Synthesis,characterization and cytotoxicity of Pt(II), Pd(II), Cu(II) and Zn(II) complexes with 4’‐substituted terpyridine

Eight novel Pt(II), Pd(II), Cu(II) and Zn(II) complexes with 4’‐substituted terpyridine were synthesized and characterized by elemental analysis, UV, IR, NMR, electron paramagnetic resonance, high‐resolution mass spectrometry and molar conductivity measurements. The cytotoxicity of these complexes against HL‐60, BGC‐823, KB and Bel‐7402 cell lines was evaluated by MTT assay. All the complexes displayed cytotoxicity with low IC₅₀ values (<20 μm ) and showed selectivity. Complexes 3 , 5 , 7 and 8 exerted 9‐, 5‐, 12‐ and 7‐fold higher cytotoxicity than cisplatin against Bel‐7402 cell line. The cytotoxicity of complexes 3 , 5 , 6 , 7 and 8 was higher than that of cisplatin against BGC‐823 cell line. Complexes 3 , 7 and 8 showed similar cytotoxicity to cisplatin against KB cell line. Complex 7 exhibited higher cytotoxicity than cisplatin against HL‐60 cell line. Among these complexes, complex 7 demonstrated the highest in vitro cytotoxicity, with IC₅₀ values of 1.62, 3.59, 2.28 and 0.63 μm against HL‐60, BGC‐823, Bel‐7402 and KB cells lines, respectively. The results suggest that the cytotoxicity of these complexes is related to the nature of the terminal group of the ligand, the metal center and the leaving groups. Copyright © 2013 John Wiley & Sons, Ltd.     

Steric protection of a photosensitizer in a N,N-bis[2-(2-pyridyl)ethyl]-2-phenylethylamine-copper(II) bowl that enhances red light-induced DNA cleavage activity

Ternary copper(II) complexes [Cu(py2phe)B](ClO4)2 (1-3), where py2phe is a tripodal ligand N,N-bis[2-(2-pyridyl)ethyl]-2-phenylethylamine and B is a heterocyclic base (viz., 1,10-phenanthroline (phen, 1), dipyrido[3,2-d:2',3'-f]quinoxaline (dpq, 2), or dipyrido[3,2-a:2',3'-c]phenazine (dppz, 3)), are prepared and their DNA-binding and photoinduced DNA-cleavage activities are studied. Complex 1 has been structurally characterized by single crystal X-ray crystallography. The molecular structure shows an axially elongated square-pyramidal (4 + 1) coordination geometry in which the phen ligand binds at the basal plane. The tripodal ligand py2phe displays an axial-equatorial binding mode with the amine nitrogen bonded at the axial site. A chemically significant CH-pi interaction involving the CH moiety of the phenyl group of the tripodal ligand and the aromatic ring of phen is observed. The complexes display good binding propensity to calf thymus DNA giving a relative order of 3 (dppz) > 2 (dpq) > 1 (phen). The DNA binding constants (K(b)) for 1-3, determined from absorption spectral studies, are 6.2 x 10(3), 1.0 x 10(4), and 5.7 x 10(4) M(-1), respectively. The complexes show chemical nuclease activity in the presence of 3-mercaptopropionic acid as a reducing agent forming hydroxyl radicals as the cleavage active species. The photoinduced DNA-cleavage activity of the complexes has been studied using UV radiation of 365 nm and red light of 632.8 and 694 nm. The phen complex in absence of any photosensitizing moiety does not show any DNA cleavage upon photoirradiation. The dpq and dppz ligands with their photoactive quinoxaline and phenazine moieties display significant photoinduced DNA-cleavage activity. The dppz complex is more active than its dpq analogue because of the better steric protection of the DNA-bound photosensitizing dppz ligand from the solvent molecules. Control experiments reveal the formation of singlet oxygen in the light-induced DNA-cleavage reactions. The observed efficient photoinduced DNA-cleavage activity of 2 and 3 is akin to the "light switch" effect known for the tris-chelates of ruthenium(II).     

Photosensitizer in a molecular bowl and its effect on the DNA-binding and -cleavage activity of 3d-metal scorpionates

Ternary 3d -metal complexes [M(Tp (Ph))(B)](ClO 4) ( 1- 8), where M is Co(II), Ni(II), Cu(II) and Zn(II), Tp (Ph) is anionic tris(3-phenylpyrazolyl)borate, and B is N,N-donor heterocyclic base, namely, 1,10-phenanthroline (phen, 1- 4) and dipyrido[3,2- d:2',3'- f]quinoxaline (dpq, 5- 8), were prepared from a reaction of the perchlorate salt of the metal with KTp (Ph) and B in CH 2Cl 2. The complexes were characterized by various physicochemical methods. 4- 6 and 8 were structurally characterized by single-crystal X-ray crystallography. The crystal structures of the complexes show the presence of discrete cationic complexes having a square-pyramidal (4 + 1) coordination geometry in which two nitrogen atoms of the phenanthroline base (B) and two nitrogen atoms of the Tp (Ph) ligand occupy the basal plane and one nitrogen of the Tp (Ph) ligand binds at the axial site. The phenyl groups of the Tp (Ph) form a bowl-shaped structure that essentially encloses the {M(phen/dpq)} moiety. DNA-binding studies were carried out using various spectral techniques and from viscosity measurements. The complexes show moderate binding propensity to calf thymus DNA at the minor groove, giving binding constant values ( K b) of approximately 10 (4) M (-1). The complexes exhibit poor DNA-cleavage activity in the dark in the presence of 3-mercaptopropionic acid (MPA) or hydrogen peroxide (H 2O 2). The photoinduced DNA-cleavage activity of the complexes was investigated using UV-A radiation of 365 nm and visible light of two different wavelengths with a tunable multicolor Ar-Kr mixed gas ion laser source. The dpq complexes show efficient photoinduced DNA-cleavage activity via a metal-assisted photoexcitation process involving the formation of singlet oxygen as the cleavage active species in a type-II pathway. The paramagnetic d (7)-Co(II)-dpq and d (9)-Cu(II)-dpq complexes exhibit efficient DNA-cleavage activity in visible light. The paramagnetic d (8)-Ni(II)-dpq complex displays only minor DNA-cleavage activity in visible light. Diamagnetic d (10)-Zn(II)-dpq complex shows only UV-A light-induced DNA cleavage but no apparent DNA-cleavage activity in visible light. Steric protection of the photoactive quinoxaline moiety of the dpq ligand inside the hydrophobic {M(Tp (Ph))} molecular bowl has a positive effect on the photoinduced DNA-cleavage activity.     

Synthesis,characterization, and antitumor activity of novel tumor-targeted platinum(IV) complexes

Four tumor-targeted platinum(IV) complexes with ammonia and cyclohexylamine as the carrier groups and biotin as the axial group were designed, synthesized, and characterized. In vitro evaluation of the antitumor activity of complexes C1–C4 against lung cancer cells (A549), liver cancer cells (SMMC-7721), breast cancer cells (MCF-7), and colon cancer cells (SW480) was carried out. Complex C3 had the best cellular activity. Compared with cisplatin, complex C3 showed good anticancer activity against A549 cell line,complex C3 (6.34±0.44) is 3 times more cytotoxic than cisplatin (19.40±0.71),and against MCF-7 cell line complex C3 (4.22±0.11) is 5.4 times more cytotoxic than cisplatin (22.96±0.58), and against SW480 cell line complex C3 (6.65±0.60) is 3.4 times more cytotoxic than cisplatin (23.15±0.22). (Table 1) Axial chloride increased the redox power of complex C3 to increase the intercellular accumulation and the introduction of mixed amine had the ability to overcome cisplatin resistance. Complex C3 works best on MCF-7, then SW480, A549, and SMMC-7721. Thus, complex C3 is targeted by the axial introduction of biotin.     

Synthesis and biological evaluation of water-soluble trans-[bicyclo[2.2.2]octane-7R,8R-diamine]platinum(II) complexes with linear or branched alkoxyacetates as leaving groups

Four platinum(II) complexes, trans-[bicyclo[2.2.2]octane-7R,8R-diamine]bis(alkoxyacetato-O,O’) platinum(II) (alkoxyacetate = methoxyacetate (2), ethoxyacetate (3), isopropoxyacetate (4), and tert-butoxyacetate (5)) were synthesized and spectrally characterized. The cytotoxicity of these water-soluble complexes was evaluated by CCK-8 assay in vitro against HCT-116, HepG-2, and A549 cancer cell lines. Most of the complexes had cytotoxic activity against the tested cancer cell lines. Among them, 3 showed more potent antitumor effect than cisplatin or oxaliplatin. Complex 3 could cause HCT-116 cell line death based on an apoptotic pathway since it has a dicyclic moiety similar to 1R,2R-diaminocyclohexane in oxaliplatin. Agarose gel electrophoresis on the interaction between 3 and DNA indicated that it has different behavior from that of cisplatin or oxaliplatin, which has a high correlation with the ligand used.     

Influence of Ligand and Nuclearity on the Cytotoxicity of Cyclometallated C^N^C Platinum(II) Complexes

A series of cyclometallated mono- and di-nuclear platinum(II) complexes and the parent organic ligand, 2,6-diphenylpyridine 1 (HC^N^CH), have been synthesized and characterized. This library of compounds includes [(C^N^C)Pt^II( L )] ( L =dimethylsulfoxide (DMSO) 2 and triphenylphosphine (PPh₃) 3 ) and [((C^N^C)Pt^II)₂( L‘ )] (where L‘ =N-heterocycles (pyrazine (pyr) 4 , 4,4‘-bipyridine (4,4‘-bipy) 5 or diphosphine (1,4-bis(diphenylphosphino)butane (dppb) 6 ). Their cytotoxicity was assessed against four cancerous cell lines and one normal cell line, with results highlighting significantly increased antiproliferative activity for the dinuclear complexes ( 4 – 6 ), when compared to the mononucleated species ( 2 and 3 ). Complex 6 is the most promising candidate, displaying very high selectivity towards cancerous cells, with selectivity index (SI) values >29.5 (A2780) and >11.2 (A2780cisR), and outperforming cisplatin by >4-fold and >18-fold, respectively.     

烷氧基酸为离去基团的铂(Ⅱ)配合物的体外活性研究

合成了5个以直链和带支链烷氧基乙酸为载体配基的顺铂类配合物,通过红外光谱、核磁共振氢谱和质谱对配合物进行了表征,并测试了化合物对肺腺癌SPC-A1和胃腺癌BGC823的体外抗肿瘤活性。生物活性测试结果表明,配合物的活性与离去基团有很大关系。配合物4(顺-二(异丙氧基乙酸根)·[(1R,2R)-1,2-反式环己二胺]合铂(Ⅱ))在2个细胞系中均显示最高的体外抗肿瘤活性,甚至超过顺铂。     

Potent Anticancer Activity and Possible Low Toxicity of Platinum(II) Complexes with Functionalized 1,1‐Cyclobutanedicarboxylate as a Leaving Ligand

Two platinum(II) complexes, DN603 and DN604, were designed and prepared by using 3‐oxocyclobutane‐1,1‐dicarboxylate as a ligand. The compounds were prepared according to the concept that incorporation of a functionalized moiety in the leaving ligand that did not affect its coordination bonding to the metal atom would play a key role in the anticancer activity of the resulting platinum complex. The newly prepared compounds were found to show potent in vitro anticancer activity comparable to cisplatin and oxaliplatin; especially DN604, which exhibited low acute toxicity similar to carboplatin, and presented acceptable solubility and stability in water. Chemical and biological results indicated that the functionalized moiety, uncoordinated, led to potent anticancer activity and low apparent toxicity of the platinum complexes by affecting the kinetic properties of the compounds.     

氨·环己胺·羧酸根合铂(Ⅱ)类配合物的合成、抗肿瘤活性和与DNA的键合水平

本工作设计合成了6种新型氨·环己胺·羧酸根合铂!类配合物[Pt(NH3)(NH2)X2](a￣f)｛其中,X=CH3COO-(乙酸根),CH2ClCOO-(氯乙酸根),C6H5-COO-(苯甲酸根),p-CH3O-C6H4-COO-(对甲氧基苯甲酸根),p-CH3-C6H4-COO-(对甲基苯甲酸根),p-NO2-C6H4-COO-(对硝基苯甲酸根)｝。通过元素分析、摩尔电导、红外光谱、紫外光谱和1H核磁共振谱对配合物进行了表征。通过MTT法研究了配合物的体外抗肿瘤活性,通过流式细胞仪以及等离子体质谱研究了配合物对细胞周期的影响以及与细胞DNA的键合量;体外抗肿瘤活性测试表明,配合物(c￣f)对EJ和HL-602种肿瘤细胞表现出好的活性,而且配合物(c),(d)和(e)对EJ和HL-602种肿瘤细胞的活性高于临床用药顺铂;配合物(a￣f)对MCF-7、HCT-8和BGC-8233种肿瘤细胞的活性低于顺铂;它们能阻止HL-60和EJ细胞G2 M→G1期的进行;配合物(a￣f)与HL-60和EJ细胞的DNA键合量从大到小的顺序为:c>d>e>cisplatin>f>a>b。     

Synthesis,characterization, and miRNA-mediated PI3K suppressing activity of novel cisplatin-derived complexes of selenones

New therapeutic options are crucially for most cancers, particularly those with poor clinical outcomes. Five new derivatives of cisplatin-containing selenone ligands with the general formula, cis-[Pt(NH₃)₂(Selenone)₂](NO₃)₂ (1–5) were synthesized and characterized using elemental analysis, Infrared, and nuclear magnetic resonance (¹H, ¹³C & ⁷⁷Se) spectroscopy. Spectroscopic and computational data supported the coordination of selenones to platinum(II). The structures of the complexes were predicted using density functional theory calculations. Molecular docking studies were carried out using the AutoDock Tools docking program. The in vitro cytotoxicity of these complexes and cisplatin against three human cancer cell lines, HeLa, A549, and HCT116 was investigated using the MTT assay. The best candidate complex, complex 3, was subjected to mechanistic assessments, including miRNA profiling, PI3K deactivation, and induction of apoptosis. Docking studies showed that all the newly synthesized platinum(II) complexes interacted with the minor DNA groove. The synthesized complexes showed promising cytotoxic effects against the tested cell lines. Complex 3 modulated the miRNA expression signature in A549 cells. Pathway enrichment analyses of differentially expressed miRNA gene targets identified the PI3K/AKT signaling pathway as a promising target. Complex 3 inhibited PI3K activity and induced apoptosis. Collectively, our study identified promising new platinum(II) derivatives such as complex 3, paving the way for future in vitro and in vivo validations and safety studies.     

Structure, cytotoxicity, and DNA-cleavage properties of the complex [Cu(II)(pbt)Br2

The reactions of the ligand 2-(2-pyridyl)benzthiazole (pbt) with CuBr 2 and ZnCl 2 in acetonitrile produce the complexes [Cu(pbt)Br 2] ( 1) and [Zn(pbt)Cl 2] ( 3), respectively. When complex 1 is dissolved in DMF, complex 2 is obtained as light-green crystals. The reaction of pbt with CuBr 2 in DMF also yields the complex [Cu(pbt)Br 2(dmf)] ( 2) (dmf = dimethylformamide). Complexes 1- 3 were characterized by X-ray crystallography. Complexes 1 and 3 have distorted tetrahedral coordination environments, and complex 2 is constituted of two slightly different copper centers, both exhibiting distorted trigonal bipyramidal geometries. Complexes 1 and 2 cleave phiX174 phage DNA, both in the presence and the absence of reductant. The free ligand pbt does not show any DNA-cleaving abilities. The poor solubility of complex 3 makes it not applicable for biological tests. The occurrence of DNA breaks in the presence of various radical scavengers suggests that no diffusible radicals are involved in the DNA cleavage by complex 1, as none of the scavengers inhibit the cleavage reaction. The DNA-cleavage products are not religated with the enzyme T4 DNA ligase, which is an additional proof that the cleavage is nonhydrolytic. Most probably the cleaving reaction involves reactive oxygen species, which could not be trapped, leading to an oxidative mechanism. An easy oxidation of Cu (II)(pbt)Br 2 to Cu (III) in DMF and the reduction of the same to Cu (I), under similar electrochemical conditions may lead to the in situ activation of molecular oxygen, resulting in the formation of metal solvated nondiffusible radicals able to prompt the oxidative cleavage of DNA. Complex 1 and the pure ligand exhibit remarkable cytotoxic effects against the cancer cell lines L1210 and A2780 and also against the corresponding cisplatin-resistant mutants of these cell lines.     

Reactivity and biological properties of a series of cytotoxic PtI2(amine)2 complexes, either cis or trans configured

Six diiodido-diamine platinum(II) complexes, either cis or trans configured, were prepared, differing only in the nature of the amine ligand (isopropylamine, dimethylamine, or methylamine), and their antiproliferative properties were evaluated against a panel of human tumor cell lines. Both series of complexes manifested pronounced cytotoxic effects, with the trans isomers being, generally, more effective than their cis counterparts. Cell cycle analysis revealed different modes of action for these new Pt(II) complexes with respect to cisplatin. The reactivity of these platinum compounds with a number of biomolecules, including cytochrome c, two sulfur containing modified amino acids, 9-ethylguanine, and a single strand oligonucleotide, was analyzed in depth by mass spectrometry and NMR spectroscopy. Interestingly, significant differences in the reactivity of the investigated compounds toward the various model biomolecules were observed: in particular we observed that trans complexes preferentially release their iodide ligands upon biomolecule binding, while the cis isomers may release the amine ligands with retention of iodides. Such differences in reactivity may have important mechanistic implications and a relevant impact on the respective pharmacological profiles.     

Synthesis,characterization, and biological activity of new mixed ammine/amine platinum(IV) complexes

A series of mixed ammine/amine platinum(IV) complexes with lipophilic ligands in their axial positions were designed, synthesized, and spectrally characterized. In vitro cytotoxicity evaluation of these complexes and their lead compounds have been carried out against A549, SMMC-7721, MCF-7, and SW480 human cancer cell lines. The introduction of carboxylate ions as leaving group can improve the aqueous solubility and stability of the platinum(II) complexes. The carboxylato ligands and chloride ligands in the axial position markedly increased the lipophilicity and cytotoxicity of compounds C4 and C5. Particularly, compound C5 showed two to eight times higher cytotoxicity than cisplatin and satraplatin against selected cell lines. For its oral activity and no cross-resistance potentiality, C5 is expected to be an antitumor platinum drug candidate. This novel class of platinum compounds represents a valuable lead in the development of new-generation agents capable of demonstrating cytotoxicity superior to that of the clinically established cisplatin.     

Cobalt(II) complexes with thiosemicarbazone as potential antitumor agents: synthesis,crystal structures,DNA interactions,and cytotoxicity

Two cobalt(II) complexes [Co(QCT)₂]·Cl·1.5H₂O (1) (QCT = quinoline-2-carboxaldehyde thiosemicarbazone) and [Co(QCMT)(CH₃OH)Cl₂] (2) (QCMT = quinoline-2-carboxaldehyde N⁴-methyl-thiosemicarbazone) have been synthesized and structurally characterized. Complex 1 crystallizes in a triclinic system with space group P–1 and complex 2 crystallizes in a monoclinic system with space group P2(1)/n. In both complexes the cobalt(II) center is six coordinated with distorted octahedral geometry. The interactions of two complexes with CT-DNA were investigated by electronic absorption spectra, circular dichroism (CD) spectra and fluorescence spectra. Results suggest that the complexes bind to DNA via groove binding mode, and complex 2 has stronger binding ability than complex 1. The in vitro cytotoxicity has been tested against the human lung adenocarcinoma cell line A-549, cisplatin-resistant cell line A-549/CDDP, and human breast adenocarcinoma cell line MCF-7. Complex 2 is more cytotoxic than complex 1, and both of them show higher cytotoxicity than the parent ligands alone. Compared with cisplatin, the two cobalt(II) complexes are more active against A-549/CDDP and MCF-7 cell lines at most experimental concentrations. Notably, although complex 2 is found to be less effective than cisplatin against the parent cell line A-549, it is much more effective than cisplatin against the resistant cell A-549/CDDP.     

Synthesis and in vitro cytotoxicity of platinum(II) complexes with chiral N-monosubstituted 1,2-cyclohexyldiamine derivatives as the carrier groups

Eight platinum(II) complexes with the new chiral ligands, (1R,2R)-N ¹-(pyridine-2-ylmethyl) cyclohexane-1,2-diamine (R) or (1S,2S)-N ¹-(pyridine-2-ylmethyl) cyclohexane-1,2-diamine (S) as the carrier groups were designed, synthesized, and spectrally characterized. All platinum(II) complexes showed much better aqueous solubility than cisplatin and oxaliplatin. In vitro cytotoxicity of the compounds against human HepG-2, MCF-7, A549, and HCT-116 cell lines was evaluated. Results indicate that all compounds with R as the carrier group showed cytotoxicity against HCT-116, A549, and MCF-7 cell lines; however, all compounds with S as carrier group exhibited disappointing cytotoxicity against tested cell lines. Compound R2, bearing ClCH₂COO^- as leaving group, exhibited better cytotoxicity than that of carboplatin against A549 and MCF-7 cell lines and also showed close activity to oxaliplatin against HCT-116 cell line.     

A photoactivated trans-diammine platinum complex as cytotoxic as cisplatin

The synthesis and X-ray structure (as the tetrahydrate) of the platinum(IV) complex trans,trans,trans-[Pt(N(3))(2)(OH)(2)(NH(3))(2)] 3 are described and its photochemistry and photobiology are compared with those of the cis isomer cis,trans,cis-[Pt(N(3))(2)(OH)(2)(NH(3))(2)] 4. Complexes 4 and 3 are potential precursors of the anticancer drug cisplatin and its inactive trans isomer transplatin, respectively. The trans complex 3 is octahedral, contains almost linear azide ligands, and adopts a layer structure with extensive intermolecular hydrogen bonding. The intense azide-to-platinum(IV) charge-transfer band of complex 3 (285 nm; epsilon=19 500 M(-1) cm(-1)) is more intense and bathochromically shifted relative to that of the cis isomer 4. In contrast to transplatin, complex 3 rapidly formed a platinum(II) bis(5'-guanosine monophosphate) (5'-GMP) adduct when irradiated with UVA light, and did not react in the dark. Complexes 3 and 4 were non-toxic to human skin cells (keratinocytes) in the dark, but were as cytotoxic as cisplatin on irradiation for a short time (50 min). Damage to the DNA of these cells was detected by using the "comet" assay. Both trans- and cis-diammine platinum(IV) diazide complexes therefore have potential as photochemotherapeutic agents.     

Synthesis and X-ray structure of platinum(II), palladium(II) and copper(II) complexes with pyridine–pyrazole ligands: Influence of ligands’ structure on cytotoxic activity

The new pyrazole ligand 5-(2-hydroxyphenyl)-3-methyl-1-(2-pyridylo)-1H-pyrazole-4-phosphonic acid dimethyl ester (2a) has been used to obtain a series of platinum(II), palladium(II) and copper(II) complexes (3a–7a) as potential anticancer compounds. The molecular structures of the platinum(II) and copper(II) complexes 3a and 6a have been determined by X-ray crystallography. The cytotoxicity of the phosphonic ligand 2a and its carboxylic analog 2b as well as their complexes has been evaluated on leukemia and melanoma cell lines. Copper(II) complexes were found to be more efficient in the induction of melanoma cell death than the platinum(II) or palladium(II) complexes. Cytotoxic effectiveness of compound 7b against melanoma WM-115 cells was two times better than that of cisplatin. The reaction of compound 5b with 9-methylguanine has been studied.     

A potent antitumor Zn2+ tetraazamacrocycle complex targeting DNA: the fluorescent recognition, interaction and apoptosis studies

A Zn(2+) tetraazamacrocycle complex (2) bearing three naphthalene moieties has been prepared. Complex 2 recognizes, binds and causes damage to DNA, and shows considerable cytotoxicity against human cervical (HeLa), breast (MCF-7) and lung (NCI-H157) cancer cell lines with a different apoptotic pathway from that of cisplatin.     

Synthesis and biological evaluation of new mono naphthalimide platinum(IV) derivatives as antitumor agents with dual DNA damage mechanism

Naphthalimide has emerged as an interesting DNA intercalator and possessed attracting antitumor properties. In this context, naphthalimide group was linked to platinum(IV) core to construct a series of new mono naphthalimide platinum(IV) derivatives. The title compounds exert effective antitumor activities to the tested tumor cells lines in vitro, especially the one with propionyl chain displays comparable or even better bioactivities than platinum(II) reference drugs cisplatin and oxaliplatin. Moreover, the mono naphthalimide platinum(IV) derivative displays comparable tumor growth inhibitory competence against CT26 xenograft tumors in BALB/c mice in vivo without severe toxic effects in contrast to oxaliplatin. A dual DNA damage mechanism was proven for the title complex. Both naphthalimide ligand and the liberated platinum(II) moiety could generate DNA lesions to tumor cells synergistically and active the apoptotic pathway by up-regulating the expression of caspase 9 and caspase 3. Meanwhile, the conversion of platinum(II) drug into tetravalent form by incorporating naphthalimide moiety increases the uptake of platinum in whole cells and DNA remarkably. All these facts might be the factors for the title platinum(IV) complexes to overcome platinum(II) drug resistance. Additionally, the mono naphthalimide platinum(IV) complex could interact with human serum albumin by hydrogen bond and van der Waals force which would further influence their storage, transport and bioactivities.     

氨·二甲胺·羧酸根合铂(Ⅱ)类配合物的合成、抗肿瘤活性和与DNA的键合水平

本工作设计合成了6种新型混胺羧酸根合铂(Ⅱ)类配合物[Pt((?)NH)(NH₃)X₂](a～f){其中，X=CH₃COO^-(乙酸根)，CH₃Cl COO^-(氯乙酸根)，CHCl₂COO^-(二氯乙酸根)，C₆H₅-COO^-(苯甲酸根)，p-CH₃-C₆H₄-COO^-(对甲基苯甲酸根)，p-CH₃O-C₆H₄-COO^-(对甲氧基苯甲酸根)}。通过元素分析、摩尔电导、差热分析、红外光谱、紫外光谱和 ¹H核磁共振谱对配合物进行了表征。通过MTT法研究了配合物的体外抗肿瘤活性，通过等离子体质谱研究了配合物与细胞DNA的键合量；体外抗肿瘤活性测试表明，配合物(a～f)对所测试的肿瘤细胞MCF-7、HCT-8和BGC-823没有表现出活性，但对EJ和HL-60两种肿瘤细胞表现出好的活性，而且配合物(d～f)对HL-60细胞的活性与顺铂相当。配合物(a～f)与HL-60细胞的DNA键合量与其作用浓度表现出一定的依赖性，从小到大的顺序为：cisplatin < c < b < a < f < e < d。