Discovery of imidazoleisoindole derivatives as potent IDO1 inhibitors: Design, synthesis, biological evaluation and computational studies

Yi Zou; Fang Wang; Yan Wang; Qirui Sun; Yue Hu; Yuezhen Li; Wen Liu; Wenjie Guo; Zhangjian Huang; Yihua Zhang; Qiang Xu; Yisheng Lai

doi:10.1016/j.ejmech.2017.09.025

Discovery of imidazoleisoindole derivatives as potent IDO1 inhibitors: Design, synthesis, biological evaluation and computational studies

Eur J Med Chem. 2017 Nov 10:140:293-304. doi: 10.1016/j.ejmech.2017.09.025. Epub 2017 Sep 18.

Authors

Yi Zou¹, Fang Wang¹, Yan Wang², Qirui Sun¹, Yue Hu², Yuezhen Li³, Wen Liu², Wenjie Guo⁴, Zhangjian Huang¹, Yihua Zhang¹, Qiang Xu⁵, Yisheng Lai⁶

Affiliations

¹ State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, PR China.
² State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, PR China.
³ Department of Organic Chemistry, School of Science, China Pharmaceutical University, Nanjing 211198, PR China.
⁴ State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, PR China. Electronic address: guowj@nju.edu.cn.
⁵ State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, PR China. Electronic address: molpharm@163.com.
⁶ State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: yslai@cpu.edu.cn.

PMID: 28963992
DOI: 10.1016/j.ejmech.2017.09.025

Abstract

Indoleamine-2,3-dioxygenase-1 (IDO1) is an attractive target for cancer immunotherapy. Herein, a series of novel imidazoleisoindole derivatives were prepared and evaluated for their ability to inhibit IDO1. Among these, derivative 11r was the most active compound with nanomolar potency in the Hela cell-based assay, while showed negligible cellular toxicity. UV-visible spectra study demonstrated that compounds 11p and 11r bound to IDO1 and coordinated with the heme iron. Furthermore, they could significantly promote T cell proliferation, increase IFN-γ production, and reduce the numbers of Foxp3⁺ regulatory T cells. Finally, induced fit docking (IFD) and quantum mechanics/molecular mechanics (QM/MM) calculation were performed to understand the interactions of these compounds to IDO1 protein, which provided a comprehensive guide for further structural modification and optimization.

Keywords: Imidazoleisoindole; Indoleamine 2,3-dioxygenase 1; Induced fit docking; QM/MM calculation.

MeSH terms

Animals
Cells, Cultured
Coculture Techniques
Drug Design*
Drug Discovery*
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / pharmacology*
HeLa Cells
Humans
Indoleamine-Pyrrole 2,3,-Dioxygenase / antagonists & inhibitors*
Indoles / chemical synthesis
Indoles / chemistry*
Indoles / pharmacology*
Mice
Mice, Inbred C57BL
Molecular Dynamics Simulation
Proton Magnetic Resonance Spectroscopy
Spectrometry, Mass, Electrospray Ionization
Spectrophotometry, Ultraviolet
T-Lymphocytes / cytology
T-Lymphocytes / drug effects

Substances

Enzyme Inhibitors
Indoleamine-Pyrrole 2,3,-Dioxygenase
Indoles