Bifunctional Mononuclear Dysprosium Complexes: Single-Ion Magnet

Article Cite This: Inorg. Chem. XXXX, XXX, XXX−XXX

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Bifunctional Mononuclear Dysprosium Complexes: Single-Ion Magnet Behaviors and Antitumor Activities Hua-Hong Zou,†,# Ting Meng,†,# Qi Chen,† Yi-Quan Zhang,*,‡ Hai-Ling Wang,† Bo Li,*,§ Kai Wang,∇ Zi-Lu Chen,† and Fupei Liang*,†,∇

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†

State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry & Pharmacy of Guangxi Normal University, Yucai Road 15, Guilin 541004, People’s Republic of China ‡ Jiangsu Key Laboratory for NSLSCS, School of Physical Science and Technology, Nanjing Normal University, Wenyuan Road 1, Nanjing 210023, People’s Republic of China § College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Wolong Road 1638, Nanyang 473061, People’s Republic of China ∇ Guangxi Key Laboratory of Electrochemical and Magnetochemical Functional Materials, College of Chemistry and Bioengineering, Guilin University of Technology, Jiangan Road 12, Guilin 541004, People’s Republic of China S Supporting Information *

ABSTRACT: Two mononuclear dysprosium complexes (Et 3 NH)[Dy(BrMQ) 4 ]·H 2 O·DMF(BrMQ-Dy) and (Et3NH)[Dy(ClMQ)4]·H2O·DMF (ClMQ-Dy) (H-BrMQ = 5,7-dibromo-2-methyl-8-quinolinol, H-ClMQ = 5,7-dichloro2-methyl-8-quinolinol) were synthesized and characterized. The Dy(III) ions in complexes BrMQ-Dy and ClMQ-Dy have a pseudo-D4d local symmetry. Magnetic characterizations reveal that complex BrMQ-Dy is a single-ion magnet and complex ClMQ-Dy exhibits field-induced slow magnetic relaxation behaviors. The calculated effective barriers of BrMQ-Dy, BrMQ-Dya, ClMQ-Dy, and ClMQ-Dya are 47.8, 27.3, 96.0, and 65.5 cm−1, respectively (BrMQ-Dya and ClMQ-Dya represent the desolvated samples of BrMQ-Dy and ClMQ-Dy, respectively). Ab initio calculations confirmed that coordination symmetry of the Dy(III) ions, electronwithdrawing ligands, and the guest molecules is a key factor affecting the magnetic dynamics of the two complexes. The IC50 values of BrMQ-Dy and ClMQ-Dy against BEL-7404, HeLa, and Hep-G2 cancer cells were 1.01−22.06 μM. Interestingly, two Dy(III) complexes were less toxic to normal HL-7702 cells. BrMQ-Dy and ClMQ-Dy significantly induced cell arrest at G2 phase and down-regulated the G2 phase-related protein levels. Various experiments suggested that BrMQ-Dy and ClMQ-Dy also caused dysfunction of mitochondrial pathways in HeLa cells. Taken together, the different in vitro anticancer activity of complexes BrMQ-Dy and ClMQ-Dy in the order of 5,7-dichloro substitution > 5,7-dibromo substitution.

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INTRODUCTION Single-molecule magnets (SMMs) are extensively studied as promising materials for information storage, spintronic devices, and quantum computing,1−5 thanks to their inherent large spin and high magnetic anisotropies. Great progress has been made in energy barriers (Ueff) and magnetic blocking temperatures (TB), especially mononuclear 4f-based single-ion magnets (SIMs). The outstanding example of SIMs is the pentagonal bipyramindal Dy(III) SIM (Ueff = 1541 cm−1) by Layfield.6 Recently, Layfield reported the astonishing finding of a dysprosium complex with magnetic hysteresis of up to 80 K over liquid nitrogen temperature.6,7 Further progress is expected in the near future of SMMs. For SIMs, the key question is on the magnetic dynamics, that is, how to control the contributions of Orbach, Raman, and direct relaxation processes to energy barriers and suppress the quantum © XXXX American Chemical Society

tunneling of magnetization (QTM). From the structural chemistry point of view, the asymmetric factors of the coordination environments of a single lanthanide ion is very important; furthermore, specific local symmetries can minimize the QTM based on the crystal field theory.8,9 Many excellent SIMs can be divided into typical local symmetries, especially D5h for pentagonal bipyramidal,7,10 D4d for square antiprismatic,11−14 and D∞h for linear15−17 and sandwich-type complexes.18−20 Dy-based SIMs with D5h local symmetry were shown to be superior for the enhancement of the effective energy barrier and suppression of QTM. However, D4d local symmetry still has not been established.21,22 Received: August 8, 2018

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DOI: 10.1021/acs.inorgchem.8b02250 Inorg. Chem. XXXX, XXX, XXX−XXX

Article

Inorganic Chemistry

complexes with H-BrMQ and H-ClMQ remain unknown. Herein, we first reported the antitumor properties of (Et3NH)[Dy(BrMQ)4]·H2O·DMF(BrMQ-Dy) and (Et3NH)[Dy(ClMQ)4 ]·H2 O·DMF (ClMQ-Dy). Both complexes BrMQ-Dy and ClMQ-Dy have a pseudo-D4d local symmetry. Complex BrMQ-Dy is a SIM, while complex ClMQ-Dy exhibits field-induced slow magnetic relaxation behaviors. Furthermore, both complexes exhibit high cytotoxicity, suggesting that they have the potential to be developed into new antitumor agents. Thus, this work provides the rare examples of new bifunctional molecules with both SIM behaviors and antitumor activities.

On the other hand, metal complexes with anticancer activity have attracted great research interest since the discovery and the clinical success of the platinum anticancer complexes.23−25 Because of the severe side effects, the acquired or intrinsic drug resistance, and the limited anticancer spectrum of the Pt(II/ V)-based drugs, metal complexes other than platinum have been intensively studied for developing non-Pt-based anticancer compounds with improved pharmacological properties.26−33 Based on their typical nature of higher affinity for tumor tissues,34−36 lanthanide complexes have naturally drawn the attention of the researchers, and many complexes have been synthesized to study their antitumor activity with different types of ligands, such as amino acid, polypyridyl, and acyhydrazone.37−43 Furthermore, for the purpose of the targeted delivery of the anticancer complexes, a targeted delivery system has been developed by encapsulating the lanthanide complexes with antitumor activity into SiO2 nanospheres, and grafting β-D-galactose onto the surface of the nanospheres.44 This compound more selective for Hep-G2 tumor cells versus 293T cells.44 This result reveals the effectiveness of the targeted delivery for improving the pharmacological properties of the anticancer metal complexes. From the viewpoint of targeted delivery, molecular systems with simultaneously magnetism and anticancer activity might be of great interest. However, such systems have been studied rarely so far.45 With those above-mentioned in mind, we intend to develop multifunctional SIMs with both slow magnetic relaxation behavior and anticancer activities. Two mononuclear dysprosium complexes with 5,7-dibromo-2-methyl-8-quinolinol (HBrMQ) and 5,7-dichloro-2-methyl-8-quinolinol (H-ClMQ) (Scheme 1) are studied in the present work. Selection of

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RESULTS AND DISCUSSION Synthesis. Reactions of dysprosium nitrate and H-BrMQ and H-ClMQ in the presence of Et3N (5:10:36 molar ratio) in a mixture of DMF and H2O (4:1) solvent resulted in yellow crystals of complexes BrMQ-Dy and ClMQ-Dy, respectively. Notably, Et3N plays a key role in keeping the charge balance of two complexes. The dihalo-substituted 2-methyl-8-hydroxylquinoline ligands exhibit bidentate-chelated coordination modes in both complexes. No crystal was obtained without adding Et3N. The reactions of H-BrMQ or H-ClMQ with different Dy(III) salts, such as DyCl3 and Dy(ClO4)3, have been tested, but no crystals were obtained. The PXRD patterns of BrMQ-Dy and ClMQ-Dy further confirmed the solid-state phase purity (see Figure S1 in the Supporting Information). Crystal Structures. X-ray diffraction (XRD) data reveal that complex BrMQ-Dy comprises a mononuclear anion complex, [Dy(C10H6NOBr2)4]−, a protonated triethylamine counter cationic, an uncoordinated DMF, and one guest water molecule. Complex BrMQ-Dy crystallized in the orthorhombic space group Pbca (Table 1). To maintain simplicity and clarity,

Scheme 1. Chemical Structure of H-BrMQ (Left) and HClMQ (Right)

Table 1. Crystal Data for Complexes BrMQ-Dy and ClMQDy

formula formula weight crystal system space group a, Å b, Å c, Å b, ° V, Å3 Z Dc, g cm−3 μ, mm−1 F(000) T, K θ, min−max, ° tot. data uniq. data Rint observed data [I > 2σ(I)] Nref, Npar R1 wR2 S min−max. resd. dens. [e/Å−3]

dihalo-substituted 2-methyl-8-quinolinol is based on the following considerations: (1) dihalo-substituted 2-methyl-8-quinolinol is easy to coordinate with chelating mode, which favors the formation of mononuclear lanthanide complex with expected geometry; (2) 8-hydroxyquinoline derivatives and some metal complexes of theirs have been found to show high in vitro antitumor activity,46−64 and their complexes with lanthanide ions may be favorable for the construction of the multifunctional system with both SMM and antitumor properties; (3) The different substituents on the 8-hydroxyquinoline are helpful for the study of the substituent effect on the magnetic and biological activities. Although the binding properties of 5,7-dibromo-8-quinolinol dysprosium(III) complex with DNA has been reported,64 a more-detailed, deeper understanding on the dysprosiummediated apoptosis-inducing effects is necessary and in favor of the development of Dy(III)-based anticancer complexes. Furthermore, the in vitro anticancer mechanism of Dy(III) B

BrMQ-Dy

ClMQ-Dy

C49H49Br8DyN6O6 1619.68 orthorhombic Pbca 21.630(4) 22.166(4) 23.582(4) 90 11306(3) 8 1.900 7.027 6208 296 1.6, 25.0 68538 9948 0.081 6603 9948, 640 0.0473 0.1389 1.07 −0.83, 1.69

C49H49Cl8DyN6O6 1264.04 monoclinic P21/n 13.139(6) 22.056(11) 18.542(9) 91.993(7) 5370(4) 4 1.562 1.842 2540 296 1.4, 29.8 75884 15270 0.040 10329 15270, 655 0.0333 0.1060 1.04 −0.51, 1.16


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Inorganic Chemistry

(Figure S2 in the Supporting Information), including one between the methyl carbon atom (C31) of the ligand and the oxygen (O5) of lattice water molecule with a C31···O5 distance of 3.170(1) Å and another between the oxygen (O5) of the lattice water molecule and nitrogen (N5) of protonated triethylamine (O5···N5 distance = 2.591(1) Å). These hydrogen bond interactions of complex BrMQ-Dy play a important role in the consolidation of the solid structure (Table S3 in the Supporting Information). The molecular structure of complex ClMQ-Dy was similar to complex BrMQ-Dy, except for the different dihalosubstituted 2-methyl-8-hydroxylquinoline ligands. However, complex ClMQ-Dy crystallized in the monoclinic space group P21/n, and Dy(III) center was also eight-coordinated with four N,O-chelated ClMQ monoanions. The molecular structures of ClMQ-Dy are shown in Figure S3 in the Supporting Information, and specific parameters are seen in Table S1. The Dy−O bond lengths are in the range of 2.204(3)− 2.337(3) Å, whereas the Dy−N bonds lie in the narrow range of 2.607(3)−2.682(3) Å. Hydrogen bonds exist between the lattice water molecule (O27) and O9 atom from DMF with an O27···O9 distance of 2.826 Å and between the O27 and the O11 atom from the ClMQ ligand with an O27···O11 distance of 2.936 Å for complex ClMQ-Dy(Table S3). In addition, the nearest Dy···Dy distances in complexes BrMQ-Dy and ClMQDy are found to be 10.83 Å (BrMQ-Dy) and 13.14 Å (ClMQDy), indicating well-isolated units (Table S4 in the Supporting Information). We found that the shortest intermolecular Dy− Dy distance of complex ClMQ-Dy is larger than that in complex BrMQ-Dy, mainly because of the space position of the solvent and related hydrogen bond interaction, which further affected the different magnetic properties of complexes BrMQ-Dy and ClMQ-Dy. Magnetic Properties. Magnetic susceptibilities of compounds BrMQ-Dy, BrMQ-Dya, ClMQ-Dy, and ClMQ-Dya (BrMQ-Dya and ClMQ-Dya represent the desolvated samples of BrMQ-Dy and ClMQ-Dy, respectively) were measured under an applied field of 1000 Oe between 300 and 2 K with polycrystalline samples (Figures S4 and S5 in the Supporting Information). At 300 K, the χMT values of BrMQ-Dy, BrMQDya, ClMQ-Dy, and ClMQ-Dya are 14.09, 13.96, 14.20, and 14.27, respectively, which are in good agreement with the expected value of 14.17 cm3 K mol−1 for a noninteracting Dy(III) ion with a 6H15/2 ground term (g = 4/3, S = 5/2, L = 5).

all H atoms and solvent molecules are not considered. The Dy(III) ion is eight-coordinated with four N,O-chelated BrMQ monoanions (Figure 1). The average bond lengths of

Figure 1. Crystal structure of BrMQ-Dy. [Color legend: Dy, purple; O, red; Br, brown; N, light blue; C, green.]

Dy−N and Dy−O are 2.669 and 2.260 Å (Table S1 in the Supporting Information), respectively. In the case of Dy, the geometry is correlated to the local anisotropy of Dy(III) ion. Therefore, we analyzed the accurate geometry of the octacoordinated Dy(III) ion using SHAPE software,65 which indicated the degree of distortion of the coordination sphere of complex (ϕ = 0, meaning the perfect polyhedron). The value of the octacoordinated square antiprism structure is smaller than that of the triangular dodecahedron and biaugmented trigonal prism structures. Thus, the coordinated geometry for BrMQ-Dy is a SAPR-8 structure (Table S2 in the Supporting Information). For the Dy(III) ion, two square antiprism are constructed by O2, N1, O4, N4 and O1, N2, O3, N3 with standard deviations of 0.0811 and 0.0726 Å, respectively. The dihedral angle of the two surfaces is 0.0202°. The distances between Dy(III) and the two surfaces are 1.406 and 1.391 Å, respectively. Therefore, complex BrMQ-Dy possesses the least-distorted DyO4N4 coordination sphere. The chelating ligands show almost identical spatial arrangements in the complex, and the arrangement of the BrMQ leads to a distorted square antiprism coordination polyhedron around Dy(III) ion (Figure 2). Interestingly, two significant intermolecular hydrogen bonds are present in BrMQ-Dy

Figure 2. Coordination polyhedrons around the Dy ion (left) and the projection showing the Dy(III) ion square-antiprismatic coordination site in complex BrMQ-Dy (right). [Color legend: Dy, purple; N, light blue; O, red.] C


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Inorganic Chemistry

Figure 3. Temperature dependence of χ″ AC susceptibility from 2 K to 35 K for complex BrMQ-Dy (left). χ″ AC magnetic susceptibility for complex BrMQ-Dy from 1 Hz to 1000 Hz at temperatures from 7 K to 20 K with 1 K intervals (top black = 7 K, right).

Figure 4. Arrhenius plot of the complex; the solid line denotes the best fits (left), and a hysteresis loop for complex BrMQ-Dy at 2 K is shown (right).

without extra DC field. When an optimum field are applied (Figures S9 and S10 in the Supporting Information), χ″ displays strong frequency dependence and peaks, exhibiting field-induced SIM behavior. At low temperature, the increase in χ″ indicates that the QTM has not been completely suppressed for complex ClMQ-Dy, which is a very common physical phenomenon in 4f-SMMs.69−73 At high temperature, the Arrhenius analyses give the Orbach process. The middle segment may be dominated by Raman processes (Figure S12 in the Supporting Information). The fits give parameters of Ueff = 95.9 cm−1 and τ0 = 8.54 × 10−6 s for ClMQ-Dy,Ueff = 54.1 cm−1 and τ0 = 3.22 × 10−7 s for ClMQ-Dya. The Cole−Cole plots presented a nonsymmetric semicircle, which can be fitted to the generalized Debye model, giving α values in the range of 0.022−0.31 for ClMQ-Dy, and 0.045−0.29 for ClMQ-Dya, indicating a moderate distribution of relaxation time (Figure S13 in the Supporting Information). The magnetization relaxation times τ were extracted from the χ″ peaks for BrMQ-Dy and BrMQ-Dya at selected temperatures under 0 Oe. The Arrhenius plot deviates from linearity (Figure 4 and Figure S14), suggesting that apart from the thermally assisted Orbach process, Raman, direct, and QTM processes also change the magnetization direction. Equation 1 was used to fit the entire temperature range:74

Upon cooling, complexes BrMQ-Dy, BrMQ-Dya, ClMQ-Dy, and ClMQ-Dya show typical stark level depopulation. At low temperatures, the isothermal M versus H (Figures S6 and S7 in the Supporting Information) of complexes BrMQ-Dy, BrMQDya, ClMQ-Dy, and ClMQ-Dya are far from reaching saturation, and the nonsuperposition of M vs H/T curves reveal the presence of a obvious magnetic anisotropy due to crystal-field effects.66,67 To explore the dynamics of magnetization, alternatingcurrent (AC) measurements were performed for compounds BrMQ-Dy, BrMQ-Dya, ClMQ-Dy, and ClMQ-Dya (see Figure 3, as well as Figures S8−S10 in the Supporting Information). The temperature and frequency dependencies of the AC susceptibilities for these complexes reveal the typical feature characteristics of SIM. From the frequency dependencies of the in-phase (χ’) and out-of-phase (χ″) components for BrMQ-Dy and BrMQ-Dya, we can derive the magnetization relaxation time in the form of ln τ plotted as a function of 1/T. For BrMQ-Dy, above 15 K, the relaxation follows a thermally activated mechanism affording an energy barrier of 52.8 cm−1 with τ0 = 7.55 × 10−6 s based on the Arrhenius law. For BrMQ-Dya,Ueff = 28.3 cm−1, and τ0 = 2.18 × 10−6 s. The Cole−Cole plots revealed a relatively moderate distribution of the relaxation time, suggesting a single relaxation process operative (Figure S11 in the Supporting Information). However, the α values (Table S5 in the Supporting Information) rapidly increased toward lower temperatures. Such low-temperature behavior indicate the fast relaxation mechanisms, which due to dipolar interactions between hyperfine interactions and paramagnetic centers.68 For complexes ClMQ-Dy and ClMQ-Dya, χ″ magnetic susceptibility showed frequency dependence with peak tails at lower temperatures. This may be attributed to the existence of QTM

i U y τ −1 = τQTM −1 + CT n + τ0−1 expjjj− eff zzz k T {

(1)

where T is the temperature of the maximum in the AC signal and τ is the inverse of AC frequency. The first and second terms refer to the QTM and Raman process, respectively, and the third term denotes the Orbach process. The best fits gave parameters of τ0 = 6.32 × 10−6 s, Ueff = 50.06 cm−1, τQTM= 0.00289 s, and C = 3.09 s−1 K−4.17 for complex BrMQ-Dy, and D


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Inorganic Chemistry

Figure 5. Magnetization blocking barriers and relaxation pathways in complexes BrMQ-Dy, BrMQ-Dya, ClMQ-Dy, and ClMQ-Dya.

Ueff = 26.1 cm−1, τ0 = 3.39 × 10−6 s, τQTM = 0.00105 s, and C = 0.46 s−1 K−6.31 complex BrMQ-Dya. To further investigate the magnetic bistability of complexes BrMQ-Dy, BrMQ-Dya, ClMQ-Dy, and ClMQ-Dya, the variable-field magnetization measurements were performed at 2 K. Complex BrMQ-Dy shows obvious butterfly-shaped hysteresis loop (Figure 4), and complexes BrMQ-Dya, ClMQ-Dy, and ClMQ-Dya displays tiny hysteresis openings (Figure S15 in the Supporting Information). Theoretical Calculations and Analysis. The calculated effective barriers of BrMQ-Dy, BrMQ-Dya, ClMQ-Dy, and ClMQ-Dya are 47.8, 27.3, 96.0, and 65.5 cm−1, respectively. The calculated gz values for the ground Kramers doublets (KDs) approach the Ising limit of 20, verifying the easy-axis type of magnetic anisotropy. As shown in Tables S6 and S7 in the Supporting Information, the calculated ground gz values of BrMQ-Dy and ClMQ-Dy are larger than those of BrMQ-Dya and ClMQ-Dya, respectively, andgx, gy values are also much smaller than the corresponding values, illustrating that BrMQDy and ClMQ-Dy present significant axial anisotropy for Dy(III) fragments. That is to say, the guest molecules can induce obvious impact on the Dy(III)-SIM. Complex BrMQDy with approximate D4d local symmetry illustrate that the electronic structure is closer to the ideal type, and the theoretical prediction is consistent with the experimental observations under 0 Oe. As for complex ClMQ-Dy, the temperature-dependent χ″ signals only display a small tail above 2 K at 0 Oe, which may be attributed to the QTM effects. An optimized DC field of 1000 Oe for complex ClMQDy was applied to bypass QTM. The probable mechanism of relaxation and the computed energies of the KDs are shown in Figure 5. The calculated energy gap between the ground and first excitation states of complex BrMQ-Dy(47.8 cm−1) is far more less than that of complex ClMQ-Dy (96.0 cm−1), because of the effect of electron-withdrawing ligands

substituted at the 5- and 7-positions. These results are consistent with the experimental results. Complexes BrMQDy and ClMQ-Dy have similar first coordination spheres and significantly different electronic structures. Based on the theoretical orientation of the magnetic easy axis obtained from the ab initio results (Figure S16 in the Supporting Information), ligand atoms of the first sphere of these complexes can be divided into two groups: (1) the axial ones comprising two O atoms and two N atoms in complexes BrMQ-Dy and ClMQ-Dy; (2) equatorial atoms consisting of two O atoms and two N atoms in complexes BrMQ-Dy and ClMQ-Dy.The magnetic easy axis lies close to the shortest Dy−O bond, approximating to the O4 atom in complexes BrMQ-Dy and ClMQ-Dy (Table S8 in the Supporting Information). Obviously, the average charges on the myopic quadrilateral plane are smaller than the axial coordination atoms in these complexes. Previous reports found that the eight-coordinated square antiprismatic geometry Dy-based SIMs with D4d local symmetry have different zenithal angles and relaxation behavior.74−78 Specific analysis demonstrates that the SIM property of complex BrMQ-Dy was better than complex ClMQ-Dy, because of hyperfine interactions, which affect the electrostatic potential around the central Dy(III) ion, and the electronic effect of halogen. In addition, the quantum tunneling limits their performance, and in zero DC field, the ligand field effect plays an important role in the slow relaxation behavior. Based on the results of the magnetic property derived from the experiment and the theoretical calculation mentioned above, we can deduce some effects on the relaxation processes of these complexes: (1) Solvent effect: both the experimental and the calculated effective barriers of BrMQ-Dya and ClMQ-Dya are smaller than those of BrMQ-Dy and ClMQ-Dy, respectively. This distinct difference indicates the different magnetic relaxation E


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Inorganic Chemistry

Figure 6. Luminescence−emission spectra of (a) H-BrMQ, (b) H-ClMQ, (c) BrMQ-Dy, and (d) ClMQ-Dy at room temperature.

Table 2. IC50 (μM) of H-BrMQ, H-ClMQ, Cisplatin, Complexes BrMQ-Dy and ClMQ-Dy on Five Human Cells for Two Days IC50 (μM) compound

BEL-7404

Hep-G2

HeLa

MCF-7

HL-7702

H-BrMQ BrMQ-Dy H-ClMQ ClMQ-Dy Dy(NO3)3·6H2O cisplatinb

>150 4.09 ± 1.06 >100 1.53 ± 0.59 >150 15.86 ± 1.07

>150 10.03 ± 0.74 >100 4.23 ± 0.79 >150 16.45 ± 1.03

>150 5.08 ± 1.91 >100 1.01 ± 1.02 >150 11.02 ± 0.87

>150 29.56 ± 0.31 >100 19.87 ± 1.82 >150 10.25 ± 0.86

>100 59.13 ± 1.01 >100 63.23 ± 0.69 >150 15.09 ± 0.69

nm peak moves to 398 nm (Figure S17 in the Supporting Information). The photoluminescent properties of H-BrMQ, H-ClMQ, BrMQ-Dy, and ClMQ-Dy were also investigated (Figure 6). The emission wavelength of H-BrMQ was 525 nm, which belongs to the π1−π1* transition of H-BrMQ, when the excitation wavelength was λ = 391 nm (Figure 6a). H-ClMQ has the same luminescence as H-BrMQ (Figure 6b). When complex BrMQ-Dy was excited with radiation having a wavelength of either 357 or 418 nm, an emission peak at 508 nm was obtained. The above emission peaks belong to the π1−π1* energy level transition and the 4F9/2 → 6H15/2 transition (Figure 6c). When complex ClMQ-Dy was excited with radiation having a wavelength of either 328 or 423 nm, an emission peak of 517 nm was obtained. The above emission peaks belong to the π2−π2* and 4F9/2 → 6H15/2 transition (Figure 6d). Antitumor Activities. Cytotoxicity. The IC50 values of Dy(NO3)3·6H2O, H-BrMQ, H-ClMQ, cisplatin, and complexes BrMQ-Dy and ClMQ-Dy against the five human cells (including BEL-7404, HL-7702, Hep-G2, HeLa, and MCF-7 cells) were determined by MTT assay. As shown in Table 2, as well as Table S9 in the Supporting Information, except for the MCF-7 tumor cells, complex ClMQ-Dy also showed stronger antiproliferative potency than H-BrMQ, H-ClMQ, cisplatin, Dy(NO3)3·6H2O, andBrMQ-Dy in other cells, which was most evident in the case of HeLa tumor cells. Meanwhile, complex ClMQ-Dy (IC50 = 1.01 ± 1.02 μM) was 10.9 and

behaviors between the compounds with and without the solvent molecules, which can be ascribed to the result of the solvent effect. Solvent-induced weak interaction leads to differences in the structure and, thus, tunes the magnetic relaxation mechanisms. (2) Electronic ef fect of halogen substituents: both the experimental and theoretical calculated effective barriers of ClMQ-Dy are larger than that of BrMQ-Dy, which is primarily attributed to the result of the electronic effect of halogen substituents. The higher electron-withdrawing substituents of Cl in ligand H-ClMQ will lead to compound ClMQ-Dy exhibiting a more-axial g-tensor in the ground KD than that of compound BrMQ-Dy with the ligand bearing lower electronwithdrawing substituents of Br, which was further confirmed by our ab initio calculations. This effect leads to a larger effective barrier for ClMQ-Dy than BrMQ-Dy, which is consistent with that reported previously by the Murugesu group.79 Absorption Spectra and Luminescent Properties. The ligands H-BrMQ and H-ClMQ, and the complexes BrMQ-Dy and ClMQ-Dy, were dissolved in N,N-dimethylformamide, respectively. H-BrMQ has an absorption shoulder at 274 nm and a broad absorption peak at 314 nm. The position of the ultraviolet−visible light (UV-vis) absorption peak of the HClMQ is the same as that of H-BrMQ. For the complexes BrMQ-Dy and ClMQ-Dy, compared to H-BrMQ and HClMQ, the absorption peak at 274 nm still exists, and the 314 F


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Figure 7. (A) Cellular uptake and (B) different fractions of BrMQ-Dy (5 μM) and ClMQ-Dy (1 μM) in HeLa tumor cells. (*) P < 0.05, treated cells versus the control cells.

Figure 8. Level of Δψ in HeLa tumor cells after treated with BrMQ-Dy (5 μM) and ClMQ-Dy (1 μM) for 24 h.

Figure 9. Activation of ROS level treated with BrMQ-Dy (5 μM) and ClMQ-Dy (1 μM) in HeLa cells for 24 h.

cisplatin (4.56 ± 0.05 nmol Pt/106 cells). In addition, metal percentage in BrMQ-Dy (5 μM) and ClMQ-Dy (1 μM), especially ClMQ-Dy treated cells (Figure 7B), was mainly distributed in mitochondrial fractions, which was obviously higher than the values in cisplatin (11 μM), indicating that their activation was relative to HeLa cell apoptotic pathways.81,82 Detection on Mitochondrial Membrane Potential (Δψ). Both BrMQ-Dy (5 μM) and ClMQ-Dy (1 μM) accumulated in the mitochondrial membrane fraction. Thus, the ΔΨ changes induced by BrMQ-Dy (5 μM) and ClMQ-Dy (1 μM) were investigated in HeLa cells using fluorescent probe JC-1, and the different ratio of the fluorescence intensity was assessed via flow cytometry (Figure 8). After treated with BrMQ-Dy (5 μM) and ClMQ-Dy (1 μM) for 24 h, and green fluorescent intensity obviously increased in HeLa tumor cells, especially complex ClMQ-Dy (1 μM) treated cells, and finally induced HeLa cell apoptosis.81,83

99.0 times more potent than cisplatin (IC50 = 11.02 ± 0.87 μM) and H-ClMQ (IC50 > 100 μM) in this cell line. In addition, the cytotoxicity of BrMQ-Dy and ClMQ-Dy toward HeLa cancer cells was enhanced by 10.9, 6.5, 2.3, 62.6, and 3.1 times, comparing with HL-7702 cells, also suggesting the selectivity of BrMQ-Dy and ClMQ-Dy on HeLa cells. Importantly, complexes BrMQ-Dy and ClMQ-Dy showed stronger antiproliferative potency against the HeLa, BEL-7404, and MCF-7 cells, compared with the 5,7-dibromo-8-quinolinol dysprosium(III) complex,64 because of the effect of the methyl (−CH3) group of H-BrMQ and H-ClMQ in complexes BrMQ-Dy and ClMQ-Dy.61,80 Cellular Uptake. BrMQ-Dy (5 μM), ClMQ-Dy (1 μM), and cisplatin (11 μM) treated with HeLa tumor cells for 24 h, the uptake of Dy were investigated using ICP-MS.81,82 As shown in Figure 6A, the maximum intake of ClMQ-Dy (1 μM) was 7.59 ± 0.08 nmol Dy/106 cells, which higher than that of BrMQ-Dy (5 μM) (5.81 ± 0.03 nmol Dy/106 cells) and G


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Figure 10. (A) Western blot of bax, bcl-2, cytochrome c, and apaf-1 protein levels in HeLa cells after treated with BrMQ-Dy (5 μM) and ClMQDy (1 μM) for 24 h. (B) Densitometric analysis of mitochondrial pathways related proteins fragment normalized with β-actin.

Figure 11. BrMQ-Dy (5 μM) and ClMQ-Dy (1 μM) activated caspase-3/caspase-9 in HeLa cells for 24 h.

Measurement of Reactive Oxygen Species (ROS) Generation. Herein, we investigated whether BrMQ-Dy (5 μM) and ClMQ-Dy (1 μM) treated with HeLa tumor cells could increase ROS levels. Figure 9 shows that HeLa tumor cells exhibited more obvious green fluorescence after treatment with BrMQ-Dy (5 μM) and ClMQ-Dy (1 μM) for 24 h comparing with the control cells, which was highly associated with HeLa tumor cell apoptosis.81,84,85 Regulating the Mitochondrial Pathways-Related Proteins. BrMQ-Dy (5 μM) and ClMQ-Dy (1 μM) could induce HeLa cell apoptosis, thus Western blot of apaf-1, bax, bcl-2, and cytochrome c proteins was performed.86 BrMQ-Dy (5 μM) and ClMQ-Dy (1 μM) treated-cells had obvious increases and decreases in the levels of apaf-1, bax, bcl-2, and cytochrome c proteins (Figure 10), respectively, especially for ClMQ-Dy (1 μM)-treated cells. In the BrMQ-Dy (5 μM) and ClMQ-Dy (1 μM)-treated HeLa, expression levels with caspase-3 and caspase-9 proteins were 17.10% and 26.80% and 10.60% and 15.30% (Figure 11), respectively, demonstrating that BrMQ-Dy (5 μM) and ClMQ-Dy (1 μM) induced HeLa cell apoptosis by triggering apoptosis-related proteins.81,86 Cell Cycle Analysis and Expressions of G2 Phase-Related Proteins. Previous studies suggested that cell cycle arrest is highly associated with cancer cell apoptosis.81,87 As shown in Figure 12, treatment with BrMQ-Dy (5 μM) and ClMQ-Dy (1 μM) for 24 h increased the cell populations at the G2/M

Figure 12. Cell cycle of HeLa tumor cells treatment with BrMQ-Dy (5 μM) and ClMQ-Dy (1 μM) for 24 h.

phase by ∼26.16% and 31.28%, respectively, compared with the control cells (7.13%). We can conclude that BrMQ-Dy (5 H


Article

Inorganic Chemistry

Figure 13. (A) Western blot of cdc25 C, cyclin B, and CDK1 proteins levels in HeLa tumor cells after treatment with BrMQ-Dy (5 μM) and ClMQ-Dy (1 μM) for 24 h. (B) Densitometric analysis of the expressions of G2 phase-related protein fragments normalized with β-actin.

Figure 14. BrMQ-Dy (5 μM)- and ClMQ-Dy (1 μM)-induced HeLa cell apoptosis for 24 h.

μM) and ClMQ-Dy (1 μM) caused G2/M phase arrest.87 In addition, treatment with BrMQ-Dy (5 μM) and ClMQ-Dy (1 μM) in HeLa tumor cells for 24 h decreased expression of cdc25 C, cyclin B, and CDK1 proteins levels, mainly due to G2/M phase arrest,88 as shown in the Western blot assay (Figure 13). Cell Apoptosis. Figure 14 shows that, in the BrMQ-Dy (5 μM) and ClMQ-Dy (1 μM)-treated HeLa tumor cells, the populations of apoptotic cells were 18.83% and 48.70%, respectively, demonstrating that BrMQ-Dy (5 μM) and ClMQ-Dy (1 μM) caused HeLa cell apoptosis via the mitochondrial dysfunction pathway.81,87 Recently, Santos and Liu testified some of halogenated substitution 8-quinolinol Pt(II) complexes has better antitumor activity and cellular uptake.46,51 In this study, ClMQ-Dy (1 μM) with 5,7-dichloro substitution showed significantly enhanced cytotoxicities against BEL-7404, Hep-G2, and HeLa cancer cells comparing with BrMQ-Dy (5 μM) and cisplatin, which exhibited obvious priority on the cell HeLa apoptosis through mitochondrial dysfunction pathway. ClMQ-Dy (1 μM) can be more obviously caused by cell cycle arrest at G2/ M phase and regulated expressions of G2 phase-related proteins than that of BrMQ-Dy (5 μM). Moreover, the same results were seen in cell uptake experiments (Cl > Br). This is the best explanation for the better anticancer effect of ClMQ-Dy (1 μM), compared to BrMQ-Dy (5 μM) until now, based on the results in this study.

strate that coordination symmetry of central Dy(III), electronwithdrawing ligands, and guest molecules can significantly affect the structures and play an important role in defining and distinguishing their magnetic behaviors. Antitumor activity investigation reveals that both complexes exhibited more selectivity for HeLa cells than HL-7702 cells. This is the first report to demonstrate that BrMQ-Dy and ClMQ-Dy caused HeLa cell apoptosis through dysfunction of mitochondrial pathway and induced cell cycle arrest at the G2 phase. These mechanistic insights demonstrated that BrMQ-Dy and ClMQDy may be an novel antitumor compounds candidates. The research provides totally different insights on the regulation of slow magnetic relaxation behaviors of 4f-based complexes. Furthermore, the bifunctional feature of two complexes with both single-ion magnet behaviors and antitumor activities provides potentially new systems of magnetic targeting drugs that are different from those traditional systems by loading drugs on a magnetic material. Thus, this work might imply a new direction, called molecule-based magnetic drugs, in the research area of magnetic targeting compounds.

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EXPERIMENTAL SECTION

Materials and Methods. All reagents were analytical grade. HBrMQ and H-ClMQ were purchased from Alfa-Aesar. IR spectra with KBr pellet were recorded on a PE Spectrum Two FT/IR spectrometer. Elemental analysis (C, H, N) was measured on an Elementar Micro cube elemental analyzer. PXRD measurements were recorded on Rigaku D/max-IIIA diffractometer. Magnetic susceptibility measurements were performed on a QD MPMS-XL magnetometer. Diamagnetic corrections were estimated using Pascal’s constants.89 In order to prevent the movement of samples, silicone grease was employed for the embedding. Single-crystal X-ray data were collected on a Bruker SMART CCD diffractometer and solved by direct methods, then refined by a full-matrix least-squares method

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CONCLUSION Two mononuclear dysprosium complexes with pseudo-D4d local symmetry are reported. Complex BrMQ-Dy is a SIM, and complex ClMQ-Dy exhibits field-induced SIM behaviors. The different magnetic dynamics of two complexes demonI


Article

Inorganic Chemistry based on F2 using SHELXL.90,91 H atoms were added geometrically and refined using the riding model for BrMQ-Dy, which is a protonated triethylamine (N5) based on equilibrium charge. Because the distances of O5 and N5 are very close, their hydrogen atoms are not found in the Fourier diagram, and are difficult to locate in the final structural refinement. We add the hydrogens in the molecular formula, which is further confirmed by elemental analyses. The CCDC reference numbers for the crystal structures of BrMQ-Dy and ClMQ-Dy are 1857464 and 1857460, respectively. Synthesis of (Et3NH)[Dy(C10H6NOBr2)4]·H2O·DMF (BrMQ-Dy). Dy(NO3)3·6H2O (0.10 mmol), H-BrMQ (0.20 mmol), DMF (1.0 mL), H2O (0.25 mL), and 0.10 mL Et3N were added in a Pyrex tube. The mixture was heated for 3 days at 80 °C and cooled to room temperature to produce yellow crystals of complex BrMQ-Dy in 61% yield. Anal. Calcd for C49H49Br8DyN6O6: C, 36.34%; H, 3.05%; N, 5.19%; Found: C, 36.51%, H, 3.32%, N, 5.25%. IR data: 3450 (s), 3046 (w), 1668 (s), 1543 (s), 1427 (s), 1350 (w), 1254 (m), 1099 (w), 917 (w), 734 (s), 647 (w). Synthesis of (Et3NH)[Dy(C10H6NOCl2)4]·H2O·DMF (ClMQ-Dy). The preparation of complex ClMQ-Dy was similar to that of complex BrMQ-Dy but used H-ClMQ instead of H-BrMQ, producing yellow crystals of complex ClMQ-Dy in 48% yield. Anal. Calcd for C49H49Cl8DyN6O6: C, 46.56%; H, 3.91%; N, 6.65%; Found: C, 46.63%, H, 4.03%, N, 6.72%. IR data: 3720 (m), 3489 (s), 2949 (w), 1639 (s), 1572 (w), 1437 (w), 1225 (w), 1091 (s), 1011 (w), 695 (w). Preparation of the Desolvated Samples BrMQ-Dya and ClMQ-Dya. The desolvation temperatures of BrMQ-Dy and ClMQDy were first setted according to the thermogravimetric analysis of the compounds (Figure S18 in the Supporting Information). The yellow crystals of BrMQ-Dy and ClMQ-Dy (∼20 mg for each complex) then were taken in a crucible, which was heated from room temperature to 198 and 182 °C, respectively, under flowing nitrogen. Keeping the temperature constant for 2 h, the corresponding desolvated samples BrMQ-Dya and ClMQ-Dya were obtained. Elemental analysis (%) calcd for BrMQ-Dya (C46H40Br8DyN5O4): C, 36.14; H, 2.64; N, 4.58. Found: C, 36.02; H, 2.78; N, 4.49; ClMQ-Dya (C46H40Cl8DyN5O4): C, 47.10; H, 3.44; N, 5.97. Found: C, 46.98; H, 3.56; N, 5.86.

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Author Contributions #

These authors contributed equally to this work.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We acknowledge financial support from the NSFC (Nos. 21771043, 21601038, 51572050, and 21401112), Guangxi Natural Science Foundation (Nos. 2015GXNSFDA139007 and 2016GXNSFAA380085), the Natural Science Foundation of Jiangsu Higher Education Institutions of China (No. 16KJB430020), and State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (No. CMEMR2017-A11).

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.inorgchem.8b02250. Figures S1−S18 and Tables S1−S9, which include bond lengths and bond angles parameters, hydrogen bond lengths (Å) and angles (deg), crystal structure of these complexes and related characterization (PDF) Accession Codes

CCDC 1857464 and 1857460 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: + 44 1223 336033.

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REFERENCES

(1) Shiddiq, M.; Komijani, D.; Duan, Y.; Gaita-Ariño, A.; Coronado, E.; Hill, S. Enhancing coherence in molecular spin qubits via atomic clock transitions. Nature 2016, 531, 348−351. (2) Thiele, S.; Balestro, F.; Ballou, R.; Klyatskaya, S.; Ruben, M.; Wernsdorfer, W. Electrically driven nuclear spin resonance in singlemolecule magnets. Science 2014, 344, 1135−1138. (3) Liu, J. L.; Chen, Y. C.; Tong, M. L. Symmetry strategies for high performance lanthanide-based single-molecule magnets. Chem. Soc. Rev. 2018, 47, 2431−2453. (4) Rinehart, J. D.; Fang, M.; Evans, W. J.; Long, J. R. Strong exchange and magnetic blocking in N23−-radical-bridged lanthanide complexes. Nat. Chem. 2011, 3, 538−542. (5) Ding, Y. S.; Chilton, N. F.; Winpenny, R. E. P.; Zheng, Y. Z. On Approaching the Limit of Molecular Magnetic Anisotropy: A nearperfect pentagonal bipyramidal dysprosium(III) single-molecule magnet. Angew. Chem., Int. Ed. 2016, 55, 16071−16074. (6) Guo, F. S.; Day, B. M.; Chen, Y. C.; Tong, M. L.; Mansikkamäki, A.; Layfield, R. A. Magnetic hysteresis up to 80 K in a dysprosium metallocene single-molecule magnet. Science 2018, 362, 1400−1403. (7) Guo, F. S.; Day, B. M.; Chen, Y. C.; Tong, M. L.; Mansikkamäki, A.; Layfield, R. A. A dysprosium metallocene single-molecule magnet functioning at the axial limit. Angew. Chem., Int. Ed. 2017, 56, 11445− 11449. (8) Gupta, S. K.; Rajeshkumar, T.; Rajaraman, G.; Murugavel, R. An air-stable Dy(III) single-ion magnet with high anisotropy barrier and blocking temperature. Chem. Sci. 2016, 7, 5181−5191. (9) Chen, Y. C.; Liu, J. L.; Ungur, L.; Liu, J.; Li, Q. W.; Wang, L. F.; Ni, Z. P.; Chibotaru, L. F.; Chen, X. M.; Tong, M. L. Symmetrysupported magnetic blocking at 20 K in pentagonal bipyramidal Dy(III) single-ion magnets. J. Am. Chem. Soc. 2016, 138, 2829−2837. (10) Liu, J.; Chen, Y. C.; Liu, J. L.; Vieru, V.; Ungur, L.; Jia, J. H.; Chibotaru, L. F.; Lan, Y.; Wernsdorfer, W.; Gao, S.; Chen, X. M.; Tong, M. L. A stable pentagonal bipyramidal Dy(III) single-ion magnet with a record magnetization reversal barrier over 1000 K. J. Am. Chem. Soc. 2016, 138, 5441−5450. (11) Ishikawa, N.; Sugita, M.; Ishikawa, T.; Koshihara, S. Y.; Kaizu, Y. Lanthanide double-decker complexes functioning as magnets at the single-molecular level. J. Am. Chem. Soc. 2003, 125, 8694−8695. (12) Jiang, S. D.; Wang, B. W.; Su, G.; Wang, Z. M.; Gao, S. A mononuclear dysprosium complex featuring single-molecule-magnet behavior. Angew. Chem. 2010, 122, 7610−7613; Angew. Chem., Int. Ed. 2010, 49, 7448−7451. (13) Chilton, N. F.; Langley, S. K.; Moubaraki, B.; Soncini, A.; Batten, S. R.; Murray, K. S. Single molecule magnetism in a family of mononuclear β-diketonate lanthanide(III) complexes: rationalization of magnetic anisotropy in complexes of low symmetry. Chem. Sci. 2013, 4, 1719−1730. (14) Blagg, R. J.; Ungur, L.; Tuna, F.; Speak, J.; Comar, P.; Collison, D.; Wernsdorfer, W.; McInnes, E. J. L.; Chibotaru, L. F.; Winpenny, R. E. P. Magnetic relaxation pathways in lanthanide single-molecule magnets. Nat. Chem. 2013, 5, 673−678.

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] (B. Li). *E-mail: [email protected] (Y.-Q. Zhang). *E-mail: fliangoffi[email protected] (F. Liang). ORCID

Yi-Quan Zhang: 0000-0003-1818-0612 Zi-Lu Chen: 0000-0003-1341-2330 Fupei Liang: 0000-0001-7435-0140 J


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Inorganic Chemistry (15) Zadrozny, J. M.; Xiao, D. J.; Atanasov, M.; Long, G. J.; Grandjean, F.; Neese, F.; Long, J. R. Magnetic blocking in a linear iron(I) complex. Nat. Chem. 2013, 5, 577−581. (16) Zadrozny, J. M.; Long, J. R. Slow magnetic relaxation at zero field in the tetrahedral complex [Co(SPh)4]2‑−. J. Am. Chem. Soc. 2011, 133, 20732−20734. (17) Poulten, R. C.; Page, M. J.; Algarra, A. G.; Le Roy, J. J.; López, I.; Carter, E.; Llobet, A.; Macgregor, S. A.; Mahon, M. F.; Murphy, D. M.; Murugesu, M.; Whittlesey, M. K. Synthesis, electronic structure, and magnetism of [Ni(6-Mes)2]+A two-coordinate nickel(I) complex stabilized by bulky N-heterocyclic carbenes. J. Am. Chem. Soc. 2013, 135, 13640−13643. (18) Jiang, S. D.; Wang, B. W.; Sun, H. L.; Wang, Z. M.; Gao, S. An organometallic single-ion magnet. J. Am. Chem. Soc. 2011, 133, 4730− 4733. (19) Meihaus, K. R.; Long, J. R. Magnetic blocking at 10 K and a dipolar-mediated avalanche in salts of the bis(η8-cyclooctatetraenide) complex [Er(COT)2]−. J. Am. Chem. Soc. 2013, 135, 17952−17957. (20) Ungur, L.; Le Roy, J. J.; Korobkov, I.; Murugesu, M.; Chibotaru, L. F. Fine-tuning the local symmetry to attain record blocking temperature and magnetic remanence in a single-ion magnet. Angew. Chem. 2014, 126, 4502−4506; Angew. Chem., Int. Ed. 2014, 53, 4413−4417. (21) Ren, M.; Bao, S. S.; Wang, B. W.; Ferreira, R. A. S.; Zheng, L. M.; Carlos, L. D. Lanthanide phosphonates with pseudo-D5h local symmetry exhibiting magnetic and luminescence bifunctional properties. Inorg. Chem. Front. 2015, 2, 558−566. (22) Zhang, J. L. Marriage of phthalocyanine chemistry with lanthanides: a single-ion magnet with a blocking temperature up to 25 K. Inorg. Chem. Front. 2017, 4, 1950−1952. (23) Liang, J. X.; Zhong, H. J.; Yang, G. J.; Vellaisamy, K.; Ma, D.; Leung, C. Recent development of transition metal complexes with in vivo antitumor activity. J. Inorg. Biochem. 2017, 177, 276−286. (24) Cheng, Y.; Qi, Y. Current progresses in metal-based anticancer complexes as mammalian TrxR inhibitors. Anti-Cancer Agents Med. Chem. 2017, 17, 1046−1069. (25) Ndagi, U.; Mhlongo, N.; Soliman, M. E. Metal complexes in caner therapy-an update from drug design perspective. Drug Des., Dev. Ther. 2017, 11, 599−616. (26) León, I. E.; Cadavid-Vargas, J. F.; Di Virgilio, A. L.; Etcheverry, S. B. Vanadium, ruthenium and copper compounds: A new class of non-platinum metallodrugs with anticancer acitivity. Curr. Med. Chem. 2017, 24, 112−148. (27) Santini, C.; Pellei, M.; Gandin, V.; Porchia, M.; Tisato, F.; Marzano, C. Advances in copper complexes as anticaner agents. Chem. Rev. 2014, 114, 815−862. (28) Ali, B.; Iqbal, M. A. Coordination complexes of manganese and their biomedical applications. ChemistrySelect. 2017, 2, 1586−1604. (29) Chen, Z. F.; Orvig, C.; Liang, H. Multi-target metal-based anticancer agents. Curr. Top. Med. Chem. 2017, 17, 3131−3145. (30) Thota, S.; Rodrigues, D. A.; Crans, D. C.; Barreiro, E. J. Ru(II) compounds: next-generation anticancer metallotherapeutics? J. Med. Chem. 2018, 61, 5805−5821. (31) Lazarević, T.; Rilak, A.; Bugarčić, Ž .D. Platinum, palladium, gold and ruthenium complexes as anticancer agents: current clinical uses, cytotoxicity studies and future perspectives. Eur. J. Med. Chem. 2017, 142, 8−31. (32) Zeng, L.; Gupta, P.; Chen, Y.; Wang, E.; Ji, L.; Chao, H.; Chen, Z. S. The development of anticancer ruthenium(II) complexes: from single molecule compounds to nanomaterials. Chem. Soc. Rev. 2017, 46, 5771−5804. (33) Yeo, C. I.; Ooi, K. K.; Tiekink, E. E. T. Gold-Based Medicine: A paradigm shift in anti-cancer therapy. Molecules 2018, 23, 1410. (34) Beyer, G. J.; Franke, W. G.; Hennig, K.; Johannsen, B. A.; Khalkin, V. A.; Kretzschmar, M.; Lebedev, N. A.; Munze, R.; Novgorodov, A. F.; Thieme, K. Comparative kinetic studies of simultaneously injected 167 Tm-and 67 Ga-citrate in normal and tumour bearing mice. Int. J. Appl. Radiat. Isot. 1978, 29, 673−681.

(35) Esposito, M.; Collecchi, P.; Brera, S.; Mora, E.; Mazzucotelli, A.; Cutolo, M.; Oddone, M. Plasma and tissue levels of some lanthanide elements in malignant and non-malignant human tissues. Sci. Total Environ. 1986, 50, 55−63. (36) Hirano, S.; Suzuki, K. T. Exposure, metabolism, and toxicity of rare earths and related compounds. Environ. Health Persp. 1996, 104, 85−95. (37) Fricker, S. P. The therapeutic application of lanthanides. Chem. Soc. Rev. 2006, 35, 524−533. (38) Zhou, J.; Wang, L. F.; Wang, J. Y.; Tang, N. Synthesis, characterization, antioxidative and antitumor activities of solid quercetin rare earth(III) complexes. J. Inorg. Biochem. 2001, 83, 41−48. (39) Hussain, A.; Gadadhar, S.; Goswami, T. K.; Karande, A. A.; Chakravarty, A. R. Photoactivated DNA cleavage and anticancer activity of pyrenyl-terpyridine lanthanide complexes. Eur. J. Med. Chem. 2012, 50, 319−331. (40) Hussain, A.; Gadadhar, S.; Goswami, T. K.; Karande, A. A.; Chakravarty, A. R. Photo-induced DNA cleavage activity and remarkable photocytotoxicity of lanthanide(III) complexes of a polypyridyl ligand. Dalton Trans. 2012, 41, 885−895. (41) Wang, L.; Li, W. J.; Song, Y. M. Antitumor activity and DNA binding studies on rare earth metal complexes with all-trans retinoic acid and L-glutamic acid. RSC Adv. 2014, 4, 42285−42292. (42) Miller-Shakesby, D. M.; Burke, B. P.; Nigam, S.; Stasiuk, G. J.; Prior, T. J.; Archibald, S. J.; Redshaw, C. Synthesis, structures and cytotoxicity studies of p-sulfonatocalix [4] arene lanthanide complexes. CrystEngComm 2016, 18, 4977−4987. (43) Cârâc, A.; Boscencu, R.; Dinicǎ, R. M.; Guerreiro, J. F.; Silva, F.; Marques, F.; Campello, M. P. C.; Moise, C.; Brîncoveanu, O.; Enǎchescu, M.; Cârâc, G.; Tǎbǎcaru, A. Synthesis, characterization and antitumor activity of two new dipyridinium ylide based lanthanide(III) complexes. Inorg. Chim. Acta 2018, 480, 83−90. (44) Xu, X.; Hu, F.; Shuai, Q. Click chemistry-assisted synthesis of a β-D-galactose-targeted SiO2@RC shell-core structure as a nanoplatfrom for metal-based complex delivery. Inorg. Chem. 2018, 57, 10694−10701. (45) Fernández, B.; Oyarzabal, I.; Fischer-Fodor, E.; Macavei, S.; Sánchez, I.; Seco, J. M.; Gómez-Ruiz, S.; Rodríguez-Diéguez, A. Multifunctional applications of a dysprosium-based metal−organic chain with single-ion magnet behaviour. CrystEngComm 2016, 18, 8718−8721. (46) Meng, T.; Tang, S. F.; Qin, Q. P.; Liang, Y. L.; Wu, C. X.; Wang, C. Y.; Yan, H. T.; Dong, J. X.; Liu, Y. C. Evaluation of the effect of iodine substitution of 8-hydroxyquinoline on its platinum(II) complex: cytotoxicity, cell apoptosis and telomerase inhibition. MedChemComm 2016, 7, 1802−1811. (47) Beck, M. W.; Derrick, J. S.; Kerr, R. A.; Oh, S. B.; Cho, W. J.; Lee, S. J. C.; Ji, Y.; Han, J.; Tehrani, Z. A.; Suh, N.; Kim, S.; Larsen, S. D.; Kim, K. S.; Lee, J. Y.; Ruotolo, B. T.; Lim, M. H. Structuremechanism-based engineering of chemical regulators targeting distinct pathological factors in Alzheimer’s disease. Nat. Commun. 2016, 7, 13115. (48) Oliveri, V.; Viale, M.; Caron, G.; Aiello, C.; Gangemi, R.; Vecchio, G. Glycosylated copper(II) ionophores as prodrugs for bglucosidase activation in targeted cancer therapy. Dalton Trans. 2013, 42, 2023−2034. (49) Oliveri, V.; Viale, M.; Aiello, C.; Vecchio, G. New 8hydroxyquinoline galactosides. The role of the sugar in the antiproliferative activity of copper(II) ionophores. J. Inorg. Biochem. 2015, 142, 101−108. (50) Tang, Q.; Ni, W. X.; Leung, C.-F.; Man, W. L.; Lau, K. K. K.; Liang, Y.; Lam, Y. W.; Wong, W. Y.; Peng, S. M.; Liu, G. J.; Lau, T. C. Synthesis and antitumor activity of a series of osmium(VI) nitrido complexes bearing quinolinolato ligands. Chem. Commun. 2013, 49, 9980−9982. (51) Santos, C. M.; Cabrera, S.; Rios-Luci, C.; Padron, J. M.; Lopez Solera, I.; Quiroga, A. G.; Medrano, M. A.; Navarro-Ranninger, C.; Aleman, J. Novel clioquinol and its analogous platinum complexes: K


Article

Inorganic Chemistry importance, role of the halogen substitution and the hydroxyl group of the ligand. Dalton Trans. 2013, 42, 13343−13348. (52) Correia, I.; Adao, P.; Roy, S.; Wahba, M.; Matos, C.; Maurya, M. R.; Marques, F.; Pavan, F. R.; Leite, C. Q. F.; Avecilla, F.; Costa Pessoa, J. Hydroxyquinoline derived vanadium(IV and V) and copper(II) complexes as potential anti-tuberculosis and anti-tumor agents. J. Inorg. Biochem. 2014, 141, 83−93. (53) Tardito, S.; Barilli, A.; Bassanetti, I.; Tegoni, M.; Bussolati, O.; Franchi-Gazzola, R.; Mucchino, C.; Marchio, L. Copper-dependent cytotoxicity of 8-hydroxyquinoline derivatives correlates with their hydrophobicity and does not require caspase activation. J. Med. Chem. 2012, 55, 10448−10459. (54) Barilli, A.; Atzeri, C.; Bassanetti, I.; Ingoglia, F.; Dall’Asta, V.; Bussolati, O.; Maffini, M.; Mucchino, C.; Marchio, L. Oxidative stress induced by copper and iron compleses with 8-hydroxyquinoline derivatives causes paraptotic death of hela cancer cells. Mol. Pharmaceutics 2014, 11, 1151−1163. (55) Yang, L.; Zhang, J.; Wang, C.; Qin, X.; Yu, Q.; Zhou, Y.; Liu, J. Interaction between 8-hydroxyquinoline ruthenium(II) complexes and basic fibroblast growth factors (bFGF): inhibiting angiogenesis and tumor growth through ERK and AKT signaling pathways. Metallomic. 2014, 6, 518−531. (56) Gobec, M.; Kljun, J.; Sosic, I.; Mlinaric-Rascan, I.; Ursic, M.; Gobec, S.; Turel, I. Structural characterization and biological evaluation of a clioquinol-ruthenium complex with copper-independent antileukaemic activity. Dalton Trans. 2014, 43, 9045−9051. (57) Chen, Z. F.; Gu, Y. Q.; Song, X. Y.; Liu, Y. C.; Peng, Y.; Liang, H. Synthesis, crystal structure, cytotoxicity and DNA interaction of 5,7-dichloro-8-quinolinolato-lanthanides. Eur. J. Med. Chem. 2013, 59, 194−202. (58) Chen, Z. F.; Peng, Y.; Gu, Y. Q.; Liu, Y. C.; Liu, M.; Huang, K. B.; Hu, K.; Liang, H. High antitumor activity of 5,7-dihalo-8quinolinolato tin(IV) complexes. Eur. J. Med. Chem. 2013, 62, 51−58. (59) Chen, Z. F.; Wei, J. H.; Liu, Y. C.; Liu, M.; Gu, Y. Q.; Huang, K. B.; Wang, M.; Liang, H. High antitumor activity of 5,7-dihalo-8quinolinolato cerium complexes. Eur. J. Med. Chem. 2013, 68, 454− 462. (60) Liu, Y. C.; Wei, J. H.; Chen, Z. F.; Liu, M.; Gu, Y. Q.; Huang, K. B.; Li, Z. Q.; Liang, H. The antitumor activity of zinc(II) and copper(II) complexes with 5,7-dihalo-substituted-8-quinolinoline. Eur. J. Med. Chem. 2013, 69, 554−563. (61) Qin, Q. P.; Chen, Z. F.; Qin, J. L.; He, X. J.; Li, Y. L.; Liu, Y. C.; Huang, K. B.; Liang, H. Studies on antitumor mechanism of two planar platinum(II) complexes with 8-hydroxyquinoline: synthesis, characterization, cytotoxicity, cell cycle and apoptosis. Eur. J. Med. Chem. 2015, 92, 302−313. (62) Filak, L. K.; Kalinowski, D. S.; Bauer, T. J.; Richardson, D. R.; Arion, V. B. Effect of the piperazine unit and metal-binding site position on the solubility and anti-proliferative activity of ruthenium(II)- and osmium(II)- arene complexes of isomeric indolo [3,2-c] quinoline-piperazine hybrids. Inorg. Chem. 2014, 53, 6934−6943. (63) Zou, B. Q.; Qin, Q. P.; Bai, Y. X.; Cao, Q. Q.; Zhang, Y.; Liu, Y. C.; Chen, Z. F.; Liang, H. Synthesis and antitumor mechanism of a new iron(III) complex with 5,7-dichloro-2-methyl-8-quinolinol as ligands. MedChemComm 2017, 8, 633−639. (64) Liu, Y. C.; Chen, Z. F.; Song, X. Y.; Peng, Y.; Qin, Q. P.; Liang, H. Synthesis, crystal structure, cytotoxicity and DNA interaction of 5,7-dibromo-8-quinolinolato-lanthanides. Eur. J. Med. Chem. 2013, 59, 168−175. (65) Llunell, M.; Casanova, D.; Cirera, J.; Alemany, P.; Alvarez, S. SHAPE, Version 2.1; University of Barcelona: Barcelona, Spain, 2013. (66) Zou, H. H.; Sheng, L. B.; Liang, F. P.; Chen, Z. L.; Zhang, Y. Q. Experimental and theoretical investigations of four 3d−4f butterfly single-molecule magnets. Dalton Trans. 2015, 44, 18544−18552. (67) Wang, H. L.; Ma, X. F.; Zou, H. H.; Wang, K.; Li, B.; Chen, Z. L.; Liang, F. P. Mixed chelating ligands used to regulate the luminescence of Ln(III) complexes and single-ion magnet behavior in Dy-based analogues. Dalton Trans. 2018, 47, 15929−15940.

(68) Biswas, S.; Das, S.; Acharya, J.; Kumar, V.; van Leusen, J.; Kogerler, P.; Herrera, J. M.; Colacio, E.; Chandrasekhar, V. Homometallic DyIII complexes of varying nuclearity from 2 to 21: synthesis, structure, and magnetism. Chem. - Eur. J. 2017, 23, 5154− 5170. (69) Athanasopoulou, A. A.; Pilkington, M.; Raptopoulou, C. P.; Escuer, A.; Stamatatos, T. C. Structural aesthetics in molecular nanoscience: a unique Ni26 cluster with a ‘rabbit-face’ topology and a discrete Ni18 ‘molecular chain’. Chem. Commun. 2014, 50, 14942− 14945. (70) Yutronkie, N. J.; Kuhne, I. A.; Korobkov, I.; Brusso, J. L.; Murugesu, M. Connecting mononuclear dysprosium single-molecule magnets to form dinuclear complexes via in situ ligand oxidation. Chem. Commun. 2016, 52, 677−680. (71) Chen, Y. C.; Liu, J. L.; Lan, Y.; Zhong, Z. Q.; Mansikkamäki, A.; Ungur, L.; Li, Q. W.; Jia, J. H.; Chibotaru, L. F.; Han, J. B.; Wernsdorfer, W.; Chen, X. M.; Tong, M. L. Dynamic magnetic and optical insight into a high performance pentagonal bipyramidal DyIII single-ion magnet. Chem. - Eur. J. 2017, 23, 5708−5715. (72) Benelli, C.; Gatteschi, D. Introduction to Molecular Magnetism: From Transition Metals to Lanthanides; John Wiley & Sons: Weinheim, Germany, 2015. (73) Cañ on-Mancisidor, W.; Miralles, S. G.; Baldoví, J. J.; Espallargas, G. M.; Gaita-Ariño, A.; Coronado, E. Sublimable single ion magnets based on lanthanoid quinolinate complexes: The role of intermolecular interactions on their thermal stability. Inorg. Chem. 2018, 57, 14170−14177. (74) Ishikawa, N.; Sugita, M.; Wernsdorfer, W. Quantum tunneling of magnetization in lanthanide single-molecule magnets: bis(phthalocyaninato)terbium and bis(phthalocyaninato)dysprosium anions. Angew. Chem., Int. Ed. 2005, 44, 2931−2935. (75) Ishikawa, N.; Sugita, M.; Wernsdorfer, W. Nuclear spin driven quantum tunneling of magnetization in a new lanthanide singlemolecule magnet:bis(Phthalocyaninato)holmium anion. J. Am. Chem. Soc. 2005, 127, 3650−3651. (76) Guo, M.; Wu, J. F.; Cador, O.; Lu, J. J.; Yin, B.; Le Guennic, B.; Tang, J. Manipulating the relaxation of quasi-D4d dysprosium compounds through alternation of the O-donor ligands. Inorg. Chem. 2018, 57, 4534−4542. (77) Wu, J.; Zhao, L.; Guo, M.; Tang, J. Constructing supramolecular grids: from 4f square to 3d−4f grid. Chem. Commun. 2015, 51, 17317−17320. (78) Chen, Q.; Meng, Y. S.; Zhang, Y. Q.; Jiang, S. D.; Sun, H. L.; Gao, S. A 1D dysprosium chain with slow magnetic relaxation constructed from a pyridine-N-oxide ligand. Chem. Commun. 2014, 50, 10434−10437. (79) Habib, F.; Brunet, G.; Vieru, V.; Korobkov, I.; Chibotaru, L. F.; Murugesu, M. Significant enhancement of energy barriers in dinuclear dysprosium single-molecule magnets through electron-withdrawing effects. J. Am. Chem. Soc. 2013, 135, 13242−13245. (80) Madonna, S.; Marcowycz, A.; Lamoral-Theys, D.; Van Goietsenoven, G.; Dessolin, J.; Pirker, C.; Spiegl-Kreinecker, S.; Biraboneye, C. A.; Berger, W.; Kiss, R.; Kraus, J. L. Bis-8hydroxyquinoline and bis-hydroxyquinaldine N-substituted amines: a single methyl group structural difference between two heterocycles, which modulates the antiproliferative effects. J. Heterocycl. Chem. 2010, 47, 719−723. (81) Qin, Q. P.; Qin, J. L.; Meng, T.; Lin, W. H.; Zhang, C. H.; Wei, Z. Z.; Chen, J. N.; Liu, Y. C.; Liang, H.; Chen, Z. F. High in vivo antitumor activity of cobalt oxoisoaporphine complexes by targeting G-quadruplex DNA, telomerase and disrupting mitochondrial functions. Eur. J. Med. Chem. 2016, 124, 380−392. (82) Schreiber, E.; Matthias, P.; Mueller, M. M.; Schaffner, W. Rapid detection of octamer binding proteins with “mini-extracts” prepared from a small number of cells. Nucleic Acids Res. 1989, 17, 6419. (83) Perelman, A.; Wachtel, C.; Cohen, M.; Haupt, S.; Shapiro, H.; Tzur, A. JC-1: alternative excitation wavelengths facilitate mitochondrial membrane potential cytometry. Cell Death Dis. 2012, 3, No. e430. L


Article

Inorganic Chemistry (84) Qin, Q. P.; Meng, T.; Tan, M. X.; Liu, Y. C.; Luo, X. J.; Zou, B. Q.; Liang, H. Synthesis and in vitro biological evaluation of three 4′(4-methoxyphenyl)-2,2′:6′,2″-terpyridine iridium(III) complexes as new telomerase inhibitors. Eur. J. Med. Chem. 2018, 143, 1387−1395. (85) Zou, H. H.; Wang, L.; Long, Z. X.; Qin, Q. P.; Song, Z. K.; Xie, T.; Zhang, S. H.; Liu, Y. C.; Lin, B.; Chen, Z. F. Preparation of 4([2,2′:6′,2″-terpyridin]-4′-yl)-N,N-diethylaniline NiII and PtII complexes and exploration of their in vitro cytotoxic activities. Eur. J. Med. Chem. 2016, 108, 1−12. (86) Li, S.; Zhang, S.; Jin, X.; Tan, X.; Lou, J.; Zhang, X.; Zhao, Y. Singly protonated dehydronorcantharidin silver coordination polymer induces apoptosis of lung cancer cells via reactive oxygen speciesmediated mitochondrial pathway. Eur. J. Med. Chem. 2014, 86, 1−11. (87) Chou, C. C.; Yang, J. S.; Lu, H. S.; Ip, S. W.; Lo, C.; Wu, C. C.; Lin, J. P.; Tang, N. Y.; Chung, J. G.; Chou, M. J.; Teng, Y. H.; Chen, D. R. Quercetin-mediated cell cycle arrest and apoptosis involving activation of a caspase cascade through the mitochondrial pathway in human breast cancer MCF-7 cells. Arch. Pharmacal Res. 2010, 33, 1181−1191. (88) Kastan, M. B.; Bartek, J. Cell-cycle checkpoints and cancer. Nature 2004, 432, 316−323. (89) Boudreaux, E. A.; Mulay, J. N. Theory and Application of Molecular Diamagnetism; John Wiley and Sons: New York, 1976. (90) Sheldrick, G. M. A short history of SHELX. Acta Crystallogr., Sect. A: Found. Crystallogr. 2008, A64, 112−122. (91) Sheldrick, G. Crystal structure refinement with SHELXL. Acta Crystallogr., Sect. C: Struct. Chem. 2015, 71, 3−8.

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