Potent Antitumor Activities and Structure Basis of the Chiral β‑Lactam Bridged Analogue of Combretastatin A‑4 Binding to Tubulin

A series of chiral β-lactam bridged analogues (3-substituted 1,4-diaryl-2-azetidinones) of combretastatin A-4 (CA-4) were synthesized asymmetrically, and their antitumor activities were evaluated in vitro and in vivo. The cocrystal structure of tubulin in complex with compound <b>9</b> was determined by X-ray crystallography, which showed that <b>9</b> binds to the same site as colchicine with similar binding mode, and the absolute configuration of its C-4 was first identified and demonstrated to be critically important for their antiproliferative activities