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Discovery of Novel Bromophenol Thiosemicarbazone Hybrids as Potent Selective Inhibitors of Poly(ADP-ribose) Polymerase-1 (PARP-1) for Use in Cancer

文献类型：期刊论文

作者Guo, Chuanlong1,2,4,6,7; Wang, Lijun1,2,4; Li, Xinxue1,2,4; Wang, Shuaiyu1,2,4; Yu, Xuemin5; Xu, Kuo1,2,4; Zhao, Yue1,2,4; Luo, Jiao1,2,4; Li, Xiangqian1,2,4; Jiang, Bo1,2,4
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2019-03-28
卷号62期号:6页码:3051-3067
ISSN号0022-2623
DOI10.1021/acs.jmedchem.8b01946
通讯作者Wang, Lijun(wanglijun@qdio.ac.cn) ; Shi, Dayong(shidayong@qdio.ac.cn)
英文摘要Poly(ADP-ribose) polymerase-1 (PARP-1) is a new potential target for anticancer drug discovery. A series of bromophenol-thiosemicarbazone hybrids as PARP-1 inhibitors were designed, synthesized, and evaluated for their antitumor activities. Among them, the most promising compound, 11, showed excellent selective PARP-1 inhibitory activity (IC50 = 29.5 nM) over PARP-2 (IC50 > 1000 nM) and potent anticancer activities toward the SK-OV-3, Bel-7402 and HepG2 cancer cell lines (IC50 = 2.39, 5.45, and 4.60 mu M), along with inhibition of tumor growth in an in vivo SK-OV-3 cell xenograft model. Further study demonstrated that compound 11 played an antitumor role through multiple anticancer mechanisms, including the induction of apoptosis and cell cycle arrest, cellular accumulation of DNA double-strand breaks, DNA repair alterations, inhibition of H2O2-triggered PARylation, antiproliferative effects via the production of cytotoxic reactive oxygen species, and autophagy. In addition, compound 11 displayed good pharmacokinetic characteristics and favorable safety. These observations demonstrate that compound 11 may serve as a lead compound for the discovery of new anticancer drugs.
资助项目National Natural Science Foundation of China[81773586] ; National Natural Science Foundation of China[81703354] ; National Natural Science Foundation of China[81600782] ; Shandong Provincial Natural Science Foundation[JQ201722] ; Key Research Program of Frontier Sciences, CAS[QYZDB-SSW-DQC014] ; Project of Discovery, Evaluation and Transformation of Active Natural Compounds ; Strategic Biological Resources Service Network Program of Chinese Academy of Sciences[ZSTH-026] ; National Program for Support of Top-notch Young Professionals ; Taishan Scholar Youth Project of Shandong Province
WOS研究方向Pharmacology & Pharmacy
语种英语
出版者AMER CHEMICAL SOC
WOS记录号WOS:000463116900013
源URL[http://ir.qdio.ac.cn/handle/337002/161188]  
专题海洋研究所_实验海洋生物学重点实验室
通讯作者Wang, Lijun; Shi, Dayong
作者单位1.Chinese Acad Sci, Inst Oceanol, Key Lab Expt Marine Biol, Qingdao 266071, Shandong, Peoples R China
2.Qingdao Natl Lab Marine Sci & Technol, Lab Marine Drugs & Bioprod, Qingdao 266071, Shandong, Peoples R China
3.Shandong Univ, State Key Lab Microbial Technol, Jinan 250100, Shandong, Peoples R China
4.Chinese Acad Sci, Ctr Ocean Mega Sci, Qingdao 266071, Shandong, Peoples R China
5.Shandong Univ, Qilu Hosp, Dept Otorhinolaryngol, Qingdao 266000, Shandong, Peoples R China
6.Qingdao Univ Sci & Technol, Coll Chem Engn, Dept Pharm, Qingdao 266042, Shandong, Peoples R China
7.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
推荐引用方式
GB/T 7714		 Guo, Chuanlong,Wang, Lijun,Li, Xinxue,et al. Discovery of Novel Bromophenol Thiosemicarbazone Hybrids as Potent Selective Inhibitors of Poly(ADP-ribose) Polymerase-1 (PARP-1) for Use in Cancer[J]. JOURNAL OF MEDICINAL CHEMISTRY,2019,62(6):3051-3067.
APA Guo, Chuanlong.,Wang, Lijun.,Li, Xinxue.,Wang, Shuaiyu.,Yu, Xuemin.,...&Shi, Dayong.(2019).Discovery of Novel Bromophenol Thiosemicarbazone Hybrids as Potent Selective Inhibitors of Poly(ADP-ribose) Polymerase-1 (PARP-1) for Use in Cancer.JOURNAL OF MEDICINAL CHEMISTRY,62(6),3051-3067.
MLA Guo, Chuanlong,et al."Discovery of Novel Bromophenol Thiosemicarbazone Hybrids as Potent Selective Inhibitors of Poly(ADP-ribose) Polymerase-1 (PARP-1) for Use in Cancer".JOURNAL OF MEDICINAL CHEMISTRY 62.6(2019):3051-3067.

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来源：海洋研究所

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