Synthesis and antitumor properties of new platinum(IV) complexes with aminonitroxyl radicals (original) (raw)
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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.
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.
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.
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.
Inorganic Chemistry, 2008
The reaction of [Pt(dmba)(PPh 3)Cl] [where dmba) N,C-chelating 2-(dimethylaminomethyl)phenyl] with aqueous ammonia in acetone in the presence of AgClO 4 gives the acetonimine complex [Pt(dmba)(PPh 3)(NHdCMe 2)]ClO 4 (1). The reaction of [Pt(dmba)(DMSO)Cl] with aqueous ammonia in acetone in the presence of AgClO 4 gives a mixture of [Pt(dmba)(NHdCMe 2) 2 ]ClO 4 (2) and [Pt(dmba)(imam)]ClO 4 (3a) (where imam) 4-imino-2-methylpentan-2-amino). [Pt(dmba)(DMSO)Cl] reacts with [Ag(NHdCMe 2) 2 ]ClO 4 in a 1:1 molar ratio to give [Pt(dmba)(DMSO)-(NHdCMe 2)]ClO 4 (4). The reaction of [Pt(dmba)(DMSO)Cl] with 20% aqueous ammonia in acetone at 70°C in the presence of KOH gives [Pt(dmba)(CH 2 COMe)(NHdCMe 2)] (5), whereas the reaction of [Pt(dmba)(DMSO)Cl] with 20% aqueous ammonia in acetone in the absence of KOH gives [Pt(dmba)(imam)]Cl (3b). The reaction of [NBu 4 ] 2 [Pt 2 (C 6 F 5) 4 (µ-Cl) 2 ] with [Ag(NHdCMe 2) 2 ]ClO 4 in a 1:2 molar ratio produces cis-[Pt(C 6 F 5) 2 (NHdCMe 2) 2 ] (6). The crystal structures of 1 • 2Me 2 CO, 2, 3a, 5, and 6 have been determined. Values of IC 50 were calculated for the new platinum complexes against a panel of human tumor cell lines representative of ovarian (A2780 and A2780cisR) and breast cancers (T47D). At 48 h incubation time complexes 1, 4, and 5 show very low resistance factors against an A2780 cell line which has acquired resistance to cisplatin. 1, 4, and 5 were more active than cisplatin in T47D (up to 30-fold in some cases). The DNA adduct formation of 1, 4, and 5 was followed by circular dichroism and electrophoretic mobility.
Platinum(II) complexes containing iminoethers: a trans platinum antitumour agent
Chemico-Biological Interactions, 1995
The biological activity of cis and truns complexes of formula [PtCl,( HN=C(OMe)Me ) J has been investigated. The iminoether ligands can have either E or Z configuration about the C=N double bond, therefore EE, EZ and ZZ isomers are obtainable. Substitution of iminoether with EE configuration for amine leads to unexpectedly high antitumour activity for the complex with tram geometry which turns out to be more active than the cis congener in the P388 leukaemia system. The same frans-EE complex shows an activity comparable to that of cisplatin in reducing the primary tumour mass and lung metastases in mice bearing Lewis lung carcinoma, thus representing a tram platinum complex active on both limphoproliferative and solid metastasizing murine tumours. Also the cytotoxicity, the inhibition of DNA synthesis and the mutagenic activity, which are greater for the ciswith respect to the fruns-isomer in the amine complexes, are instead greater for the transthan for the cisisomer in the case of iminoether compounds. Binding to calf thymus DNA is slower for iminoether complexes than it is for amine complexes, however after 24 h reaction time the level of binding is similar for both types of complexes. Tram-EE, like trans-DDP, does not give the DNA conformational alterations (terbium fluorescence) typical of antitumour-active cis-Abbreviations: cis-DDP, cisplatin, cis-[PQ(NH,),]; trans-DDP, frans-[PtCl&NH,),]; (DM)b, number of bound platinum atoms/nucleotide; (D/N)f, platinum complex/nucleotide formal concentration ratio; cis-and trons-EE, cis-and trans-[PQ( (E)HN=C(OMe)Me) *I; ID,, and ID,, concentrations inhibiting 50% and 90% cell growth, respectively; PBS, phosphate buffered saline. * Corresponding author, Tel.: +39 80 278412.
European Journal of Medicinal Chemistry, 2011
A series of six novel bis(carboxylato)dichloridobis(ethylamine)platinum(IV) complexes was synthesized and characterized in detail by elemental analysis, FT-IR, ESI-MS, HPLC, multinuclear ( 1 H, 13 C, 15 N, 195 Pt) NMR spectroscopy and in one case by X-ray diffraction. Cytotoxic properties of the complexes were evaluated in four human tumor cell lines originating from ovarian carcinoma (CH1 and SK-OV-3), colon carcinoma (SW480) and non-small cell lung cancer (A549) by means of the MTT colorimetrical assay. In addition, their octanol/water partition coefficients (log P values) were determined. Remarkably the most active (and also most lipophilic) compounds, having 4-propyloxy-4-oxobutanoato and 4-(2-propyloxy)-4-oxobutanoato axial ligands, showed IC 50 values down to the low nanomolar range.
Inorganica Chimica Acta, 2006
The design and synthesis of three asymmetrical platinum(II) analogues of cisplatin with substituents on the amine, varying in polarity and steric bulk is presented. Their biological activities, as studied using in vitro cytotoxicity studies in cisplatin sensitive and the corresponding cisplatin resistant cell lines, cellular uptake experiments and in a reaction with model DNA base GMP, are presented. All compounds exhibit promising cytotoxicity in the cisplatin sensitive cell lines albeit lower than cisplatin. On the other hand, the complexes partly overcome cisplatin resistance in the resistant cell lines. A direct correlation between cytotoxicity and cellular uptake was found. Conversely, the rate of reaction of all compounds with the model base GMP was found to be very similar and faster than cisplatin. It was therefore concluded that the difference in activity observed for these complexes is due to differential cellular uptake rather than the reactivity towards the cellular target of platinum complexes, nuclear DNA.