159701-67-4Relevant articles and documents
Kinetics and mechanism for reduction of oral anticancer platinum(iv) dicarboxylate compounds by L-ascorbate ions
Lemma, Kelemu,Sargeson, Alan M.,Elding, Lars I.
, p. 1167 - 1172 (2000)
Ascorbate(Asc) reductions of the oral anticancer platinum(iv) prodrugs m,trans,cu-[PtCl2(OAc)2(cha)(NH 3)](JM216) and cis, trans;,cis-[PtCl2(OCOC3H7) 2(cha)(NH3)](JM221) and of the isomers of JM216, viz.trans,cis,cis-[PtCl2(OAc)2(cha)(NH3)](JM394) and trans,trans,trans-[PtCI2(OAc)2(cha)(NH 3)](JM576)(OAc = acetate, cha = cyclohexylamine) have been investigated in a 1.0 M aqueous perchlorate medium using stopped-flow and conventional UV/VIS spectrophotometry as a function of temperature and pH. JM216 and 221 are reduced to ra-[PtCl2(cha)(NH3)](JM118) and JM394 and 576 to CM- and trans-[Pt(OAc)2(cha)(NH3)], respectively. The redox reactions follow the second-order rate law: -d[Pt(iv)]/dt = k [Pt(iv)] [Asc]tot where k is a pH dependent second-order overall rate constant and [Asc]tot = [Asc2-] + [H2Asc] + [H2Asc]. Reduction of JM216 and JM221 is slow(overall rate constants k298 = 5.08 ±10-2 and 3.25 × 1(T2 mol-1 dm3 s-1 at pH 7.12, respectively) and is suggested to take place via an outer-sphere mechanism. Reductions of JM394 and JM576 are more than three orders of magnitude faster(k298 = 230 ±6 mol-1 dm3 s-1 at pH 7.0 for JM394). They are suggested to take place by a mechanism involving a reductive attack on one of the mutually trans chloride ligands by Asc2 and less efficiently by H Asc- leading to the formation of a chloride-bridged activated complex. The second-order rate constants for reduction of JM394 by HAsc- and Asc2- at 25 °C are 0.548 ±0.004 and(4.46 ±0.01) × 106 mol-1 dm3 s-1, respectively. The rate constants for reduction of JM216 and JM221 by Asc2- at 25 °C are calculated to be 672 ±15 and 428 ±10 mol1 dm3 s-1, respectively and reduction by HAsc- was not observed under these conditions. Thus, Asc2- is up to 7 orders of magnitude more efficient as a reductant than HAsc-. H2Asc is virtually inactive. The activation parameters Asc2- and AS+ for reduction of JM216, JM221, JM394, and JM576 by Asc2- are 52 ±1,46 ±1, 56.2 ±0.5, and 63 ±2 kJ mol-1 and -97 ±4, -120 ±4, -24 ±2, and -8 ±5 J K-1 mol-1, respectively. An isokinetic relationship gives further support to the mechanistic assignments. The Royal Society of Chemistry 2000.
Dependence of the reduction products of platinum(IV) prodrugs upon the configuration of the substrate, bulk of the carrier ligands, and nature of the reducing agent
Sinisi, Marilù,Intini, Francesco P.,Natile, Giovanni
, p. 9694 - 9704 (2012/10/29)
Most evidence indicates that platinum(IV) prodrugs are rapidly reduced under physiological conditions by biologically relevant reducing agents, such as ascorbic acid and glutathione; however, the precise mechanisms of reduction are not fully understood, thus preventing rational design of compounds with better pharmacological properties. In the present study, reduction of three all-trans platinum(IV) compounds of formula [PtCl2(CH3COO) 2LL′] (LL′ = {E-HN = C(CH3)OCH 3}2, 1c, (H3N)(cyclohexylamine), 2c, and (H3N)(1-adamantylamine), 3c) by two biologically relevant reductants (ascorbic acid and glutathione) and by a classical coordination chemistry reductant (triphenylphosphine) has been investigated. Reduction by triphenylphosphine and glutathione leads, in all cases examined, to loss of the two chlorides and formation of the diacetato species trans-[Pt(CH 3COO)2LL′]. This is in accord with an inner-sphere redox process in which a chlorido ligand bridges the reductant with the platinum(IV) center. In contrast, reduction by ascorbic acid/sodium ascorbate 1:1 leads, in addition to the diacetato complex, also to formation of a significant amount of dichlorido species, particularly in the case of 1c (31%) and to a lesser extent of 3c (16%). The latter results indicate that ascorbic acid is less efficient to promote an inner-sphere redox process (attack on a chlorido ligand), therefore allowing participation of an outer-sphere mechanism, ultimately leading to formation of the more stable dichlorido species. The dependence of the yield of diacetato species upon the steric hindrance of the carrier ligand (69%, 84%, and 95% for 1c, 3c, and 2c, respectively) points to the possible participation of a second type of inner-sphere mechanism in which the interaction between the ascorbate and a chlorido ligand of the platinum(IV) substrate is mediated by a platinum(II) catalyst, the transition state resembling that of a platinum(II)-catalyzed ligand substitution at a platinum(IV) center. This investigation demonstrates that different species can be obtained by reduction of a platinum(IV) prodrug (depending upon the configuration of the substrate and the nature of the intervening reducing agent) and can explain some lack of correlation between prodrug and putative active species as well as contrasting literature results.
Crystal and Molecular Structures of Asymmetric cis- and trans-Platinum(II/IV) Compounds and Their Reactions with DNA Fragments
Talman, Eduard G.,Brüning, Wolfgang,Reedijk, Jan,Spek, Anthony L.,Veldman, Nora
, p. 854 - 861 (2008/10/09)
The asymmetrically substituted platinum(II) complexes cis-Pt(NH3)(c-C5H11NH2)Cl 2 and trans-Pt(NH3)(c-C6H11-NH2)Cl 2 have been synthesized and their crystal structures have been determined. Crystals of cis-Pt(NH3)(c-C6H11NH2)Cl 2 (1) are orthorhombic, space group Pbca (no. 61) with a = 10.1994(12), b = 10.494(2), c = 18.826(2) ?, Z = 8. The structure refinement converged to R1 = 0.0518 and wR2 = 0.1143. Crystals of trans-Pt(NH3)(c-C6H11NH2)Cl 2 (2) are monoclinic, space group P21/c (no. 14) with a = 12.141(3), b = 6.0965(9), c = 19.864(3) ?, β= 118.71(2)°, Z = 4. The structure refinement converged to R1 = 0.0711 and wR2 = 0.1846. In addition, the Pt(IV) analogues with axial hydroxide ligands have been synthesized. Also the corresponding bis(carboxylato)-platinum(IV) compound of formula trans,cis,cis-Pt(NH3)(c-C6H11NH 2)Cl2(OOCCH3)2 has been obtained by conversion of the hydroxide with acetic anhydride. Reactions of these platinum complexes with 9-methylhy-poxanthine and guanosine-5′-monophosphate (5′-GMP) have been studied in significant detail. The course of the reactions was followed by NMR spectroscopy, and 1H and 195Pt techniques were used to identify the formation of the products. It was found that the Pt(II) compounds easily react with the bases at the N7 position, whereas the Pt(IV) compounds react very slowly (for trans,cis,cis-Pt(NH3)(c-C6H11NH 2)Cl2(OOCCH3)2) or not at all (for trans,trans,trans-Pt(NH3)(c-C6H11NH 2)Cl2(OH)2). Only in the presence of glutathione does a reaction of the latter with 5′-GMP takes place. In this case a major product was found to be the reduced trans-Pt(II) complex with one molecule of 5′-GMP and one molecule of S-bonded glutathione.
