Synthesis and Structure−Activity Relationship of Novel Antitumoral Platinum Xanthate Complexes

To establish structure-activity relationships, derivatives of a recently described sulfur-containing antitumoral platinum complex, bis(O-ethyldithiocarbonato)platinum(II), named thioplatin, were analyzed. Twenty different bis(O-alkyldithiocarbonato)platinum(II) complexes were synthesized and tested for cytotoxic activity in a panel of six human tumor lines. Derivatives with up to 7-fold increased activity compared to thioplatin and up to 25-fold more activity than cisplatin were identified. Bis(O-alkyldithiocarbonato)platinum(II) complexes with short n-alkyl chains such as methyl, ethyl, propyl, and butyl were found to be superior to compounds with long n-alkyl chains such as hexyl, octyl, and decyl. Complexes derived from secondary xanthates displayed significantly higher activity than those derived from primary xanthates with the same number of C atoms. Like thioplatin, all tested platinum complexes were more active at pH 6.8 than at pH 7.4. A pH of 6.8 and lower has been frequently found in solid tumors because of the tendency of tumor cells to undergo anaerobic fermentation. Drugs with such pH-dependent antitumoral activity have an improved therapeutic index compared to drugs that are active irrespective of pH.