Chemical Diversity and Biological Significance of Sesquiterpene Lactones: From Biosynthesis to Anticancer Mechanisms

ABSTRACT

Cancer is one of the world's leading causes of death, demanding novel therapies with potent and selective anticancer activity. Sesquiterpene lactones (SLs) are structurally diverse secondary metabolites derived from plants, predominantly found in the Asteraceae family, and are recognised for their extensive pharmacological significance. Characterised by a 15‐carbon skeleton and an electrophilic α ‐methylene‐ γ ‐lactone moiety, SLs exhibit notable anticancer, anti‐inflammatory, and immunomodulatory activities. Relevant original research and review articles published between 1994 and 2026 were identified through scientific databases such as Science Direct and Google Scholar. The biosynthesis of SLs from isopentenyl diphosphate and dimethylallyl diphosphate via farnesyl diphosphate highlights enzymatic cyclisation and oxidation steps that generate distinct carbocyclic frameworks. Structure‐activity relationship studies emphasise the critical role of Michael acceptor functionalities in mediating biological activity through covalent interaction with cellular nucleophiles. Mechanistically, SLs exert anticancer effects by inhibiting NF‐ κ B signalling, inducing oxidative stress, activating apoptotic pathways, causing cell‐cycle arrest, and modulating MAPK signalling. Recent advances in semisynthetic modification strategies aimed at improving potency and selectivity are discussed. Highlighting the need for more comprehensive pharmacokinetic, toxicological, and clinical investigations. Overall, SLs represent valuable, structurally versatile scaffolds for anticancer drug discovery, although further optimisation and clinical validation are required to establish therapeutic potential.