Design, synthesis and structure-activity relationship study of novel naphthoindolizine and indolizinoquinoline-5,12-dione derivatives as IDO1 inhibitors

Bioorg Med Chem. 2018 Sep 15;26(17):4886-4897. doi: 10.1016/j.bmc.2018.08.028.

Rui Yang ¹, Yu Chen ¹, Liangkun Pan ¹, Yanyan Yang ¹, Qiang Zheng ¹, Yue Hu ², Yuxi Wang ¹, Liangren Zhang ¹, Yang Sun ², Zhongjun Li ¹, Xiangbao Meng ³

Affiliations

1 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
2 State Key Laboratory of Pharmaceutical Biotechnology and Collaborative Innovation Center of Chemistry for Life Sciences, School of Life Sciences, Nanjing University, Nanjing 210023, China.
3 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China. Electronic address: xbmeng@bjmu.edu.cn.

PMID: 30170925 DOI: 10.1016/j.bmc.2018.08.028

Abstract

Indoleamine 2,3-dioxygenase 1 (IDO1) is regarded as a promising target for Cancer Immunotherapy. Many naphthoquinone derivatives have been reported as IDO1 inhibitors so far. Herein, two series of naphthoquinone derivatives, naphthoindolizine and indolizinoquinoline-5,12-dione derivatives, were synthesized and evaluated for their IDO1 inhibitory activity. Most of the target compounds showed significant inhibition potency and high selectivity for IDO1 over tryptophan 2,3-dioxygenase (TDO). The structure-activity relationship was also summarized. The most potent compounds 5c (IC₅₀ 23 nM, IDO1 Enzyme), and 5b' (IC₅₀ 372 nM, HeLa cell) were identified as promising lead compounds.

Keywords

Cancer immunotherapy; Indoleamine 2,3-dioxygenase 1; Indolizinoquinoline-5,12-dione derivatives; Naphthoindolizine.

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