Design, synthesis and pharmacological evaluation of new PARP1 inhibitors by merging pharmacophores of olaparib and the natural product alantolactone
文献类型：期刊论文
| 作者 | Kayumov, Muzaffar1,2,3,4; Jia, Li2,3; Pardaev, Azizbek1,2,3,4; Song, Shan-Shan2; Mirzaakhmedov, Sharafitdin4; Ding, Chunyong1; Cheng, Yong-Jun2; Zhang, Ruihan (Isabella)5; Bao, Xubin2; Miao, Ze-Hong2,3 |
| 刊名 | EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
 |
| 出版日期 | 2022-10-05 |
| 卷号 | 240页码:114574 |
| ISSN号 | 0223-5234 |
| 关键词 | PARP1 Olaparib Alantolactone Syntheticlethality BRCA1/2mutant |
| DOI | 10.1016/j.ejmech.2022.114574 |
| 文献子类 | Article |
| 英文摘要 | Based on the reported synthetic lethality of the combination of PARP inhibitor olaparib with the natural product alantolactone, we designed several series of new PARP1 inhibitors by structurally merging both compounds into a single hybrid compound. Among them, compounds 20e and 25a displayed not only high biochemical activity (IC50 = 2.99 nM and 5.91 nM vs 11.36 nM), but also higher inhibitory effects against proliferation of BRCA1- deficient UWB1.289 cells than olaparib (IC50 = 0.27 mu M and 0.41 mu M vs 0.66 mu M). Much weak activity was observed in BRCA1 wild-type human fetal lung IMR-90 and WI-38 cells (IC50s > 10 mu M). Treatment with compounds 20e and 25a was found to induce increased levels of yH2AX in a concentration-dependent manner in both MDA-MB-436 and Capan-1 cells to a degree comparable with that of olaparib. Further mechanism study indicated that these compounds activated the cell cycle checkpoints, and subsequently induced G2/M arrest and apoptosis. The results validated that merging PARP inhibitors with other DNA-damage related compounds would produce more potent PARP inhibitors for anticancer studies. However, the poor aqueous solubility and low cell penetration of the current hybrid compounds call for further structural optimization. |
| WOS关键词 | POLY(ADP-RIBOSE) POLYMERASE INHIBITOR ; DNA-REPAIR ; ANTICANCER ACTIVITY ; BEARING ; CELLS |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| 出版者 | ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER |
| WOS记录号 | WOS:000826542200007 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/309330]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | He, Jin-Xue; Zhang, Ao |
| 作者单位 | 1.Shanghai Jiao Tong Univ, Pharm X Ctr, Sch Pharmaceut Sci, Shanghai 200240, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, Canc Res Ctr, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 3.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China; 4.Acad Sci Uzbek, Inst Bioorgan Chem, Tashkent 100125, Uzbekistan; 5.WLSA Shanghai Acad, Shanghai 200433, Peoples R China |
| 推荐引用方式 GB/T 7714 | Kayumov, Muzaffar,Jia, Li,Pardaev, Azizbek,et al. Design, synthesis and pharmacological evaluation of new PARP1 inhibitors by merging pharmacophores of olaparib and the natural product alantolactone[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2022,240:114574. |
| APA | Kayumov, Muzaffar.,Jia, Li.,Pardaev, Azizbek.,Song, Shan-Shan.,Mirzaakhmedov, Sharafitdin.,...&Zhang, Ao.(2022).Design, synthesis and pharmacological evaluation of new PARP1 inhibitors by merging pharmacophores of olaparib and the natural product alantolactone.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,240,114574. |
| MLA | Kayumov, Muzaffar,et al."Design, synthesis and pharmacological evaluation of new PARP1 inhibitors by merging pharmacophores of olaparib and the natural product alantolactone".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 240(2022):114574. |
入库方式： OAI收割
来源：上海药物研究所
浏览0
下载0
收藏0
其他版本
除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。