Synthesis and biological evaluation of new berberine derivatives as cancer immunotherapy agents through targeting IDO1
| Autor: | Zhe–Song Deng, Yan–Xiang Wang, Jian–Dong Jiang, Wei–Qiang Pang, Qing–Xuan Zeng, Tian–Yun Fan, Hongbin Deng, Dan–Qing Song |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Lung Neoplasms Berberine Cell Survival medicine.medical_treatment Pharmacology Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Cancer immunotherapy Drug Discovery Tumor Cells Cultured medicine Humans Indoleamine-Pyrrole 2 3 -Dioxygenase Structure–activity relationship STAT1 Cytotoxicity Dose-Response Relationship Drug Molecular Structure biology Organic Chemistry AMPK General Medicine Small molecule 030104 developmental biology chemistry Biochemistry 030220 oncology & carcinogenesis biology.protein Phosphorylation Immunotherapy |
| Zdroj: | European Journal of Medicinal Chemistry. 143:1858-1868 |
| ISSN: | 0223-5234 |
| DOI: | 10.1016/j.ejmech.2017.10.078 |
| Popis: | To discover small-molecule cancer immunotherapy candidates through targeting Indoleamine 2,3-dioxygenase 1 (IDO1), twenty-five new berberine (BBR) derivatives defined with substituents on position 3 or 9 were synthesized and examined for repression of IFN-γ-induced IDO1 promoter activities. Structure-activity relationship (SAR) indicated that large volume groups at the 9-position might be beneficial for potency. Among them, compounds 2f, 2i, 2n, 2o and 8b exhibited increased activities, with inhibition rate of 71-90% compared with BBR. Their effects on IDO1 expression were further confirmed by protein level as well. Furthermore, compounds 2i and 2n exhibited anticancer activity by enhancing the specific lysis of NK cells to A549 through IDO1, but not cytotoxicity. Preliminary mechanism revealed that both of them inhibited IFN-γ-induced IDO1 expression through activating AMPK and subsequent inhibition of STAT1 phosphorylation. Therefore, compounds 2i and 2n have been selected as IDO1 modulators for small-molecule cancer immunotherapy for next investigation. |
| Databáze: | OpenAIRE |
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