Coumarin derivatives as promising anticancer drugs: a comprehensive review from synthesis to anticancer applications

Natural products have long been an important source of anticancer drugs. Coumarins are a class of natural products that contain a core structure of benzo-α-pyranone and exhibit a wide range of pharmacological activities. In recent years, coumarin compounds have garnered increasing research attention as anticancer lead compounds. However, issues such as the low solubility, low bioavailability, and poor selectivity of natural coumarins have limited their clinical applications. Research into the synthetic chemistry of coumarins, which could address these issues, has received far less systematic attention than their biological mechanisms. Therefore, this review will explore both aspects in conjunction. This article summarizes the classical synthetic routes for the coumarin core and modern synthetic strategies for various coumarin derivatives, such as transition-metal-catalyzed cross-coupling, multicomponent and one-pot reactions, click chemistry, green and biocatalytic protocols, and metal complexation. Subsequently, the article discusses the mechanisms of action of the synthesized coumarin derivatives. Structure-activity relationship (SAR) data indicate that the derivatives incorporating nitrogen-containing heterocycles generally exhibit high potency and selectivity, with their IC₅₀ values typically ranging from the low micromolar to nanomolar ranges. Finally, the article discusses future design directions for coumarin derivatives, such as nanocarrier delivery, prodrug design, multi-target approaches, and computer-aided drug design. It is hoped that this article will enable readers interested in coumarin anticancer lead compounds to gain a comprehensive understanding of both their chemical synthesis and biological activity in a single resource, thereby providing guidance for the synthesis of coumarin anticancer derivatives.