Synthesis and antitumor activity of new platinum complexes (original) (raw)
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Diastereomerically pure platinum(II) complexes as antitumoral agents
Journal of Inorganic Biochemistry, 2013
Diastereomerically pure platinum(II) complexes as antitumoral agents. The influence of the mode of binding {(N), (N,O) − or (C,N)} − of (1S,2R)\[(η 5-C 5 H 5) Fe{(η 5-C 5 H 4)\CH_N\CH(Me)\CH(OH)\C 6 H 5 }] and the arrangement of the auxiliary ligands
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, 2007
Four dipeptide complexes of the type [PtX 2 (dipeptide)] AE H 2 O (X = Cl, I, dipeptide = L-methionylglycine, L-methionyl-L-leucine) were prepared. The complexes were characterized by 1 H, 13 C, 195 Pt NMR and infrared spectroscopy, DTG and elemental analysis. From the infrared, 1 H and 13 C NMR spectroscopy it was concluded that dipeptides coordinate bidentately via sulfur and amine nitrogen donor atoms. Confirmed with 13 C and 195 Pt NMR spectroscopy, each of the complexes exists in two diastereoisomeric forms, which are related by inversion of configuration at the sulfur atom. The 1 H NMR spectrum for the platinum(II) complex with L-methionylglycine and chloro ligands exhibited reversible, intramolecular inversion of configuration at the S atom; DG 6 ¼ = 72 kJ mol À1 at coalescence temperature 349 K was calculated. In vitro cytotoxicity studies using the human tumor cell lines liposarcoma, lung carcinoma A549 and melanoma 518A2 revealed considerable activity of the platinum(II) complex with L-methionylglycine and chloro ligands. Further in vitro cytotoxic evaluation using human testicular germ cell tumor cell lines 1411HP and H12.1 and colon carcinoma cell line DLD-1 showed moderate cytotoxic activity for all platinum(II) complexes only in the cisplatin-sensitive cell line H12.1. Platinum uptake studies using atomic absorption spectroscopy indicated no relationship between uptake and activity. Potential antitumoral activity of this class of platinum(II) complexes is dependent on the kind of ligands as well as on tumor cell type.
Platinum Complexes as Anticancer Agents
Recent Patents on Anti-cancer Drug Discovery, 2006
The application of inorganic chemistry to medicine is a rapidly developing field, and novel therapeutic and diagnostic metal complexes are now having an impact on medical practice. Advances in biocoordination chemistry are crucial for improving the design of compounds to reduce toxic side effects and understand their mechanisms of action. Cisplatin, as one of the leading metal-based drugs, is widely used in the treatment of cancer. Significant side effects and drug resistance, however, have limited its clinical applications. Biological carriers conjugated to cisplatin analogs have improved specificity for tumor tissue, thereby reducing side effects and drug resistance. Platinum complexes with distinctively different DNA binding modes from that of cisplatin also exhibit promising pharmacological properties. This review focuses on recent advances in developing platinum anticancer agents with an emphasis on platinum coordination complexes.
Trans-Platinum Complexes with Promising Antitumor Properties
Medicinal Chemistry Reviews - Online, 2005
Wide range of dose-limiting toxicities and tumor resistance to drug are significant limitations to the successful use of Cis-diammine dichloroplatinum (cis-DDP). For a long time it was believed that generally trans-isomers of platinum containing complexes are devoid of biological activity. Data accumulated by the structure-activity relationship studies up to date, confirmed that trans-platinum(II) and trans-platinum(IV) complexes often exhibit enhanced activity in cisplatin resistant cell lines in comparison to their cisanalogues, indicating that trans-platinum compounds follow some different pattern of antitumor activity in comparison to their cis-isomers. Trans-platinum complexes that have been tested to date and shown to possess attractive antitumor properties represent diverse group of compounds, and can be classified according to structure and nature of nonleaving (amine) ligand as following: Trans-ammine(amine) platinum(IV) complexes, trans-platinum(II) complexes with planar ligands, trans-platinum(II) complexes with heterocyclic amine ligands, trans-platinum(II) complexes with iminoether ligands, trans-platinum(II) complexes with asymmetric aliphatic amine ligands, bifunctional dinuclear and trinuclear transplatinum(II) complexes. Potential of trans-platinum complexes to follow some different mechanisms of cell killing in comparison to cis-DDP and thus circumvent cis-DDP resistance, raises interest for their further preclinical evaluation.
Synthesis and antitumor properties of new platinum(IV) complexes with aminonitroxyl radicals
Russian Chemical Bulletin, 2006
Acylation of cis,trans,cis Pt IV (RNH 2)(NH 3)(OH) 2 Cl 2 with acetic anhydride afforded com plexes cis,trans,cis Pt IV (RNH 2)(NH 3)(OAc) 2 Cl 2 , where R is 2,2,6,6 tetramethyl 1 oxyl piperidin 4 yl (1b) or 2,2,5,5 tetramethyl 1 oxylpyrrolidin 3 yl (2b). The complexes were characterized by elemental analysis, HPLC, and IR, UV, and ESR spectra. Complex 1b exhibits high antitumor activity comparable with that of Cisplatin against leukemia P388 used as the experimental tumor. Simultaneous administration of low doses of 1b and Cisplatin (1/20 of LD 50 each) results in synergism of the antitumor activity and 100% cure of animals.
Inorganica Chimica Acta, 2014
A series of Pt(II) complexes with 3-ethyl-5-methyl-5-(4-pyridyl)hydantoin, 3-propyl-5-methyl-5-(4-pyridyl)hydantoin and 3-benzyl-5-methyl-5-(4-pyridyl)hydantoin with general formulae cis-[Pt(L) 2 Cl 2 ], cis-[Pt(NH 3)LCl 2 ] and trans-[Pt(NH 3)LCl 2 ] were synthesized. The new compounds were characterized by means of elemental analysis, IR, 1 H and 13 C NMR spectroscopy. The studies showed that the ligands coordinate to the platinum ions in a monodentate manner through the nitrogen atom from the pyridine ring. The cytotoxic activity in vitro of the complexes as well as of their previously prepared Pt(II) analogues with other derivatives of 5-methyl-5-(4-pyridyl)hydantoin was screened against a panel of human tumor cell lines. Cytotoxicity was strongly dependent on their lipophilicity, while the most lipophilic Pt(II) complex, carrying 3-benzyl-5-methyl-5-(4-pyridyl)hydantoin as carrier ligand inhibited the viability of tested cells at low micromolar concentrations with IC 50 values comparable to that of cisplatin. A preliminary pharmacodynamic investigation showed that its cytotoxicity is mediated through induction of apoptosis. The cis-and trans-analogues consisting one ammine group in the molecules exhibited far less cytotoxicity in corroboration to the well established structure-activity rules for dia(m)mine platinum(II) complexes.
International Journal of Molecular Sciences, 2021
Three novel platinum(II) complexes bearing N-heterocyclic ligands, i.e., Pt2c, Pt-IV and Pt-VIII, were previously prepared and characterized. They manifested promising in vitro anticancer properties associated with non-conventional modes of action. To gain further mechanistic insight, we have explored here the reactions of these Pt compounds with a few model proteins, i.e., hen egg white lysozyme (HEWL), bovine pancreatic ribonuclease (RNase A), horse heart cytochrome c (Cyt-c) and human serum albumin (HSA), primarily through ESI MS analysis. Characteristic and variegate patterns of reactivity were highlighted in the various cases that appear to depend both on the nature of the Pt complex and of the interacting protein. The protein-bound Pt fragments were identified. In the case of the complex Pt2c, the adducts formed upon reaction with HEWL and RNase A were further characterized by solving the respective crystal structures: this allowed us to determine the exact location of the var...
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).