Synthesis of novel tryptanthrin derivatives as dual inhibitors of indoleamine 2,3-dioxygenase 1 and tryptophan 2,3-dioxygenase

Yuanyuan Li; Shengnan Zhang; Rong Wang; Menghan Cui; Wei Liu; Qing Yang; Chunxiang Kuang

doi:10.1016/j.bmcl.2020.127159

Synthesis of novel tryptanthrin derivatives as dual inhibitors of indoleamine 2,3-dioxygenase 1 and tryptophan 2,3-dioxygenase

Bioorg Med Chem Lett. 2020 Jun 1;30(11):127159. doi: 10.1016/j.bmcl.2020.127159. Epub 2020 Mar 29.

Authors

Yuanyuan Li¹, Shengnan Zhang², Rong Wang³, Menghan Cui⁴, Wei Liu⁵, Qing Yang⁶, Chunxiang Kuang⁷

Affiliations

¹ Shanghai Key Lab of Chemical Assessment and Sustainability, School of Chemical Science and Engineering, Tongji University, 1239 Siping Road, 200092 Shanghai, China. Electronic address: 1731041@tongji.edu.cn.
² State Key Laboratory of Genetic Engineering, Department of Biochemistry, School of Life Sciences, Fudan University, 2005 Songhu Road, 200438 Shanghai, China. Electronic address: 17110700084@fudan.edu.cn.
³ Shanghai Key Lab of Chemical Assessment and Sustainability, School of Chemical Science and Engineering, Tongji University, 1239 Siping Road, 200092 Shanghai, China. Electronic address: 1831059@tongji.edu.cn.
⁴ Shanghai Key Lab of Chemical Assessment and Sustainability, School of Chemical Science and Engineering, Tongji University, 1239 Siping Road, 200092 Shanghai, China. Electronic address: 1931000@tongji.edu.cn.
⁵ School of Pharmacy, Nantong University, 19 Qixiu Road, 226001 Nantong, China. Electronic address: weiliu2015@ntu.edu.cn.
⁶ State Key Laboratory of Genetic Engineering, Department of Biochemistry, School of Life Sciences, Fudan University, 2005 Songhu Road, 200438 Shanghai, China. Electronic address: yangqing68@fudan.edu.cn.
⁷ Shanghai Key Lab of Chemical Assessment and Sustainability, School of Chemical Science and Engineering, Tongji University, 1239 Siping Road, 200092 Shanghai, China. Electronic address: kuangcx@tongji.edu.cn.

PMID: 32247733
DOI: 10.1016/j.bmcl.2020.127159

Abstract

Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO) are promising drug development targets due to their implications in pathologies such as cancer and neurodegenerative diseases. The search for IDO1 inhibitor has been intensely pursued but there is a paucity of potent TDO and IDO1/TDO dual inhibitors. Natural product tryptanthrin has been confirmed to bear IDO1 and/or TDO inhibitory activities. Herein, twelve novel tryptanthrin derivatives were synthesized and evaluated for the IDO1 and TDO inhibitory potency. All of the compounds were found to be IDO1/TDO dual inhibitors, in particular, compound 9a and 9b bore IDO1 inhibitory activity similar to that of INCB024360, and compound 5a and 9b had remarkable TDO inhibitory activity superior to that of the well-known TDO inhibitor LM10. This work enriches the collection of IDO1/TDO dual inhibitors and provides chemical molecules for potential development into drugs.

Keywords: IDO1 inhibitor; IDO1/TDO dual inhibitor; Novel tryptanthrin derivative; TDO inhibitor; Water solubility.

Publication types

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

MeSH terms

Drug Design
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / metabolism
Humans
Indoleamine-Pyrrole 2,3,-Dioxygenase / antagonists & inhibitors*
Indoleamine-Pyrrole 2,3,-Dioxygenase / metabolism
Inhibitory Concentration 50
Quinazolines / chemistry*
Quinazolines / metabolism
Solubility
Structure-Activity Relationship
Tryptophan Oxygenase / antagonists & inhibitors*
Tryptophan Oxygenase / metabolism

Substances

Enzyme Inhibitors
Indoleamine-Pyrrole 2,3,-Dioxygenase
Quinazolines
tryptanthrine
Tryptophan Oxygenase