Coumarin-Based Compounds as Multifunctional Anticancer Agents: Chemical Innovation, Mechanistic Convergence, and Translational Challenges in Modern Oncology

Over the past decade, coumarin derivatives have emerged as versatile anticancer scaffolds through extensive structural modification, hybridisation strategies, and improved understanding of their biological activities. Despite extensive synthetic diversification and widespread reports of anticancer activity, the field continues to face major challenges. Mechanistic evidence is often incomplete, translational considerations are limited, and clear guidelines for structural optimisation remain underdeveloped. This critical review evaluates the chemical, biological, and pharmacological foundations of contemporary coumarin research and examines the robustness and translational relevance of recent advances. Relevant studies were identified through structured searches of PubMed, Scopus, and Web of Science using predefined mechanistic and pharmacokinetic terms, with emphasis on publications from 2010 to 2025 and inclusion of earlier seminal work where appropriate. Recent advances in scaffold engineering, hybrid pharmacophores, metal-assisted photodynamic systems, and nanoparticle-enabled delivery are critically evaluated, with attention to structural features that reliably enhance biological performance. Major mechanistic themes discussed include oxidative stress induction, kinase pathway inhibition, suppression of epithelial–mesenchymal transition, and modulation of the tumour microenvironment. Key limitations are highlighted, such as metabolic instability, low target specificity, and the limited predictive value of conventional in vitro models. Future research should prioritise pharmacokinetic/pharmacodynamic-guided scaffold design, advanced tumour-mimetic systems, and standardised multi-omic approaches for mechanistic validation. Overall, coumarin-based scaffolds remain promising candidates for multifunctional cancer therapy; however, successful clinical translation will require closer integration of medicinal chemistry, pharmacology, toxicology, and translational research.