Design, synthesis and biological evaluation of curcumin analogues as novel LSD1 inhibitors
| Autor: | Qinwen Jiang, Maosheng Cheng, Xiangyu Zhang, Xinran Wang, Wei Li, Dongmei Zhao, Jiangkun Yan, Jiming Wang |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Curcumin
animal structures Clinical Biochemistry Pharmaceutical Science 01 natural sciences Biochemistry Structure-Activity Relationship chemistry.chemical_compound Drug Discovery Humans Molecular Biology IC50 Histone Demethylases A549 cell Biological Products Natural product Molecular Structure biology 010405 organic chemistry Organic Chemistry Active site Enzyme assay 0104 chemical sciences Molecular Docking Simulation 010404 medicinal & biomolecular chemistry Histone chemistry biology.protein Molecular Medicine Demethylase |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 29:126683 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2019.126683 |
| Popis: | Histone lysine-specific demethylase 1 (LSD1) was the first discovered histone demethylase. Inactivating LSD1 or downregulating its expression inhibits cancer-cell development, and thus, it is an attractive molecular target for the development of novel cancer therapeutics. In this study, we worked on the structural optimization of natural products and identified 30 novel LSD1 inhibitors. Utilizing a structure-based drug design strategy, we designed and synthesized a series of curcumin analogues that were shown to be potent LSD1 inhibitors in the enzyme assay. Compound WB07 displayed the most potent LSD1 inhibitory activity, with an IC50 value of 0.8 μM. Moreover, WA20 showed an anticlonogenic effect on A549 cells with an IC50 value of 4.4 μM. Molecular docking simulations were also carried out, and the results indicated that the inhibitors bound to the protein active site located around the key residues of Asp555 and Asp556. These findings suggested that compounds WA20 and WB07 are the first curcumin analogue-based LSD1 inhibitors with remarkable A549 suppressive activity, providing a novel scaffold for the development of LSD1 inhibitors. |
| Databáze: | OpenAIRE |
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