Reduction of Cisplatin and Carboplatin Pt(IV) Prodrugs by Homocysteine: Kinetic and Mechanistic Investigations

Abstract

Pt(IV) anticancer active complexes are commonly regarded as prodrugs, and the reduction of the prodrugs to their Pt(II) analogs is the activation process. The reduction of a cisplatin prodrug cis-[Pt(NH 3 ) 2 Cl 4 ] and a carboplatin prodrug cis,trans-[Pt(cbdca)(NH 3 ) 2 Cl 2 ] by DL-homocysteine (Hcy) has been investigated kinetically in a wide pH range in this work. The reduction process follows overall second-order kinetics: −d[Pt(IV)]/dt = k [Hcy] tot [Pt(IV)], where [Hcy] tot stands for the total concentration of Hcy and k pertains to the observed second-order rate constants. The k versus pH profiles have been established for both prodrugs. Spectrohotometric titrations reveal a stoichiometry of [Pt(IV)]: [Hcy] tot = 1:2; homocystine is identified as the major oxidation product of Hcy by high-resolution mass spectrometry. A reaction mechanism has been proposed, which involves all the four protolysis species of Hcy attacking the Pt(IV) prodrugs in parallel. Moreover, these parallel attacks are the rate-determining steps, resulting in a Cl + transfer from the Pt(IV) prodrugs to the attacking sulfur atom. Rate constants An Accumet Basic AB15 Plus pH meter, equipped with an Accumet AccutupH R combination pH electrode (Fisher Scientific, Pittsburgh, PA), was used to measure the pH values of buffer solutions. Each time, the electrode was calibrated using the standard buffers

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

“…The initial absorption decline of the kinetic trace, being enlarged and shown in the insert of Figure 2, is designated to the reduction of cis-[Pt(NH 3 ) 2 Cl 4 ] to cisplatin; while the second phase, that is, the subsequent absorption increase, is much slower, which can be assigned to the substitution of the coordination chloride(s) in cisplatin by the excess CA in the reaction mixture. 19 In the oxidation of Pen by the Pt(IV) compound, similar biphasic kinetic traces were also observed, cf Figures S2 and S3 in the SM. Since the kinetic trace is basically separable on the time scale, the initial kinetic phase was well-simulated by a single exponential equation cf Equation 1, where A t , A 0 , and A ∞ pertain to the…”

“…In the last few years, we have been focusing on the mechanistic elucidations for some redox reactions concerning a few important drugs. [16][17][18][19][20] We thus performed a detailed kinetic analysis of oxidation reactions of CA and Pen by cis-diamminetetrachloroplatinum(IV) (cis-[Pt(NH 3 ) 2 Cl 4 ]) and divulge the results in the present work. cis-[Pt(NH 3 ) 2 Cl 4 ] is an anticancer active Pt(IV) compound and is in fact a cisplatin prodrug since it can be easily reduced to cisplatin (cis-[Pt(NH 3 ) 2 Cl 2 ]) [21][22][23] ; its reductive activation processes by some biologically important molecules and by an electrochemical approach have been studied.…”

“…cis-[Pt(NH 3 ) 2 Cl 4 ] is an anticancer active Pt(IV) compound and is in fact a cisplatin prodrug since it can be easily reduced to cisplatin (cis-[Pt(NH 3 ) 2 Cl 2 ]) [21][22][23] ; its reductive activation processes by some biologically important molecules and by an electrochemical approach have been studied. 17,19,[23][24][25] On the other hand, it was reported that mechanistically, a combination of Pen and platinum anticancer drugs synergistically inhibited tumor growth. 26 The above-mentioned impetuses promoted us to undertake the present study, enabling us to have a mechanistic scrutiny on the oxidation reactions and to unravel the mechanistic similarities and differences.…”

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

“…The dipeptide Cys–Gly (purity >95%) was purchased from Dgpeptide Co., Ltd (Hongzhou, China). The prodrug cis,trans -[Pt(cbdca)(NH 3 ) 2 Cl 2 ] (cbdca = cyclobutane-1,1-dicarboxylate) was from a batch synthesized and characterized recently [36]. Acetic acid, sodium acetate, sodium chloride, hydrochloric acid, phosphoric acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium bicarbonate, sodium carbonate, trisodium phosphate, and sodium perchlorate were all obtained in their purest forms available either from Alfa Aesar (Shanghai, China) or from Fisher Scientific (Shanghai, China) and were used without further purification.…”

“…Doubly distilled water was used to prepare all solutions. Buffers with pH between 2.47 and 11.24 and an ionic strength ( μ ) of 1.0 M were prepared as described previously [23,36].…”