Inhibitors of
poly(ADP-ribose) polymerase-1 (PARP-1) have shown to be promising in clinical trials against
cancer and other diseases, and lots of efforts have been put into the development of organic compounds as more potent PARP-1 inhibitors. Here we describe a strategy to conveniently obtain
metal-based PARP-1 inhibitors with enhanced
biological activities by conjugating
platinum moiety with an original inhibitor, e.g.,
benzonaphthyridone. Based on the structure-activity relationship analysis of PARP-1 inhibitors, three platinated PARP-1 inhibitors were designed, and the complexes were synthesized and characterized. Complex 3 presented significantly enhanced cytotoxicity against a panel of human
cancer cells and a 10-fold increased inhibitory effect against recombinant PARP-1 compared with the original PARP-1 inhibitor. Complex 3 was as cytotoxic as
cisplatin and its spectrum of anticancer activity was identical to that of
cisplatin. The complex was able to enter into
cancer cells efficiently, bind to
DNA well, and block cell cycle at G₂/M phase, indicating that complex 3 is an effective
anticancer agent with a distinct mechanism of action. Our study implies that the conjugation of
platinum with PARP-1 inhibitors could be a valid strategy to obtain more potent
anticancer agents with improved
biological activities.