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

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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.

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Abbreviations

cha:

cyclohexylamine

dach:

±trans-1,2-diaminocyclohexane

GSH:

glutathione

RSH:

thiol

Tz:

thiazole

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Author information

Author notes

  1. Kelemu Lemma

    Present address: Department of Chemistry, Addis Ababa University, P.O. Box 1176, Addis Ababa, Ethiopia

  2. Johan Berglund

    Present address: Research and Development, Pharmacia and Upjohn, P.O.B. 941, SE-25109, Helsingborg, Sweden

Authors and Affiliations

  1. Inorganic Chemistry 1, Chemical Center, Lund University, P.O. Box 124, SE-22100, Lund, Sweden

    Kelemu Lemma, Johan Berglund & Lars I. Elding

  2. Department of Chemistry, Virginia Commonwealth University, Richmond, VA, 23284-2006, USA

    Nicholas Farrell

Authors
  1. Kelemu Lemma
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  2. Johan Berglund
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  3. Nicholas Farrell
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  4. Lars I. Elding
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Corresponding author

Correspondence to Lars I. Elding.

Additional information

Supplementary material. Tables S1-S7 are available in electronic form on Springer-Verlag’s server at http://link.springer.de/journals/jbic/

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Lemma, K., Berglund, J., Farrell, N. et al. Kinetics and mechanism for reduction of anticancer-active tetrachloroam(m)ine platinum(IV) compounds by glutathione. JBIC 5, 300–306 (2000). https://doi.org/10.1007/PL00010658

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