Unlocking the Anticancer Potential of Benzodi(tri)azepines: Advances in Synthetic Strategies, Mechanistic Insights, and Structure-ActivityRelationships

Fused azepines and their derivatives, especially benzodiazepines and benzotriazepines, are well-known drug discovery templates, primarily for the treatment of neurological conditions. Recently, fused azepines have emerged as promising scaffolds for anticancer drug discovery due to their diverse mechanisms of action, including inhibition of kinases (e.g., cyclin-dependent kinases), histone deacetylases, tubulin, PARP enzymes, and DNA intercalation, leading to cell cycle arrest and induction of apoptosis. Despite their therapeutic potential, the translation of these compounds into clinical oncology remains limited, with only a few approved molecules, such as the pyrrolobenzodiazepine dimer-based antibody-drug conjugate, loncastuximab tesirine. This review consolidates recent advances in the synthesis and pharmacological evaluation of 1,3-, 1,4-, and 1,5- benzodiazepines and benzotriazepine derivatives, with a specific focus on anticancer activity. Various synthetic strategies, ranging from classical cyclization reactions to multicomponent, catalytic, and green chemistry approaches, are critically summarized. The review also highlights the biological activities of these derivatives, elucidating their mechanisms and discussing structure-activity relationship (SAR) studies class-wise to identify key pharmacophoric features that contribute to potency, selectivity, and synergistic potential with established chemotherapeutics. The integration of synthetic methodologies, mechanistic insights, and SAR findings is anticipated to guide rational design, structural optimization, and computational exploration, ultimately accelerating the development of novel fused azepine derivatives as anticancer agents with improved efficacy and translational potential.