机构：[1]Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, The Second Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China广东省中医院[2]State Key Laboratory of Drug Research, The Center for Chemical Biology, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China[3]School of Pharmacy, Nanchang University, Nanchang, China[4]Guangzhou Key Laboratory of Chirality Research on Active Components of Traditional Chinese Medicine, Guangzhou, China[5]School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China浙江省肿瘤医院[6]Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China[7]State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangzhou, China[8]Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou University of Chinese Medicine, Guangzhou, China
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.
基金：
Key-Area Research and Development Program of Guangdong Province [2020B1111110007]; National Natural Science Foundation of China [81202398, 81703415, 21820102008]; special foundation of Guangzhou Key Laboratory [202002010004]; Natural Science Foundation of Guangdong Province [2017B030314166, 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, 2021XK08]; Science and Technology Commission of Shanghai Municipality [21ZR1474700, 19XD1404700]; Youth Innovation Promotion Association of CAS [2022279]; collaborative innovation project of "Double first class" of Guangzhou University of Chinese Medicine [2021XK69, 2021XK08]
第一作者机构：[1]Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, The Second Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
共同第一作者：
通讯作者：
通讯机构：[1]Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, The Second Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China[2]State Key Laboratory of Drug Research, The Center for Chemical Biology, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China[4]Guangzhou Key Laboratory of Chirality Research on Active Components of Traditional Chinese Medicine, Guangzhou, China[5]School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China[6]Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China[7]State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangzhou, China[8]Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou University of Chinese Medicine, Guangzhou, China[*1]Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Road, Guangzhou 510530, China[*2]State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China[*3]The Second Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, 510006, 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.doi:10.1080/14756366.2022.2079640.
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)
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
