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

  • J Med Chem. 2016 Nov 23;59(22):10329-10334. doi: 10.1021/acs.jmedchem.6b01268.
Pengfei Zhou  1 ,  Yan Liu  2 ,  Lu Zhou  1 ,  Kongkai Zhu  2 ,  Kechang Feng  1 ,  Hao Zhang  2 ,  Yuru Liang  1 ,  Hualiang Jiang  2 ,  Cheng Luo  2 ,  Mingming Liu  1 ,  Yang Wang  1
Affiliations
  • 1. School of Pharmacy, Fudan University , Shanghai 201203, China.
  • 2. Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
PMID: 27805821 DOI: 10.1021/acs.jmedchem.6b01268
Abstract

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.

Products