Reduction of Anticancer Prodrugs Cis-Diamminetetra- Chloroplatinum(Iv) and Ormaplatin by a Large Series of Thiols: Phenomenal Structure-Reactivity Correlations

Abstract

ABSTRACT Cis-diamminetetrachloroplatinum(IV) (cis-[Pt(NH3)2Cl4], the first cisplatin Pt(IV) prodrug) and ormaplatin (tetraplatin, [Pt(dach)Cl4]) represent one of three primary structural prototypes of Pt(IV) anticancer prodrugs. Reduction of cis-[Pt(NH3)2Cl4] by a large series of thiols has been characterized kinetically in a broad pH range. For all the thiols, the reduction reactions strictly followed overall second-order kinetics, and the observed second-order rate constants versus pH profiles were established at 25.0 oC and 1.0 M ionic strength. Moreover, for each thiol, rate constants of the rate-determining steps for all the protolytic species were derived from the proposed reaction mechanism. The species reactivity versus pH distribution diagrams were constructed, indicating that for each thiol, the thiolate species dominated the total reactivity of that thiol in the biologically important pH region. An excellent Brønsted correlation between logkRS- and the thiol dissociation constants pKRSH was revealed: logkRS- = (0.54 ± 0.02)·pKRSH + (0.73 ± 0.12); the correlation involves 15 thiols. For the reduction of ormaplatin, the previously reported correlation was attested by an additional thiol (thioacetic acid with pKa = 3.20), conferring a highly reliable correlation: logkRS- = (0.50 ± 0.02)·pKRSH + (0.62 ± 0.10). When the large structural change (size and steric hindrance) and the broad variation of pKRSH of the thiols involved in the correlations are considered, these correlations are phenomenal. The slopes of the correlations being in middle-ranged values endow that the basicity of a thiol group is a leading factor in determining the reactivity of its conjugate thiolate. It can be concluded that when cis-[Pt(NH3)2Cl4] and [Pt(dach)Cl4]) are exposed to a pool of thiols with varying pKRSH in the physiological matrix, the reactivity of a particular thiolate species towards the reduction of this type of Pt(IV) anticancer prodrugs is well predictable by use of the correlations as long as its pKRSH is known.

Keywords: cis-[Pt(NH3)2Cl4], Ormaplatin, Anticancer prodrugs, Structure-reactivity correlations