4,6-Substituted-1H-Indazoles as potent IDO1/TDO dual inhibitors
| Autor: | Emmanuel Mfotie Njoya, Zhouyu Wang, Junlin He, Congqiang Xie, Chen Jianjun, Wenze Huang, Chen Yang, Siyan Liu, Li Yuzhi, Fei Wang, Yang Lingling, Shan Qian |
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| Rok vydání: | 2019 |
| Předmět: |
Indazoles
medicine.medical_treatment Clinical Biochemistry Pharmaceutical Science Antineoplastic Agents Pharmacology 01 natural sciences Biochemistry HeLa Structure-Activity Relationship Western blot Cancer immunotherapy In vivo Cell Line Tumor Neoplasms Drug Discovery medicine Animals Humans Indoleamine-Pyrrole 2 3 -Dioxygenase Enzyme Inhibitors Molecular Biology IC50 chemistry.chemical_classification Mice Inbred BALB C medicine.diagnostic_test biology 010405 organic chemistry Organic Chemistry Tryptophan biology.organism_classification Tryptophan Oxygenase 0104 chemical sciences 010404 medicinal & biomolecular chemistry Enzyme chemistry Cancer cell Molecular Medicine |
| Zdroj: | Bioorganic & Medicinal Chemistry. 27:1087-1098 |
| ISSN: | 0968-0896 |
| Popis: | 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 μM in an enzymatic assay and 1.37 μM in HeLa cells. Quantitative analysis of the Western blot results indicated that 35 significantly decreased the INFγ-induced IDO1 expression in a concentration-dependent manner. In addition, 35 showed promising TDO inhibition with an IC50 value of 2.93 μM in the enzymatic assay and 7.54 μM 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. |
| Databáze: | OpenAIRE |
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