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: [email protected].
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.