Physicochemical factors for cytotoxic activity in platinum dinuclear complexes with pyrimidine and imide ligands

The relationship between cytotoxic activity of platinum dinuclear complexes toward cancer cells and their intrinsic properties (electrophilicity and h ydrophobicity) have been examined. It is shown that the reactivity with chl oride anion is a good index of the electrophilicity of the platinum-complex es. By assuming a cell kill pharmacodynamic model, the relation between IC5 0 value and the electrophilicity is obtained. It is concluded that inside c ells the reactivity of the platinum complexes having imide ligands is highe r than that of CDDP. The other important factor which affects the cytotoxic activity is hydrophobicity. The log k' values (k': capacity factor) are fo und useful to estimate the hydrophobicity of platinum complexes. The accumu lation of platinum into cells is dominated by the hydrophobicity and the ch arge of platinum complexes. Highly hydrophobic complexes are thought to be adsorbed in,cell membranes, resulting in low cytotoxic activity since they cannot reach DNA. A schematic model of the interaction between platinum com plexes and serum proteins reveals that more hydrophobic complexes tend to b ind to serum proteins more stably. At least three possible paths of the cel lular platinum accumulation are suggested: direct accumulation of the plati num complexes, incorporation in the form of CDDP produced from the complexe s, and incorporation through protein-platinum complexes, although the contr ibution of the third one may be small. (C) 1998 Elsevier Science B.V. All r ights reserved.