4,6-Substituted-1 H-Indazoles as potent IDO1/TDO dual inhibitors

doi:10.1016/j.bmc.2019.02.014

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	4,6-Substituted-1 H-Indazoles as potent IDO1/TDO dual inhibitors
	Yang, Lingling 3; Chen, Yang 3; He, Junlin 2; Njoya, Emmanuel Mfotie 1; Chen, Jianjun 3; Liu, Siyan 3; Xie, Congqiang 3; Huang, Wenze 3; Wang, Fei 1; Wang, Zhouyu 3
刊名	BIOORGANIC & MEDICINAL CHEMISTRY
	2019
卷号	27 期号:6 页码:1087-1098
关键词	Indoleamine 2,3-dioxygenase 1 (IDO1) Tryptophan 2,3-dioxygenase (TDO) 1H-Indazoles Dual inhibitor Cancer immunotherapy Antitumor activity
ISSN号	0968-0896
DOI	10.1016/j.bmc.2019.02.014
产权排序	3
文献子类	Article
英文摘要	Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO) are constitutively overexpressed in many types of cancer cells and exert important immunosuppressive functions. In this article, a series of 4,6-substituted-1H-indazole derivatives were synthesized and evaluated the inhibitory activities against IDO1 and TDO, as well as their structure-activity relationships (SARs). Among these, compound 35 displayed the most IDO1 inhibitory potency with an IC50 value of 0.74 mu M in an enzymatic assay and 1.37 mu M in HeLa cells. Quantitative analysis of the Western blot results indicated that 35 significantly decreased the INF gamma-induced IDO1 expression in a concentration-dependent manner. In addition, 35 showed promising TDO inhibition with an IC50 value of 2.93 mu M in the enzymatic assay and 7.54 mu M in A172 cells. Moreover, compound 35 exhibited in vivo antitumor activity in the CT26 xenograft model. These findings suggest that 1H-indazole derivative 35 is a potent IDO1/TDO dual inhibitor, and has the potential to be developed for IDO1/TDO-related cancer treatment.
学科主题	Chemistry & Analysis
URL标识	查看原文
WOS研究方向	Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Chemistry
语种	英语
出版者	PERGAMON-ELSEVIER SCIENCE LTD
WOS记录号	WOS:000462478700016
内容类型	期刊论文
源URL	[http://210.75.237.14/handle/351003/30931]
专题	国家天然药物工程技术研究中心_天然产物研究
作者单位	1.Chinese Acad Sci, Chengdu Inst Biol, Key Lab Nat Med & Clin Translat, Chengdu 610041, Sichuan, Peoples R China 2.Chengdu Univ Tradit Chinese Med, Coll Pharm, Key Lab Systemat Res Dev & Utilizat Chinese Med R, Chengdu 610091, Sichuan, Peoples R China; 3.Xihua Univ, Sch Food & Bioengn, Dept Pharmaceut Engn, Chengdu 610039, Sichuan, Peoples R China;
推荐引用方式 GB/T 7714	Yang, Lingling,Chen, Yang,He, Junlin,et al. 4,6-Substituted-1 H-Indazoles as potent IDO1/TDO dual inhibitors[J]. BIOORGANIC & MEDICINAL CHEMISTRY,2019,27(6):1087-1098.
APA	Yang, Lingling.,Chen, Yang.,He, Junlin.,Njoya, Emmanuel Mfotie.,Chen, Jianjun.,...&Qian, Shan.(2019).4,6-Substituted-1 H-Indazoles as potent IDO1/TDO dual inhibitors.BIOORGANIC & MEDICINAL CHEMISTRY,27(6),1087-1098.
MLA	Yang, Lingling,et al."4,6-Substituted-1 H-Indazoles as potent IDO1/TDO dual inhibitors".BIOORGANIC & MEDICINAL CHEMISTRY 27.6(2019):1087-1098.