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 9 was determined by X-ray crystallography,
which showed that 9 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.