Dipartimento Farmaco-Chimico, Università degli Studi di Bari A. Moro, Via E. Orabona 4, 70125 Bari, Italy.
Inorg Chem. 2012 Sep 17;51(18):9694-704. doi: 10.1021/ic300957v. Epub 2012 Aug 24.
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 [PtCl(2)(CH(3)COO)(2)LL'] (LL' = {E-HN═C(CH(3))OCH(3)}(2), 1c, (H(3)N)(cyclohexylamine), 2c, and (H(3)N)(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(3)COO)(2)LL']. 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.
大多数证据表明，生理条件下生物相关还原剂（如抗坏血酸和谷胱甘肽）会迅速将铂（IV）前药还原；然而，还原的确切机制尚未完全了解，因此无法合理设计具有更好药理特性的化合物。在本研究中，研究了三种全反式铂（IV）化合物[PtCl2（CH3COO）2（LL']（LL'= {E-HN═C（CH3）OCH3}（2），1c，（H3N）（环己胺），2c 和（H3N）（1-金刚烷胺），3c）与两种生物相关还原剂（抗坏血酸和谷胱甘肽）和一种经典配位化学还原剂（三苯基膦）的还原。三苯基膦和谷胱甘肽的还原在所有检查的情况下都会导致两个氯化物的丢失，并形成二乙酸酯物种反式-[Pt（CH3COO）2（LL']。这与“内球”氧化还原过程一致，其中一个氯化物配体桥接还原剂与铂（IV）中心。相比之下，抗坏血酸/抗坏血酸钠 1:1 的还原除了形成二乙酸酯配合物外，还会形成大量的二氯化物物种，特别是在 1c（31%）的情况下，在较小程度上也会形成 3c（16%）。后一种结果表明，抗坏血酸促进内球氧化还原过程（攻击氯化物配体）的效率较低，因此允许“外球”机制的参与，最终导致更稳定的二氯化物物种的形成。二乙酸酯物种的产率取决于载体配体的空间位阻（1c、3c 和 2c 分别为 69%、84%和 95%），这表明可能存在第二种内球机制，其中抗坏血酸盐与铂（IV）底物的氯化物配体之间的相互作用由铂（II）催化剂介导，过渡态类似于铂（IV）中心的铂（II）催化配体取代。这项研究表明，通过铂（IV）前药的还原可以获得不同的物种（取决于底物的构型和介入还原剂的性质），并可以解释一些前药和假定的活性物种之间缺乏相关性以及对比文献结果。
