Introduction of Fluorine into Antitumor-Active Dinuclear Platinum(II) Complexes Leads to Modulation of In Vivo Antitumor Activity in Mice.

Tetrazolato-bridged dinuclear platinum(II) complexes ([{ cis -Pt(NH 3 ) 2 } 2 (μ-OH)(μ-5-R-tetrazolato- N2 , N3 )] 2+ ; tetrazolato-bridged complexes) show remarkable cytotoxic effects in vitro and antitumor activity in vivo . Here, we examined the structure-activity relationship of a series of fluorine-containing derivatives (R = CFH 2 , CF 2 H, or CF 3 ), focusing on their lipophilicity, cellular accumulation, cytotoxicity, interactions with a nucleobase and double-stranded deoxyribonucleic acid, and in vivo antitumor efficacy. Fluorination had a little effect on the properties of the derivatives in vitro ; however, marked differences in in vitro cytotoxicity and in vivo tumor growth inhibition activity were observed. In BALB/c mice bearing colon-26 tumors, the antitumor efficacies of the derivatives were markedly altered, even by changing the number of fluorine atoms by one. In addition, one derivative, [{ cis -Pt(NH 3 ) 2 } 2 (μ-OH)(μ-5-difluoromethyltetrazolato- N2 , N3 )](NO 3 ) 2 , showed a significantly higher antitumor efficacy compared with oxaliplatin, a current first-line drug and the only platinum-based drug approved for the treatment of colon cancer. Together, the present results indicate that introducing fluorine into tetrazolato-bridged complexes may be useful for modulating in vivo activities.