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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
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; Shi, Dayong1,2,3,4
2019-03-28
Source PublicationJOURNAL OF MEDICINAL CHEMISTRY
ISSN0022-2623
Volume62Issue:6Pages:3051-3067
Corresponding AuthorWang, Lijun(wanglijun@qdio.ac.cn) ; Shi, Dayong(shidayong@qdio.ac.cn)
AbstractPoly(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.
DOI10.1021/acs.jmedchem.8b01946
Indexed BySCI
Language英语
Funding ProjectNational 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 Research AreaPharmacology & Pharmacy
WOS SubjectChemistry, Medicinal
WOS IDWOS:000463116900013
PublisherAMER CHEMICAL SOC
Citation statistics
Cited Times:1[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttp://ir.qdio.ac.cn/handle/337002/161189
Collection实验海洋生物学重点实验室
Corresponding AuthorWang, Lijun; Shi, Dayong
Affiliation1.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
First Author AffilicationInstitute of Oceanology, Chinese Academy of Sciences
Corresponding Author AffilicationInstitute of Oceanology, Chinese Academy of Sciences
Recommended Citation
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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