2. Academic Validation
  3. Design, synthesis, antitumor activities and biological studies of novel diaryl substituted fused heterocycles as dual ligands targeting tubulin and katanin

Design, synthesis, antitumor activities and biological studies of novel diaryl substituted fused heterocycles as dual ligands targeting tubulin and katanin

  • Eur J Med Chem. 2019 Sep 15:178:177-194. doi: 10.1016/j.ejmech.2019.05.072.
Feng Gao 1,  Yuru Liang 1,  Pengfei Zhou 2,  Jiayi Cheng 1,  Kuiling Ding 3,  Yang Wang 4
Affiliations

Affiliations

  • 1 School of Pharmacy, Fudan University, Shanghai, 201203, China.
  • 2 State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 200032, China.
  • 3 State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 200032, China. Electronic address: kding@sioc.ac.cn.
  • 4 School of Pharmacy, Fudan University, Shanghai, 201203, China; Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, Shanghai Jiao Tong University, Shanghai, 200240, China. Electronic address: wangyang@shmu.edu.cn.
PMID: 31185410 DOI: 10.1016/j.ejmech.2019.05.072
Abstract

Microtubule is one of the important targets for Cancer treatment. A novel class of diaryl substituted imidazo[4,5-c]pyridin-2-ones and imidazo[4,5-c]pyridines were designed based on combination principles by merging the structures of β-lactams and purine-type compounds known as tubulin polymerization inhibitor and katanin activity up-regulator, respectively. Their antitumor activities were evaluated in vitro and the mechanism was elucidated, leading to the identification of 1,6-diaryl-1H-imidazo[4,5-c]pyridin-2(3H)-one 20b as the first bifunctional agent that can target both tubulin and katanin simultaneously. The in vivo assays verified that compound 20b significantly inhibited xenograft tumor growth with good pharmacokinetic characteristics, demonstrating a promising potential for further development into anti-tumor drug candidates with a unique mechanism of dual-targeting microtubule.

Keywords

Antitumor; Imidazo[4,5-c]pyridin-2-one; Katanin; Tubulin polymerization.

Figures