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

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Kinetics and mechanism for reduction of anticancer active tetrachloroam(m)ine platinum(IV) compounds by glutathione. / Lemma, Kelemu; Berglund, Johan; Farrell, Nicholas; Elding, Lars Ivar.

I: Journal of Biological Inorganic Chemistry, Vol. 5, Nr. 3, 2000, s. 300 - 306.

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T1 - Kinetics and mechanism for reduction of anticancer active tetrachloroam(m)ine platinum(IV) compounds by glutathione

AU - Lemma, Kelemu

AU - Berglund, Johan

AU - Farrell, Nicholas

AU - Elding, Lars Ivar

PY - 2000

Y1 - 2000

N2 - 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.

AB - 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.

KW - Anti cancer active compounds

KW - Platinum(IV)

KW - Glutathione

KW - Reduction

KW - Reaction mechanism

U2 - 10.1007/PL00010658

DO - 10.1007/PL00010658

M3 - Article

VL - 5

SP - 300

EP - 306

JO - Journal of Biological Inorganic Chemistry

JF - Journal of Biological Inorganic Chemistry

SN - 1432-1327

IS - 3

ER -