Investigations of the Kinetics and Mechanism of Reduction of a Carboplatin Pt(IV) Prodrug by the Major Small-Molecule Reductants in Human Plasma

Abstract

The development of Pt(IV) anticancer prodrugs to overcome the detrimental side effects of Pt(II)-based anticancer drugs is of current interest. The kinetics and reaction mechanisms of the reductive activation of the carboplatin Pt(IV) prodrug cis,trans-[Pt(cbdca)(NH3)2Cl2] (cbdca = cyclobutane-1,1-dicarboxylate) by the major small-molecule reductants in human plasma were analyzed in this work. The reductants included ascorbate (Asc), the thiol-containing molecules L-cysteine (Cys), DL-homocysteine (Hcy), and glutathione (GSH), and the dipeptide Cys–Gly. Overall second-order kinetics were established in all cases. At the physiological pH of 7.4, the observed second-order rate constants k′ followed the order Asc << Cys–Gly ~ Hcy < GSH < Cys. This reactivity order together with the abundances of the reductants in human plasma indicated Cys as the major small-molecule reductant in vivo, followed by GSH and ascorbate, whereas Hcy is much less important. In the cases of Cys and GSH, detailed reaction mechanisms and the reactivity of the various protolytic species at physiological pH were derived. The rate constants of the rate-determining steps were evaluated, allowing the construction of reactivity-versus-pH distribution diagrams for Cys and GSH. The diagrams unraveled that species III of Cys (−SCH2CH(NH3+)COO−) and species IV of GSH (−OOCCH(NH3+)CH2CH2CONHCH(CH2S−)- CONHCH2COO−) were exclusively dominant in the reduction process. These two species are anticipated to be of pivotal importance in the reduction of other types of Pt(IV) prodrugs as well.

Antioxidative Reactivity of L-Ascorbic Acid and D-Isoascorbic Acid Species towards Reduction of Hexachloroiridate (IV)

“…e stoichiometric ratios were determined in a medium of 0.10 M HClO 4 and 0.90 M NaClO 4 by use of spectrophotometric titration method which was demonstrated to be a very useful approach [28][29][30][31]. e absorption values at 488 nm as a function of [AA] tot or [IAA] tot are shown in Figure 5; in either case, the data points all follow two crossing straight lines.…”

Mechanistic scrutiny of the oxidations of thiol‐containing drugs cysteamine and d‐penicillamine by cis‐diamminetetrachloroplatinum(IV)

“…A spectrophotometric titration approach was opted to study the reaction stoichiometry of the present redox processes. [32][33][34] was estimated from the intersection point. Essentially, the estimated ratio is very close to a theoretical stoichiometry of 1:2 if CA was assumed to be oxidized to CA disulfide (H 2 NCH 2 CH 2 SSCH 2 CH 2 NH 2 or CA-disulfide) as expressed by Equation 3:…”

Interactions between mitochondria-damaging platinum(iv) prodrugs and cytochrome c

“…[19][20][21][22] Recent studies show that modification to the axial ligands enables the generation of mitochondria-damaging Pt(IV) prodrugs. [23][24][25] Mitochondria-damaging Pt(IV) prodrugs have been proven effective against drug-resistant ovarian cancer cells and cancer stem cells, which face long-standing issues in traditional platinum chemotherapy. 6,26 Currently, there are only a few studies on mitochondria-damaging Pt(IV) prodrugs.…”