Kinetics and mechanism for reduction of anticancer-active tetrachloroam(m)ine platinum(IV) compounds by glutathione
Glutathione (GSH) reduction of the anticancer-active platinum(IV) compounds trans-[PtCl4(NH3)(thiazole)] (1), trans-[PtCl4(cha)(NH3)] (2), cis-[PtCl4(cha)(NH3)] (3) (cha=cyclohexylamine), and cis-[PtCl4(NH3)2] (4) has been investigated at 25 °C in a 1.0 M aqueous medium at pH 2.0–5.0 (1) and 4.5–6.8 (2–4) using stopped-flow spectrophotometry. The redox reactions follow the second-order rate law d[Pt(IV)]/dt=k[GSH] tot[Pt(IV)], where k is a pH-dependent rate constant and [GSH] tot the total concentration of glutathione. The reduction takes place via parallel reactions between the platinum(IV) complexes and the various protolytic species of glutathione. The pH dependence of the redox kinetics is ascribed to displacement of these protolytic equilibria. The thiolate species GS− is the major reductant under the reaction conditions used. The second-order rate constants for reduction of compounds 1–4 by GS− are (1.43±0.01)×107, (3.86±0.03)×106, (1.83±0.01)×106, and (1.18±0.01)×106 M−1 s−1, respectively. Rate constants for reduction of 1 by the protonated species GSH are more than five orders of magnitude smaller. The mechanism for the reductive elimination reactions of the Pt(IV) compounds is proposed to involve an attack by glutathione on one of the mutually trans coordinated chloride ligands, leading to two-electron transfer via a chloride-bridged activated complex. The kinetics results together with literature data indicate that platinum(IV) complexes with a trans Cl-Pt-Cl axis are reduced rapidly by glutathione as well as by ascorbate. In agreement with this observation, cytotoxicity profiles for such complexes are very similar to those for the corresponding platinum(II) product complexes. The rapid reduction within 1 s of the platinum(IV) compounds with a trans Cl-Pt-Cl axis to their platinum(II) analogs does not seem to support the strategy of using kinetic inertness as a parameter to increase anticancer activity, at least for this class of compounds.
Key wordsKinetics and mechanism Reduction Platinum(IV) compounds Anticancer active Glutathione
Unable to display preview. Download preview PDF.
- 4.Gelasco A, Lippard SJ (1999) In: Clarke MJ, Sadler PJ (eds) Topics in biological inorganic chemistry, vol 1. Springer, Berlin Heidelberg New York, pp 73–98Google Scholar
- 9.Barnard CFJ, Raynaud FI, Kelland LR (1999) In: Clarke MJ, Sadler PJ (eds) Topics in biological inorganic chemistry, vol 1. Springer, Berlin Heidelberg New York, pp 45–71Google Scholar
- 12.Natile G, Coluccia M (1999) In: Clarke MJ, Sadler PJ (eds) Topics in biological inorganic chemistry, vol 1. Springer, Berlin Heidelberg New York, pp 45–71Google Scholar
- 17.Roat R, Jerardi MJ, Kopai CB, Heath DC, Clark JA, DeMars JA, Weaver JM, Bezemer E, Reedijk J (1997) J Chem Soc Dalton Trans 3615–3621Google Scholar
- 24.Shi T, Berglund J, Elding LI (1997) J Chem Soc Dalton Trans 2073–2077Google Scholar
- 25.Lemma K, Shi T, Elding LI (2000) Inorg Chem 39: (in press)Google Scholar
- 26.Chen L, Lee PF, Ranford JD, Vittal JJ, Wong SY (1999) J Chem Soc Dalton Trans 1209–1212Google Scholar
- 28.Lemma K, Sargeson AM, Elding LI (2000) J Chem Soc Dalton Trans 1167–1172Google Scholar
- 36.Bridgart GJ, Wilson IR (1973) J Chem Soc Dalton Trans 1281–1284Google Scholar