Antitumor activity of binuclear cationic complexes of platinum (II) (original) (raw)
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Anticancer activity assessment of two novel binuclear platinum (II) complexes
In the current study, two binuclear Pt (II) complexes, containing cis, cis-[Me 2 Pt (μ-NN) (μ-dppm) PtMe 2 ] (1), and cis,cis-[Me 2 Pt(μ-NN)(μ dppm) Pt((CH 2) 4)] (2) in which NN = phthalazine and dppm = bis (diphenylphosphino) methane were evaluated for their anticancer activities and DNA/purine nucleotide binding properties. These Pt (II) complexes, with the non-classical structures, demonstrated a significant anticancer activity against Jurkat and MCF-7 cancer cell lines. The results of ethidium bromide/acridine orange staining and Caspase-III activity suggest that these complexes were capable to stimulate an apoptotic mechanism of cell death in the cancer cells. Using different biophysical techniques and docking simulation analysis, we indicated that these complexes were also capable to interact efficiently with DNA via a non-intercalative mechanism. According to our results, substitution of cyclopentane (in complex 2) with two methyl groups (in complex 1) results in significant improvement of the complex ability to interact with DNA and subsequently to induce the anticancer activity. Overall, these binuclear Pt (II) complexes are promising group of the non-classical potential anticancer agents which can be considered as molecular templates in designing of highly efficient platinum an-ticancer drugs.
Journal of Medicinal Chemistry, 1990
The antitumor and DNA-binding properties of a group of oligomeric platinum(I1) and platinum(1V) complexes are described. The compounds, having the stoichiometry [C~~-P~~(X),(~-OH)]~(NO~)~, where X is NH,, NH2CH2CH3, and NH2CH(CH3)2, were found to be inactive or only weakly active against L-1210 leukemia. In vitro studies involving PM2-DNA show that these compounds bind to and unwind closed circular DNA in a manner similar to cis-Pt"-(NH3)2C12. The Pt(1V) complexes produced by hydrogen peroxide oxidation of the Pt(I1) dimers are inactive as antitumor agents and are incapable of unwinding PM2-DNA. The cyclotrimer [C~S-P~"(RR-DACH)(~-OH)]~(NO~)~, where RR-DACH is (R,R)-1,2 diaminocyclohexane, exhibits potent antitumor activity against L-1210 leukemia and modest activities with B-16 and M5076 tumor lines. This compound platinates DNA, causing DNA unwinding and mobility shifts. 'The Bristol Myers Co.
Journal of Inorganic Biochemistry, 1993
Some DNA-binding experiments employing a selected number of novel dinuclear platinum complexes with the 4,4'-dipyrazolylmethane (dpzm) ligand are reported. A DNA-cleavage assay using Eco RI and Bam HI restriction endonudeases to probe the binding of the complexes at or near their unique restriction sequences of pUC9 DNA has been examined. The complex /3-[Cl2Pt(dpzm)2PtCl 2] has a greater affinity for DNA at the Eco RI restriction sequence over the Barn HI site. To our knowledge, the preferential inhibition of Eco RI activity is unprecedented for any platinum species reported to date. Further, the dinuclear complexes /~[Cl2Pt(dpzm)2PtCl2], /3-[Cl4Pt(dpzm)2PtCl4]-0.5dmf.0.5H20 and [Cl4Pt(dpzra)2PtCl2] are capable of inh~iting Eco RI activity to a far greater extent than the platinum anticancer drug c/s-[PtCIE(NH3)2] (cisplatin). The in vivo and in vitro anticancer properties of some of the platinum complexes are also described. The complexes ,v-[Cl2Pt(dpzm)2PtCl2]. 0.5dmf and /3-[CIEPt(dpzm)2PtCl 2] display significant activity against P388 lymphocytic leukemia in mice.
Journal of Medicinal Chemistry, 2008
A selected chemical library of six platinum(II) complexes having 1,2-bis(aminomethyl)carbobicyclic ligands were synthesized after a rational design in order to evaluate their antiproliferative activity and the structure-activity relationships. The cytotoxicity studies were performed using cancer cell lines sensitive (A2780) and resistant (A2780R) to cisplatin. Excellent cytotoxicity was observed for most of complexes, which presented better resistance factors than cisplatin against the A2780R cell line. The interaction of these complexes with DNA, as the target biomolecule, was evaluated by several methods: DNA-platinum binding kinetics, changes in the DNA melting temperature, evaluation of the unwinding angle of supercoiled DNA, evaluation of the interstrand cross-links, and replication mapping. The kinetics of the interaction with glutathione was also investigated to better understand the resistant factors observed for the new complexes.
Inorganic Chemistry, 2008
Pd(II) and Pt(II) complexes with the anions of the model nucleobases 1-methylthymine (1-MethyH), 1-methyluracil (1-MeuraH), and 1-methylcytosine (1-MecytH) of the types [Pd(dmba)(µ-L)] 2 [dmba) N,C-chelating 2-((dimethylamino)methyl)phenyl; L) 1-Methy, 1-Meura or 1-Mecyt] and [M(dmba)(L)(L′)] [L) 1-Methy or 1-Meura; L′) PPh 3 (M) Pd or Pt), DMSO (M) Pt)] have been obtained. Palladium complexes of the types [Pd(C 6 F 5)(N−N)(L)] [L) 1-Methy or 1-Meura; N−N) N,N,N′,N′-tetramethylethylenediamine (tmeda), 2,2′-bipyridine (bpy), or 4,4′dimethyl-2,2′-bipyridine (Me 2 bpy)] and [NBu 4 ][Pd(C 6 F 5)(1-Methy) 2 (H 2 O)] have also been prepared. The crystal structures of [Pd(dmba)(µ-1-Methy)] 2 , [Pd(dmba)(µ-1-Mecyt)] 2 ‚2CHCl 3 , [Pd(dmba)(1-Methy)(PPh 3)]‚3CHCl 3 , [Pt(dmba)-(1-Methy)(PPh 3)], [Pd(tmeda)(C 6 F 5)(1-Methy)], and [NBu 4 ][Pd(C 6 F 5)(1-Methy) 2 (H 2 O)]‚H 2 O have been established by X-ray diffraction. The DNA adduct formation of the new platinum complexes synthesized was followed by circular dichroism and electrophoretic mobility. Atomic force microscopy images of the modifications caused by the platinum complexes on plasmid DNA pBR322 were also obtained. Values of IC 50 were also calculated for the new platinum complexes against the tumor cell line HL-60. All the new platinum complexes were more active than cisplatin (up to 20-fold in some cases).
Synthesis and antitumor activity of 1,2-diaminocyclohexane platinum(IV) complexes
Journal of Inorganic Biochemistry, 1994
The synthesis, characterization, and antitumor activity of a series of platinum(IV) complexes of the type DACH-Pt'"(X),Y (where DACH = truns-dl, or buns-1-1,2-diaminocyclohexane, X = OH or Cl, and Y = oxalato, malonato, methylmalonato, tartronato, ketomalonato, l,l-cyclopropanedicarboxylato, or l,l-cyclobutanedicarbor@ato, are described. These complexes have been characterized by elemental analysis, HPLC, and infrared and '95Pt NMR spectroscopic techniques. The complexes had good in vitro cytotoxic activity (IC,, = 0.14-7.6 pg/ml) and were highly active in vivo against leukemia L1210 cells (%T/C = 152-> 600, cisplatin = 218). In addition, excellent in vivo antitumor activities against B16 melanoma (%T/C = 309), M.5076 reticulosarcoma (100% cures) and cisplatin-resistant Ll%lO/DDP (%T/C = 217) cell lines were also exhibited by an analog selected for further evaluation.
Journal of Inorganic Biochemistry, 2018
Four new complexes [Pd(H 2 L tBu)Cl]Cl (Pd1), [Pt(H 2 L tBu)Cl]Cl (Pt1), [Pd(Me 2 L tBu)Cl]Cl (Pd2) and [Pt (Me 2 L tBu)Cl]Cl (Pt2) (where H 2 L tBu = 2,6-bis(5-(tert-butyl)-1H-pyrazol-3-yl)pyridine and Me 2 L tBu = 2,6-bis(5-(tert-butyl)-1-methyl-1H-pyrazol-3-yl)pyridine) were synthesized and characterized by elemental microanalysis, IR, 1 H NMR and ESI-MS methods. The reactivity of complexes towards thiourea (Tu), L-methionine (L-Met), Lcysteine (L-Cys) and guanosine-5′-monophosphate (5′-GMP) was investigated. The obtained order was established as follows: Tu > L-Cys > L-Met > 5′-GMP. Complexes Pd1 and Pt1, that contain H 2 L tBu as chelator, showed higher reactivity towards biomolecules than those with Me 2 L tBu. The interaction of complexes with calf thymus DNA (CT-DNA) and bovine serum albumin (BSA) was studied by UV-Vis and fluorescence spectroscopy. The results have shown that complexes can bind to DNA exhibiting high binding constants (K b = 10 4 M −1). Obtained results during the examination of competitive reaction with ethidium bromide (EB) showed that complexes can replace EB-bound DNA. High values of binding constants indicate good binding affinity of complexes towards BSA. We evaluated the stability differences between complexes based on terpy as well as H 2 L tBu /Me 2 L tBu by DFT calculations (B3LYP(CPCM)/LANL2DZp), showing that both tridentate ligand systems lead to complexes of similar stability. The results of biological testing showed that all complexes exert moderate to high selective cytotoxicity, inducing apoptosis and autophagy in HeLa and PANC-1 tumor cell lines. Pd1 exhibited the strongest cytotoxic effect. Finally, cell cycle analysis showed that in HeLa cells Pd1, Pd2 and Pt1 induced accumulation of cells in S phase, whereas in PANC-1 cells Pd2 and Pt1 induced G2/M cycle arrest and Pd1 induced G0/G1 arrest. 1. Introduction Platinum-based drugs are widely used anticancer agents with a broad range of antitumor activities [1,2]. Although, cisplatin, cis-[Pt (NH 3) 2 Cl 2 ], is one of the most common chemotherapy drugs, the acquired resistance and serious side effects limit its clinical use [3-5]. These limitations have stimulated the investigations for improvement of existing platinum antitumor drugs and development of new derivatives that display better therapeutic properties. Therefore, a significant number of different platinum complexes were synthesized with the goal to overcome the disadvantages of cisplatin [6-11]. However, the long-term application of platinum complexes was leading to examination of complexes of some other metals, such as palladium [12-14]. It is well established that palladium(II) complexes
Journal of Inorganic Biochemistry, 2008
A series of platinum compounds with an analogue structure to cisplatin have been synthesized and their biological activity against HL-60 cancer cell line has been studied. The interaction with DNA was evaluated by circular dichroism (CD), electrophoresis and atomic force microscopy (AFM) techniques showing slight but significant structure-dependent differences among the evaluated complexes. The cytotoxicity assays afforded interesting relationships between the structure and the biological activity, thus, a better antiproliferative activity was observed for the complexes with higher hydrophobicity: the methoxylated complexes showed better activity than the hydroxylated ones (17 versus 20 and 19 versus 21). Especially compound 22 having a fatty acid subunit presented a promising cytotoxic activity. On the other hand, dichloro complexes 12 and 13 had better activities than the diiodo complexes, probably due to their better metabolic stability. Between both dichloro complexes the aromatic one showed much higher activity, which could be rationalized on the basis of the intercalating ability of the benzene ring. The flow cytometry assays indicated that most of the complexes induced the cell death by apoptosis except for aromatic compound 12 and the lipophilic compound 22 that induced preferably a mechanism of necrosis.