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Journal of Biological Inorganic Chemistry

, Volume 5, Issue 3, pp 300–306 | Cite as

Kinetics and mechanism for reduction of anticancer-active tetrachloroam(m)ine platinum(IV) compounds by glutathione

  • Kelemu Lemma
  • Johan Berglund
  • Nicholas Farrell
  • Lars I. Elding
Original Article

Abstract

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 words

Kinetics and mechanism Reduction Platinum(IV) compounds Anticancer active Glutathione 

Abbreviations

cha

cyclohexylamine

dach

±trans-1,2-diaminocyclohexane

GSH

glutathione

RSH

thiol

Tz

thiazole

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Copyright information

© SBIC 2000

Authors and Affiliations

  • Kelemu Lemma
    • 1
  • Johan Berglund
    • 1
  • Nicholas Farrell
    • 2
  • Lars I. Elding
    • 1
  1. 1.Inorganic Chemistry 1, Chemical CenterLund UniversityLundSweden
  2. 2.Department of ChemistryVirginia Commonwealth UniversityRichmondUSA

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