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

Feng Gao; Yuru Liang; Pengfei Zhou; Jiayi Cheng; Kuiling Ding; Yang Wang

doi:10.1016/j.ejmech.2019.05.072

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. Epub 2019 May 31.

Authors

Feng Gao¹, Yuru Liang¹, Pengfei Zhou², Jiayi Cheng¹, Kuiling Ding³, Yang Wang⁴

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.

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacokinetics
Antineoplastic Agents / therapeutic use*
Apoptosis / drug effects
Carcinoma, Endometrioid / drug therapy
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Design
Drug Screening Assays, Antitumor
Female
G2 Phase Cell Cycle Checkpoints / drug effects
Human Umbilical Vein Endothelial Cells
Humans
Imidazoles / chemical synthesis
Imidazoles / chemistry
Imidazoles / pharmacokinetics
Imidazoles / therapeutic use*
Katanin / antagonists & inhibitors*
Katanin / metabolism
Ligands
Mice, Inbred BALB C
Mice, Inbred ICR
Mice, Nude
Molecular Structure
Ovarian Neoplasms / drug therapy
Pyridines / chemical synthesis
Pyridines / chemistry
Pyridines / pharmacokinetics
Pyridines / therapeutic use*
Structure-Activity Relationship
Tubulin / metabolism
Tubulin Modulators / chemical synthesis
Tubulin Modulators / chemistry
Tubulin Modulators / pharmacokinetics
Tubulin Modulators / therapeutic use*
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents
Imidazoles
Ligands
Pyridines
Tubulin
Tubulin Modulators
Katanin