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Design, synthesis, and biological evaluation of novel carbazole derivatives as potent DNMT1 inhibitors with reasonable PK properties

文献类型：期刊论文

作者Li, Ennian8; Wang, Kai8; Zhang, Bei8; Guo, Siqi6,7; Xiao, Senhao7; Pan, Qi8; Wang, Xiaowan8; Chen, Weiying5,8; Wu, Yunshan5,8; Xu, Hesong4,7
刊名JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
出版日期2022-12-31
卷号37期号:1页码:1537-1555
关键词DNMT1 inhibitor A549 cell lines HCT116 cell lines antitumor activity pharmacokinetic
ISSN号1475-6366
DOI10.1080/14756366.2022.2079640
通讯作者Kong, Xiangqian(kong_xiangqian@gibh.ac.cn) ; Chen, Shijie(shijiechen@simm.ac.cn) ; Liu, Bo(doctliu@263.net)
英文摘要The DNA methyltransferases (DNMTs) were found in mammals to maintain DNA methylation. Among them, DNMT1 was the first identified, and it is an attractive target for tumour chemotherapy. DC_05 and DC_517 have been reported in our previous work, which is non-nucleoside DNMT1 inhibitor with low micromolar IC50 values and significant selectivity towards other S-adenosyl-(L)-methionine (SAM)-dependent protein methyltransferases. In this study, through a process of similarity-based analog searching, a series of DNMT1 inhibitors were designed, synthesized, and evaluated as anticancer agents. SAR studies were conducted based on enzymatic assays. And most of the compounds showed strong inhibitory activity on human DNMT1, especially WK-23 displayed a good inhibitory effect on human DNMT1 with an IC50 value of 5.0 mu M. Importantly, the pharmacokinetic (PK) profile of WK-23 was obtained with quite satisfying oral bioavailability and elimination half-life. Taken together, WK-23 is worth developing as DNMT1-selective therapy for the treatment of malignant tumour.
WOS关键词DNA METHYLTRANSFERASE ; HUMAN-DISEASE ; METHYLATION ; EPIGENETICS ; CANCER ; GENES ; MECHANISM ; INSIGHTS ; AGENTS ; RG108
资助项目Key-Area Research and Development Program of Guangdong Province[2020B1111110007] ; National Natural Science Foundation of China[81202398] ; National Natural Science Foundation of China[81703415] ; National Natural Science Foundation of China[21820102008] ; special foundation of Guangzhou Key Laboratory[202002010004] ; Natural Science Foundation of Guangdong Province[2017B030314166] ; Natural Science Foundation of Guangdong Province[2022A1515010103] ; Special Funds for Inheriting and Developing the Traditional Chinese Medicine from TCM Bureau of Guangdong Province[20191142] ; Specific Research Fund for TCM Science and Technology of Guangdong Provincial Hospital of Chinese Medicine[YN2019MJ05] ; High-level University Construction of Guangzhou University of Chinese Medicine[2021XK69] ; High-level University Construction of Guangzhou University of Chinese Medicine[2021XK08] ; Science and Technology Commission of Shanghai Municipality[21ZR1474700] ; Science and Technology Commission of Shanghai Municipality[19XD1404700] ; Youth Innovation Promotion Association of CAS[2022279] ; collaborative innovation project of Double first class of Guangzhou University of Chinese Medicine[2021XK69] ; collaborative innovation project of Double first class of Guangzhou University of Chinese Medicine[2021XK08]
WOS研究方向Biochemistry & Molecular Biology ; Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000807359300001
出版者TAYLOR & FRANCIS LTD
源URL[http://119.78.100.183/handle/2S10ELR8/301468]  
专题新药研究国家重点实验室
通讯作者Kong, Xiangqian; Chen, Shijie; Liu, Bo
作者单位1.Guangzhou Univ Chinese Med, Guangdong Hong Kong Macau Joint Lab Chinese Med &, Guangzhou, Peoples R China
2.State Key Lab Dampness Syndrome Chinese Med, Guangzhou, Peoples R China
3.Chinese Acad Sci, Guangzhou Inst Biomed & Hlth, 190 Kaiyuan Rd, Guangzhou 510530, Peoples R China
4.Univ Chinese Acad Sci, Sch Pharmaceut Sci & Technol, Hangzhou Inst Adv Study, Hangzhou, Peoples R China
5.Guangzhou Key Lab Chiral Res Act Components Tradi, Guangzhou, Peoples R China
6.Nanchang Univ, Sch Pharm, Nanchang, Jiangxi, Peoples R China
7.Chinese Acad Sci, Ctr Chem Biol, Drug Discovery & Design Ctr, Shanghai Inst Mat Med,State Key Lab Drug Res, Shanghai, Peoples R China
8.Guangzhou Univ Chinese Med, Clin Med Coll 2, Guangdong Prov Key Lab Clin Res Tradit Chinese Me, Guangzhou, Peoples R China
推荐引用方式
GB/T 7714		 Li, Ennian,Wang, Kai,Zhang, Bei,et al. Design, synthesis, and biological evaluation of novel carbazole derivatives as potent DNMT1 inhibitors with reasonable PK properties[J]. JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY,2022,37(1):1537-1555.
APA Li, Ennian.,Wang, Kai.,Zhang, Bei.,Guo, Siqi.,Xiao, Senhao.,...&Liu, Bo.(2022).Design, synthesis, and biological evaluation of novel carbazole derivatives as potent DNMT1 inhibitors with reasonable PK properties.JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY,37(1),1537-1555.
MLA Li, Ennian,et al."Design, synthesis, and biological evaluation of novel carbazole derivatives as potent DNMT1 inhibitors with reasonable PK properties".JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY 37.1(2022):1537-1555.

入库方式： OAI收割

来源：上海药物研究所

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