Reduction and Anticancer Activity of Platinum(IV) Complexes

Abstract

A series of PtIV anticancer complexes with chloro leaving groups have been investigated for the effects of axial and carrier ligands on the reduction and cytotoxicity. The reduction rates of the PtIV complexes such as Pt(d,l)(1,2-(NH2)2C6H10)Cl4 (tetraplatin, Pt(dach)Cl4; dach = diaminocyclohexane), cis,trans,cis-[Pt((CH3)2CHNH2)2(OH)2Cl2] (iproplatin, Pt(ipa)(OH)2Cl2; ipa = isopropylamine), cis,trans,cis-[Pt(NH3)(C6H11NH2)(OCOCH3)2Cl2] (JM-216, Pt(a,cha)(OCOCH3)2Cl2; a = ammine, cha = cyclohexylamine), cis,trans,cis-[Pt(NH3)(C6H11NH2)(OCOC3H7)2Cl2] (JM-221, Pt(a,cha)(OCOC3H7)2Cl2), cis,trans,cis-[Pt(en)(OH)2Cl2], Pt(en)Cl4 (en = ethylenediamine), cis,trans,cis-[Pt(en)(OCOCH3)2Cl2], and cis,trans,cis-[Pt(en)(OCOCF3)2Cl2] by ascorbate and cathodic reduction potentials strongly depend on the electron-withdrawing power and the steric hindrance of the axial and carrier ligands. Beginning with PtIV complexes bearing en carrier ligands, reduction rates and reduction potentials increase in the following order of axial ligand substitutions: OH < OCOCH3 < Cl < OCOCF3, coinciding with increasing electron-withdrawing power of the axial ligand. PtIV complexes with en carrier ligands tend to show slower reduction rates than the corresponding complexes with ipa or cha carrier ligands. Ascorbic acid does not reduce Pt(en)(OH)2Cl2, but reduces Pt(ipa)(OH)2Cl2. The reduction rate of Pt(a,cha)(OCOCH3)2Cl2 is about 12 times higher than that of Pt(en)(OCOCH3)2Cl2. Overall, there is no strong correlation between reduction rate and cytotoxicity toward cisplatin-sensitive L1210/0 cells among the eight complexes studied. However, when the four compounds with en carrier ligands were compared with one another, the one with the fastest reduction rate exhibited the highest cytotoxicity. The cytotoxicity increases with axial ligand substitution in the order OH < OCOCH3 < Cl < OCOCF3, following the same trend as reduction rate. Comparing complexes having different carrier ligands but the same axial ligands reveals that the compound with the faster reduction rate exhibits the higher cytotoxicity. Reduction rate and cytotoxicity increase in the order Pt(en)(OH)2Cl2 < Pt(ipa)(OH)2Cl2, Pt(en)(OCOCH3)2Cl2 < Pt(a,cha)(OCOCH3)2Cl2, Pt(en)Cl4 < Pt(dach)Cl4.

Engineering of self-assembled nanoparticle platform for precisely controlled combination drug therapy

“…These values indicate that the presence of the polymeric backbone does not significantly influence the electronic or steric environment of the tethered platinum center and that this construct will effectively release active cisplatin required for anticancer activity. The low values of the cathodic peak for PLA-Pt(IV) also augurs well for the clinical requirement that this construct not be prematurely released in blood (42,43).…”

Kinetics and Mechanism of Oxidation of L-Ascorbic Acid by Pt(IV)(aq) in Aqueous Hydrochloric Acid Medium

“…The knowledge of the reactivity of Pt(IV) compounds towards the reduction by potential bioreductant like ascorbic acid may be important for understanding the mechanism of where antitumor activity as well as for designing new compounds with the least side effect. Chois et al [17] reported that there is a correlation between the rate of the reduction and anticancer activity in a series of homologous Pt(IV) complex without going into the details of reaction mechanism. The present study was undertaken with the aim of extending the knowledge of the kinetics and thermodynamic parameters that characterized the reduction of Pt(IV) complex by ascorbic acid and clarifying the mechanism details using the model complex PtCl 6 2− .…”

Mitaplatin, a potent fusion of cisplatin and the orphan drug dichloroacetate

“…The cathodic reduction potential depends on the electronwithdrawing power and the bulkiness of the axial and auxiliary ligands. The low reduction potential of mitaplatin is influenced by the presence of chlorine atoms from the DCA molecules near the platinum center (29).…”