Reduction and Anticancer Activity of Platinum(IV) Complexes

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.