The Impact of Modification of the Coumarin Moiety on Cancer Treatment

INTRODUCTION: Coumarin and its derivatives are naturally occurring benzopyrone compounds with multiple pharmacological activities. Recent studies indicate that they possess notable anticancer potential, particularly relevant for cancers with the highest rates of incidence and mortality worldwide. This article aims to provide a comprehensive overview of the pharmacological activities of coumarin derivatives against the top nine cancers worldwide, categorized by incidence and mortality, and to evaluate their potential as lead molecules in cancer drug discovery. METHODS: A comprehensive review of coumarin derivatives reported to be active against the top nine cancer types, including their mechanisms of action, structure-activity relationships, and pharmacological relevance, was summarized. RESULTS: Coumarin derivatives have demonstrated notable anticancer activity across the top nine cancer types. Their mechanisms of action include COX-2 inhibitory activity; induction of apoptosis through regulation of pro- and anti-apoptotic proteins such as BAK, APAF-1, p53, BAD, BAX, Bcl- 2, and Bcl-XL; and cell cycle arrest at both the G1 and G2/M phases. Additional effects involve inhibition of angiogenesis, suppression of metastasis, and downregulation of oncogenic long noncoding RNAs (SNHG6 and CASC11) along with their associated targets. Moreover, coumarin derivatives modulate multiple oncogenic signaling pathways, including PI3K/Akt, MAPK, NF-κB, PI3K/Akt/mTOR, and AMPK/mTOR, highlighting their potential as multitargeted anticancer agents. DISCUSSION: Coumarin derivatives have significant anticancer potential but lack clinical evidence. Currently, it is limited to becoming a potent anticancer candidate for drug delivery. Therefore, future research should be designed to conduct clinical studies to validate the potential of coumarin derivatives as anticancer agents. CONCLUSION: Coumarin derivatives demonstrate considerable potential as anticancer agents, particularly against malignancies with the highest global incidence and mortality. Their structural diversity, multitargeted mechanisms of action, and ability to circumvent drug resistance underscore their value as scaffolds for future anticancer drug development. Rigorous clinical investigations are essential to establish their therapeutic utility.