Cytotoxicity of Platinum(IV) and Platinum(II) Complexes Containing 1R, 2R-Cyclohexanediamine as a Ligand

抄録

Several Pt(IV) and Pt(II) complexes containing 1R, 2R-cyclohexanediamine (1R, 2R-dach) as a carrier ligand were synthesized. The cytotoxicities and the uptake of the platinum complexes by leukemia L1210 cells were compared in order to study the correlation between their structures and cytotoxicities.[Pt(II)Cl₂(1R, 2R-dach)], [(Pt(II)(oxalato)(1R, 2R, -dach)], and [Pt(II)(malonato)(1R, 2R-dach)], which have excellent anticancer properties, exhibited very high cytotoxicities and were easily taken up by leukemia L1210 cells. [Pt(IV)Cl₄(1R, 2R-dach)], trans(Cl)-[Pt(IV)Cl₂(oxalato)(1R, 2R-dach)], and trans(Cl)-[Pt(IV)Cl₂(malonato)(1R, 2R-dach)] also had high cytotoxicities. After a short incubation time, the uptake of [Pt(II)Cl₂(1R, 2R-dach)], [Pt(II)(oxalato)(1R, 2R-dach)], and [Pt(II)(malonato)(1R, 2R-dach)] by leukemia L1210 cells were respectively very similar to those of [Pt(IV)Cl₄(1R, 2R-dach)], trans(Cl)-[Pt(IV)Cl₂(oxalato)(1R, 2R-dach)], and trans(Cl)-[Pt(IV)Cl₂(malonato)(1R, 2R-dach)].In addition, trans(OH)-[Pt(IV)(OH)₂Y₂(1R, 2R-dach)] (Y₂ : oxalato or malonato) did not exhibit cytotoxicity towards leukemia L1210 cells, whereas trans(Cl)-[Pt(IV)Cl₂Y₂(1R, 2R-dach)] (Y₂ : oxalato or malonato) were highly cytotoxic. The accumulation of trans(OH)-[Pt(IV)(OH)₂Y₂(1R, 2R-dach)] in leukemia L1210 cells was much lower than that of trans(Cl)-[Pt(IV)Cl₂Y₂(1R, 2R-dach)]. Platinum(IV) complexes, in which leaving groups are replaced by hydroxide groups, have decreased cytotoxic activity, because the hydroxide groups of the platinum(IV) complex reduce the uptake of platinum by the cells. trans(OH), cis(Cl)-[Pt(IV)(OH)₂Cl₂(1R, 2R-dach)], which has hydroxide and chloride groups, was easily incorporated into the cells and exhibited the high cytotoxic activity. This behavior indicates that the chloride group apparently overcomes the ameliorating effect of the hydroxide group.