2. Academic Validation
  3. Design, synthesis, biological evaluation and cocrystal structures with tubulin of chiral β-lactam bridged combretastatin A-4 analogues as potent antitumor agents

Design, synthesis, biological evaluation and cocrystal structures with tubulin of chiral β-lactam bridged combretastatin A-4 analogues as potent antitumor agents

  • Eur J Med Chem. 2018 Jan 20:144:817-842. doi: 10.1016/j.ejmech.2017.12.004.
Pengfei Zhou 1,  Yuru Liang 2,  Hao Zhang 3,  Hao Jiang 3,  Kechang Feng 2,  Pan Xu 3,  Jie Wang 2,  Xiaoming Wang 4,  Kuiling Ding 5,  Cheng Luo 6,  Mingming Liu 7,  Yang Wang 8
Affiliations

Affiliations

  • 1 School of Pharmacy, Fudan University, Shanghai 201203, China; State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China.
  • 2 School of Pharmacy, Fudan University, Shanghai 201203, China.
  • 3 Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 4 State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China.
  • 5 State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China. Electronic address: kding@sioc.ac.cn.
  • 6 Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: cluo@simm.ac.cn.
  • 7 School of Pharmacy, Fudan University, Shanghai 201203, China. Electronic address: lmm@fudan.edu.cn.
  • 8 School of Pharmacy, Fudan University, Shanghai 201203, China. Electronic address: wangyang@shmu.edu.cn.
PMID: 29306206 DOI: 10.1016/j.ejmech.2017.12.004
Abstract

A diverse of chiral β-lactam bridged analogues of combretastatin A-4 (CA-4), 3-substituted 1,4-diaryl-2-azetidinones, were asymmetrically synthesized and biologically evaluated, leading to identify a number of potent anti-proliferative compounds represented by 14b and 14c with IC50 values of 0.001-0.021 μM, against four human Cancer cell lines (A2780, Hela, SKOV-3 and MDA-MB-231). Structure-activity relationship (SAR) studies on all stereoisomers of 14b and 14c revealed that the absolute configurations of the chiral centers at 3- and 4-position were critically important for the activity and generally a trans configuration between the "A" and "B" rings is optimal. In addition, 14b and 14c displayed less cytotoxicity on normal human oviduct epithelial cells than malignant cells indicating good selectivity in vitro. Further biochemical evaluation and cocrystal structures with tubulin demonstrated that both compounds disrupted tubulin polymerization through interacting at the colchicine-binding site, suppressed angiogenesis in vitro and in vivo, blocked cell cycle progression at mitotic phase and induced cellular Apoptosis. The in vivo assays verified that both compounds inhibited xenograft tumor growth in nude mice with acceptable therapeutic window, showing promising potentials for further clinical development.

Keywords

1,4-Diaryl-2-azetidinone; Antitumor; Combretastatin A-4; Tubulin polymerization.

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