Design, Synthesis, and Biological Evaluation of HDAC Inhibitors Containing Natural Product-Inspired N-Linked 2-Acetylpyrrole Cap
文献类型：期刊论文
| 作者 | Zhang, Han3,4; Shen, Qianqian2; Hu, Zhu3; Wu, Pei-Qian3; Chen, Yi1,2 ; Zhao, Jin-Xin1,3; Yue, Jian-Min1,3,4
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| 刊名 | MOLECULES
 |
| 出版日期 | 2024-10-01 |
| 卷号 | 29期号:19页码:26 |
| 关键词 | HDAC inhibitors anti-cancer activity natural products pyrrole derivatives molecular docking molecular dynamics simulation |
| DOI | 10.3390/molecules29194653 |
| 通讯作者 | Chen, Yi(ychen@simm.ac.cn) ; Zhao, Jin-Xin(jxzhao@simm.ac.cn) ; Yue, Jian-Min(jmyue@simm.ac.cn) |
| 英文摘要 | Drawing inspiration from the structural resemblance between a natural product N-(3-carboxypropyl)-2-acetylpyrrole and phenylbutyric acid, a pioneer HDAC inhibitor evaluated in clinical trials, we embarked on the design and synthesis of a novel array of HDAC inhibitors containing an N-linked 2-acetylpyrrole cap by utilizing the pharmacophore fusion strategy. Among them, compound 20 exhibited potential inhibitory activity on HDAC1, and demonstrated notable potency against RPMI-8226 cells with an IC50 value of 2.89 +/- 0.43 mu M, which was better than chidamide (IC50 = 10.23 +/- 1.02 mu M). Western blot analysis and Annexin V-FTIC/propidium iodide (PI) staining showed that 20 could enhance the acetylation of histone H3, as well as remarkably induce apoptosis of RPMI-8226 cancer cells. The docking study highlighted the presence of a hydrogen bond between the carbonyl oxygen of the 2-acetylpyrrole cap group and Phe198 of the HDAC1 enzyme in 20, emphasizing the crucial role of introducing this natural product-inspired cap group. Molecular dynamics simulations showed that the docked complex had good conformational stability. The ADME parameters calculation showed that 20 possesses remarkable theoretical drug-likeness properties. Taken together, these results suggested that 20 is worthy of further exploration as a potential HDAC-targeted anticancer drug candidate. |
| WOS关键词 | HISTONE DEACETYLASE INHIBITORS ; PYRROLE ; PLASMA |
| 资助项目 | National Natural Science Foundation of China ; Youth Innovation Promotion Association of Chinese Academy of Sciences (CAS)[2022282] ; Shandong Laboratory Program[SYS202205] ; Shanghai Institute of Materia Medica of CAS[SIMM0120231002] ; [22237007] ; [T2192972] |
| WOS研究方向 | Biochemistry & Molecular Biology ; Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:001334436700001 |
| 出版者 | MDPI |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/313829]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Chen, Yi; Zhao, Jin-Xin; Yue, Jian-Min |
| 作者单位 | 1.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, 198 East Binhai Rd, Yantai 264117, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Chem Biol, 501 Haike Rd, Shanghai 201203, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, Ethnomed & Biofunct Mol Res Ctr, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China 4.Nanjing Univ Chinese Med, Sch Chinese Mat Med, 138 Xianlin Rd, Nanjing 210023, Peoples R China |
| 推荐引用方式 GB/T 7714 | Zhang, Han,Shen, Qianqian,Hu, Zhu,et al. Design, Synthesis, and Biological Evaluation of HDAC Inhibitors Containing Natural Product-Inspired N-Linked 2-Acetylpyrrole Cap[J]. MOLECULES,2024,29(19):26. |
| APA | Zhang, Han.,Shen, Qianqian.,Hu, Zhu.,Wu, Pei-Qian.,Chen, Yi.,...&Yue, Jian-Min.(2024).Design, Synthesis, and Biological Evaluation of HDAC Inhibitors Containing Natural Product-Inspired N-Linked 2-Acetylpyrrole Cap.MOLECULES,29(19),26. |
| MLA | Zhang, Han,et al."Design, Synthesis, and Biological Evaluation of HDAC Inhibitors Containing Natural Product-Inspired N-Linked 2-Acetylpyrrole Cap".MOLECULES 29.19(2024):26. |
入库方式： OAI收割
来源：上海药物研究所
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