. His research interests extend over a wide range of biologically active molecules, mostly anticancer agents, such as monoclonal antibodies and natural products.

ACKNOWLEDGMENTS I thank colleagues from the Centre de Recherche en Oncologie Expérimentale (CROE) at the Institut de Recherche Pierre Fabre (IRPF, Toulouse, France) for their dedicated work on anticancer agents. REFERENCES (1) Bancaud, A.; Huet, S.; Daigle, N.; Mozziconacci, J.; Beaudouin, J.; Ellenberg, J. EMBO J. 2009, 28, 3785. (2) Roca, J. Nucleic Acids Res. 2009, 37, 721. (3) McClendon, A. K.; Osheroff, N. Mutat. Res. 2007, 623, 83. (4) Chikamori, K.; Grozav, A. G.; Kozuki, T.; Grabowski, D.; Ganapathi, R.; Ganapathi, M. K. Curr. Cancer Drug Targets 2010, 10, 758. (5) Wang, J. C. Annu. Rev. Biochem. 2009, 78, 31. (6) Graille, M.; Cladière, L.; Durand, D.; Lecointe, F.; Gadelle, D.; Quevillon-Cheruel, S.; Vachette, P.; Forterre, P.; van Tilbeurgh, H. Structure 2008, 16, 360. (7) Laponogov, I.; Pan, X. S.; Veselkov, D. A.; McAuley, K. E.; Fisher, L. M.; Sanderson, M. R. PLoS One 2010, 5, e11338. (8) Bax, B. D.; Chan, P. F.; Eggleston, D. S.; Fosberry, A.; Gentry, D. R.; Gorrec, F.; Giordano, I.; Hann, M. M.; Hennessy, A.; Hibbs, M.; Huang, J.; Jones, E.; Jones, J.; Brown, K. K.; Lewis, C. J.; May, E. W.; Saunders, M. R.; Singh, O.; Spitzfaden, C. E.; Shen, C.; Chillings, A.; Theobald, A. J.; Wohlkonig, A.; Pearson, N. D.; Gwynn, M. N. Nature 2010, 466, 935.

AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected]. Notes

The authors declare the following competing financial interest(s):Compound F14512 is currently developed by Pierre Fabre Medicament. 3633


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