l-Selenomethionine reduces platinum(iv) anticancer model compounds at strikingly faster rates thanl-methionine

Abstract

L-Selenomethionine (SeMet), the predominant form of selenium acquired from the diet by humans, has been used as a supplement, and exhibit some important functions like cancer prevention and antioxidative defense. Its interactions with Pt(II) anticancer drugs have been characterized, but its redox reactions with platinum(IV) anticancer prodrugs have not been exploited. In this work, the oxidation of SeMet by Pt(IV) anticancer model compounds trans-[PtX2(CN)4](2-) (X = Cl, Br) was characterized. A stopped-flow spectrometer was used to record the rapid scan spectra and to follow the reaction kinetics over a wide pH range. An overall second-order rate law was derived: -d[Pt(IV)]/dt = k'[Pt(IV)][SeMet], where k' pertains to the observed second-order rate constants. The k'-pH profiles showed that k' increased only about 6 times even though the solution pH was varied from 0.25 to 10.5. The redox stoichiometry was determined as Δ[Pt(IV)]/Δ[SeMet] = 1 : (1.07 ± 0.07), suggesting that SeMet was oxidized to selenomethionine selenoxide. The selenoxide together with its hydrated form was identified explicitly by high resolution mass spectral analysis. A reaction mechanism was proposed which encompassed three parallel rate-determining steps relying on the protolytic species of SeMet. Rate constants of the rate-determining steps were obtained from the simulations of the k'-pH profiles. Activation parameters were determined for the reactions of the zwitterionic form of SeMet with the Pt(IV) complexes. A bridged electron transfer process is delineated in the rate-determining steps and several lines of evidence support the bridged electron transfer mode. Strikingly, reduction of [PtX2(CN)4](2-) by SeMet is 3.7 × 10(3)-5.7 × 10(4) times faster than that by L-methionine. Some potential biological consequences resulting from the strikingly fast reduction are discussed.

Reduction of ormaplatin and cis-diamminetetrachloroplatinum(iv) by ascorbic acid and dominant thiols in human plasma: kinetic and mechanistic analyses

“…atom of the reductants. [30][31][32][33][38][39][40]52,53 In the present reaction systems, the proposed bridge formation in the transition states is illustrated in Fig. S4 in the ESI.…”

A kinetic analysis of oxidation of the antioxidant N-acetyl-l-cysteine (NAC) by Pt(IV) complexes

“…This type of electron transfer mode implies that in similar molecules, a better bridging atom will give rise to a faster rate [46][47][48][49][50][51][52]. We recently observed that the reduction of trans-[PtCl 2 (CN) 4 ] 2-by L-selenomethionine is 37,000 times faster than by L-methionine [24]. This can be regarded as a line of evidence which strongly supports to a bridge formation in the rate-determining steps.…”

“…After clinical trials, ormaplatin was abandoned because of its severe nephrotoxicity [23]. cis-[Pt(NH 3 ) 2 Cl 4 ] is the prodrug of cisplatin, while trans-[PtCl 2 (CN) 4 ] 2-has been utilized as a model compound for the Pt(IV) prodrugs [24]. We herein report our results.…”

Characterization of the mechanism of reduction of trans-diamminetetrachloroplatinum(IV) by l-cysteine and dl-homocysteine

“…Some dominant small molecule reductants in plasma [10] such as L-cysteine, glutathione, and ascorbic acid are believed to be responsible for the reduction of Pt(IV) anticancer prodrugs [11][12][13][14][15]. However, large molecules like proteins [16][17][18][19] and selenium-containing antioxidants [20] might be strong competitors to these small reductants, at least under some circumstances.…”

“…Trans-[Pt(NH 3 ) 2 Cl 4 ] was chosen as a representative for the class of Pt(IV) anticancer active compounds bearing a transdiammine configuration in the equatorial plane [7]. To the best of our knowledge, the kinetic and mechanistic aspects of the reduction of Pt(IV) anticancer prodrugs with a transdiammine configuration in their equatorial planes by thiolcontaining compounds have not been studied before [11][12][13][14][15][16][17][18][19][20].…”