Design, Synthesis, and Molecular Docking Studies of 2-Azetidinone-Based Combretastatin A-4 Analogues with Anticancer Activity

This study develops new combretastatin A-4 (CA-4) analogues to enhance anticancer efficacy, selectivity, and address drug resistance. A series of 2-azetidinones, designed as CA-4 analogues, feature two substituted phenyl rings bridged by an amidic carbonyl and a β-lactam ring. Target compounds (7–11, 20–23, and 28–31) were synthesized through two-step routes and characterized using FT-IR, ¹H NMR, ¹³C NMR, and mass spectrometry. Anti-proliferative activity against the breast cancer cell line MCF-7 and the normal cell line WRL 68 revealed compounds 9 and 21 as the most potent, with IC₅₀ values of 34.27 and 28.86 µM, respectively. Molecular docking studies of these compounds showed high binding affinity to the colchicine site on tubulin (PDB ID: 4O2B). Results suggest that symmetrical aromatic rings in this scaffold may enhance anticancer activity, highlighting compounds 9 and 21 as promising candidates.