Antitumor Pharmacological Mechanisms and Preclinical Advances of Coumarin Derivatives

Coumarin is a class of benzopyrone heterocyclic compounds widely distributed in natural plants. Its relatively simple scaffold, generally low toxicity, ease of structural modification and favorable biocompatibility make it an attractive core for natural-product chemistry and anticancer drug development. However, the intrinsic antitumor activity of many natural coumarins is limited. Derivatives generated through scaffold modification, side-chain substitution and heterocyclic hybridization can substantially strengthen target-oriented anticancer activity while improving aqueous solubility and metabolic stability. Recent pharmacological evidence indicates that coumarin derivatives can exert broad antitumor effects through multiple targets and pathways, including tumor-cell-cycle arrest, induction of apoptosis and autophagy, inhibition of tumor angiogenesis, blockade of proliferative signaling, reversal of multidrug resistance and regulation of the tumor microenvironment. Activity has been reported against lung, liver, breast, ovarian and gastrointestinal malignancies. This paper examines the structural characteristics and structure–activity relationships of coumarin compounds, evaluates their major antitumor pharmacological mechanisms, and synthesizes representative preclinical evidence from cellular and animal studies. It also considers efficacy-enhancing strategies involving structural optimization and combination therapy. Particular attention is given to persistent limitations, including insufficient potency in some derivatives, restricted target specificity, suboptimal drug-like properties and incomplete safety assessment. Future development should integrate rational structural optimization with target-directed delivery, pharmacokinetic validation and stronger translational models to improve the probability that coumarin-based candidates progress from promising preclinical compounds to clinically relevant anticancer agents.