Development of a series of 4-hydroxycoumarin platinum(IV) hybrids as antitumor agents: Synthesis, biological evaluation and action mechanism investigation.

Abstract A series of new 4-hydroxycoumarin platinum(IV) complexes were designed, synthesized and evaluated as antitumor agents. All the title compounds display moderate to effective antitumor activities toward the tested cell lines and two prominent compounds were screened out with activities comparable to cisplatin and oxaliplatin. The mechanism investigation demonstrates that the platinum(IV) compounds could be reduced to bivalence and exert significant genotoxicity to tumor cells. Meanwhile the coumarin moiety endows the title compounds with cyclooxygenase inhibitory competence which might favour the reduction of tumor-related inflammation and further influence tumor proliferation. The coumarin platinum(IV) complex could effectively induce apoptosis of SKOV-3 cells through up-regulating the expression of caspase3 and caspase9. Furthermore, the conversion of platinum(II) drugs to platinum(IV) form via the conjunction with 4-hydroxycoumarin enhances the drug uptake in whole cells and DNA simultaneously. Moreover, the 4-hydroxycoumarin platinum(IV) complex could combine with human serum albumin via van der Waals force and hydrogen bond, which would influence their transport and bioactivities in vivo. Graphical abstract New 4-hydroxycoumarin platinum(IV) hybrids were designed, synthesized and evaluated as antitumor agents. The platinum(IV) core could be reduced to bivalence and display significant genotoxicity. Meanwhile the coumarin group endows the title compounds with cyclooxygenase inhibitory competence which would favour of reducing tumor-related inflammation and further influencing tumor proliferation. Unlabelled Image Highlights • Development of 4-hydroxycoumarin platinum(IV) hybrids as antitumor agents • Antitumor activities were evaluated and the action mechanism was investigated. • Active apoptotic pathway by up-regulating the expression of caspase3 and caspase9 • Exert higher accumulation in both whole cells and DNA than platinum(II) drugs • Combine with human serum albumin effectively by noncovalent forces [ABSTRACT FROM AUTHOR]