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

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.

journal_name

Eur J Med Chem

journal_title

European journal of medicinal chemistry

authors

Gao F,Liang Y,Zhou P,Cheng J,Ding K,Wang Y

doi

10.1016/j.ejmech.2019.05.072

subject

Has Abstract

pub_date

2019-09-15 00:00:00

pages

177-194

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(19)30490-8

journal_volume

178

pub_type

杂志文章

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