CYTOTOXICITY OF PLATINUM(II) DINUCLEAR COMPLEXES WITH 1-ALKYLTHYMINE LIGANDS AGAINST MOUSE SARCOMA-180 CELLS

We synthesized five platinum(II) dinuclear complexes containing 1-alky lated thymines. Two of the 1-alkylated thymine, 1-MeThy and 1-EtThy, c omplexes afforded good crystals. The X-ray structures of these complex es were determined. The 1-MeThy complex has a head-to-head (H-H) arran gement, while the 1-EtThy complex has a head-to-tail (H-T) arrangement . The 1-MeThy complex (H-H) shows high electrophilicity against chlori de anion (Cl-) and high cytotoxicity against mouse sarcoma 180 (S-180) cells in vitro. The 1-EtThy complex (H-T) is inactive. The other 1-Me Thy complex does not produce CDDP in the reaction with chloride ion an d is inactive against the S-180 cell line. This complex is assumed to have an H-T arrangement. Similarly, two different 1-Pr(n)Thy complexes , one with high electrophilicity and cytotoxicity and the other withou t, must have an H-H and H-T arrangement, respectively. For comparison, we investigated six complexes, 1-methyluracil (1-MeUra) (H-H) dimer, alpha-pyridone (H-T) dimer, alpha-pyridone blue tetramer (PPB), l-meth ylcytosine (1-MeCyt) (H-T) dimer, acetate dimer, and 1-MeUra monomer c omplexes. The alpha-pyridone (H-T), PPB, 1-MeCyt (H-T) dimer, and 1-Me Ura monomer complexes are inert to chloride ion and inactive against m ouse sarcoma S-180. The 1-MeUra (H-H) dimer and acetate dimer complexe s show high electrophilicity and high cytotoxicity. Cellular accumulat ion of the platinum complexes phenomenally shows that all are incorpor ated to cancer cells to a lesser extent than CDDP. The relationships b etween the accumulation, the electrophilicity, and the interaction of these complexes with proteins are discussed.