Design, synthesis and biological evaluation of bicyclic carboxylic acid derivatives as IDO1 inhibitors

Shi Cai; Xiaojun Yang; Pan Chen; Xueting Liu; Jinpei Zhou; Huibin Zhang

doi:10.1016/j.bioorg.2019.103356

Design, synthesis and biological evaluation of bicyclic carboxylic acid derivatives as IDO1 inhibitors

Bioorg Chem. 2020 Jan:94:103356. doi: 10.1016/j.bioorg.2019.103356. Epub 2019 Nov 21.

Authors

Shi Cai¹, Xiaojun Yang¹, Pan Chen², Xueting Liu², Jinpei Zhou³, Huibin Zhang⁴

Affiliations

¹ Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
² Department of Medicinal Chemistry, China Pharmaceutical University, TongjiaXiang 24, 210009 Nanjing, PR China.
³ Department of Medicinal Chemistry, China Pharmaceutical University, TongjiaXiang 24, 210009 Nanjing, PR China. Electronic address: jpzhou668@163.com.
⁴ Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China. Electronic address: zhanghb80@cpu.edu.cn.

PMID: 31785855
DOI: 10.1016/j.bioorg.2019.103356

Abstract

Indoleamine 2,3-dioxygenase 1 (IDO1) plays a vital role in tumor immune escape and has emerged as a promising target for cancer immunotherapy. In this study, a novel series of bicyclic carboxylic acid derivatives were designed, synthesized and evaluated for inhibitory activities against IDO1. Among these, compound 9c exhibited strong IDO1 inhibitory activity (HeLa cellular IC₅₀ = 2.6 nM, THP-1 cellular IC₅₀ = 11.2 nM). Further anti-tumor studies in vivo have shown that compound 9c has a great inhibitory effect on tumor growth in mice CT26 model as a single agent or in combination with 5-fluorouracil (inhibition rate was 53.9% and 92.7%, respectively). These results indicate that compound 9c is a effective IDO1 inhibitor for further investigation.

Keywords: Hela cell assay; IDO1 inhibitors; Immunotheraphy; l-tryptophan.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Carboxylic Acids / chemical synthesis
Carboxylic Acids / chemistry*
Carboxylic Acids / pharmacology*
Drug Design*
HeLa Cells
Humans
Indoleamine-Pyrrole 2,3,-Dioxygenase / antagonists & inhibitors*
Molecular Docking Simulation
THP-1 Cells

Substances

Carboxylic Acids
IDO1 protein, human
Indoleamine-Pyrrole 2,3,-Dioxygenase