Exploring the interactions of a “rule-breaker” iodo-platinum(II) complex with cytochrome c by mass spectrometry

Within research of new anticancer drugs there is now great interest in the design of innovative platinum(II) compounds that might exhibit chemical and biological profiles substantially different from cisplatin (CDDP). The iodo analogue of CDDP complex cis-diiododiisopropylamineplatinum(II) 1 turned out to manifest a higher antiproliferative activity than CDDP against a panel of representative human tumor cell lines. In order to shed light on the possible mechanisms of action of this promising diiodo-platinum(II) complex we investigated its interactions with cytochrome c (cyt c) using electrospray ionization mass spectrometry (ESI-MS). ESI-MS allowed a rapid characterization of adducts formed between 1 and cyt c, providing specific information on the nature of the protein-bound metallofragments and the extent of protein metallation. Interestingly, complex 1, compared to CDDP, exhibited a greater and unconventional reactivity with cyt c, characterized by the loss of amine ligands. This finding is in sharp contrast to the established canonical rules governing structure-activity relationship for platinum antitumor complexes. In light of these results, expanding the investigations on “rule-breaker” iodo-platinum(II) complexes as cytotoxic agents with an innovative mechanism of action appears to be of utmost importance.