REDUCTION AND ANTICANCER ACTIVITY OF PLATINUM(IV) COMPLEXES

A series of pt(IV) anticancer complexes with chloro leaving groups hav e been investigated for the effects of axial and carrier ligands on th e reduction and cytotoxicity. The reduction rates of the Pt-IV complex es such as Pt(d,l)-(1,2-(NH2)(2)C6H10)Cl-4 (tetraplatin, Pt(dach)Cl-4; dach=diaminocyclohexane), cis,trans,cis-[Pt((CH3)(2)CHNH2)(2)(OH)(2)- Cl-2] (iproplatin, Pt(ipa)(OH)(2)Cl-2; ipa=isopropylamine), cis,trans, cis-[Pt(NH3)(CaH11NH2)(OCOCH3)(2)Cl-2] (JM-216, Pr(a,cha)(OCOCH3)(2)Cl -2.; a=ammine, cha=cyclohexylamine), cis,trans,cis-[Pt(NH3)(C6H11NH2)( OCOC3H7)(2)Cl-2] (JM-221, Pt(a,cha)(OCOC3H7)(2)Cl-2), cis,trans,cis-[P t(en)(OH)(2)Cl-2], Pt(en)Cl-4 (en=ethylenediamine), cis,trans,cis-[Pt( en)(OCOCF3)(2)Cl-2], and cis,trans,cis-[Pt(en)(OCOCF3)(2)Cl-2] by asco rbate and cathodic reduction potentials strongly depend on the electro n-withdrawing power and the steric hindrance of the axial and carrier ligands. Beginning with Pt-IV complexes bearing en carrier ligands, re duction races 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. Pt-IV complexes with en carrier ligands tend to show slower reduction rates than the corresponding complexes with ipa or cha carrier ligands. Asco rbic acid does not reduce Pt(en)(OH)(2)Cl-2, but reduces Pt(ipa)(OH)(2 )Cl-2. The reduction rate of Pt(a,cha)(OCOCH3)(2)Cl-2 is about 12 time s higher than that of Pt(en)(OCOCH3)(2)Cl-2. Overall, there is no stro ng correlation between reduction rate and cytotoxicity toward cisplati n-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 highes t cytotoxicity. The cytotoxicity increases with axial ligand substitut ion in the order OH < OCOCH3 < Cl < OCOCF3, following the same tend as reduction rate. Comparing complexes having different carrier ligands but the same axial ligands reveals that the compound with the faster r eduction rate exhibits the higher cytotoxicity. Reduction rate. and cy totoxicity increase in the order Pt(en)(OH)(2)Cl-2 < Pt(ipa)(OH)(2)Cl- 2,Pt(en)(OCOCH3)(2)Cl-2 < Pt(a,cha)(OCOCH3)(3)Cl-2, Pt(en)Cl-4 < Pt(da ch)Cl-4.