Natural protoberberine alkaloids, identified as potent selective LSD1 inhibitors, induce AML cell differentiation
| Autor: | Mamun Maa, Hai-Fang Cheng, Feng-Zhi Suo, Bin Yu, Hong-Min Liu, Li-Juan Zhao, Yan-Jia Guo, Dan-Dan Shen, Yi-Chao Zheng, Sheng-Hui Niu, Zhen-Zhen Liu, Zhong-Rui Li |
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| Rok vydání: | 2020 |
| Předmět: |
animal structures
Cell Survival Cellular differentiation CD14 Berberine Alkaloids Antineoplastic Agents HL-60 Cells Mice SCID Pharmacology 01 natural sciences Biochemistry Mice chemistry.chemical_compound In vivo Drug Discovery Animals Humans Isoquinoline Molecular Biology Histone Demethylases CD86 biology 010405 organic chemistry Chemistry Organic Chemistry Myeloid leukemia Cell Differentiation 0104 chemical sciences Leukemia Myeloid Acute 010404 medicinal & biomolecular chemistry Integrin alpha M Toxicity biology.protein Female |
| Zdroj: | Bioorganic Chemistry. 97:103648 |
| ISSN: | 0045-2068 |
| DOI: | 10.1016/j.bioorg.2020.103648 |
| Popis: | Natural protoberberine alkaloids were first identified and characterized as potent, selective and cellular active lysine specific demethylase 1 (LSD1) inhibitors. Due to our study, isoquinoline-based tetracyclic scaffold was identified as the key structural element for their anti-LSD1 activity, subtle changes of substituents attached to the core structure led to dramatic changes of the activity. Among these protoberberine alkaloids, epiberberine potently inhibited LSD1 (IC50 = 0.14 ± 0.01 μM) and was highly selective to LSD1 over MAO-A/B. Furthermore, epiberberine could induce the expression of CD86, CD11b and CD14 in THP-1 and HL-60 cells, confirming its cellular activity of inducing acute myeloid leukemia (AML) cells differentiation. Moreover, epiberberine prolonged the survival of THP-1 cells bearing mice and inhibited the growth of AML cells in vivo without obvious global toxicity. These findings give the potential application of epiberberine in AML treatment, and the isoquinoline-based tetracyclic scaffold could be used for further development of LSD1 inhibitors. |
| Databáze: | OpenAIRE |
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