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Synthesis, biological evaluation and structure-activity relationship of novel dichloroacetophenones targeting pyruvate dehydrogenase kinases with potent anticancer activity

文献类型：期刊论文

作者Xu, Biao3; Wang, Zhi-Peng4,5; Liu, Qingwang2; Yang, Xiaohong3; Li, Xuemin3; Huang, Ding3; Qiu, Yanfei3; Tam, Kin Yip1; Zhang, Shao-Lin3; He, Yun3
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2021-03-15
卷号214页码:16
ISSN号0223-5234
关键词Pyruvate dehydrogenase kinase Proliferation Cancer metabolism Structure-activity relationship
DOI10.1016/j.ejmech.2021.113225
通讯作者Zhang, Shao-Lin(zhangsl@cqu.edu.cn) ; He, Yun(yun.he@cqu.edu.cn)
英文摘要Pyruvate dehydrogenase kinases (PDKs) are promising therapeutic targets that have received increasing attentions in cancer metabolism. In this paper, we report the synthesis and biological evaluation of a series of novel dichloroacetophenones as potent PDKs inhibitors. Structure-activity relationship analysis enabled us to identify a potent compound 6u, which inhibited PDKs with an EC50 value of 0.09 mu M, and reduced various cancer cells proliferation with IC50 values ranging from 1.1 to 3.8 mu M, while show weak effect against non-cancerous L02 cell (IC50 > 10 mu M). In the A375 xenograft model, 6u displayed an obvious antitumor activity at a dose of 5 mg/kg, but with no negative effect to the mice weight. Molecular docking suggested that 6u formed direct hydrogen bond interactions with Ser75 and Gln61 in PDK1, and meanwhile the aniline skeleton in 6u was sandwiched by the conserved hydrophobic residues Phe78 and Phe65, which contribute to the biochemical activity improvement. Moreover, 6u induced A375 cell apoptosis and cell arrest in G1 phase, and inhibited cancer cell migration. In addition, 6u altered glucose metabolic pathway in A375 cell by decreasing lactate formation and increasing ROS production and OCR consumption, which could serve as a potential modulator to reprogram the glycolysis pathway in cancer cell. (C) 2021 Elsevier Masson SAS. All rights reserved.
资助项目National Natural Science Foundation of China[21807008] ; Chongqing Science and Technology Bureau[csts2019jcyj-zdxmX0021] ; Science and Technology Development Fund, Macau SAR[0057/2018/A2] ; University of Macau[MYRG2019-00034-FHS]
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:000629633800022
源URL[http://119.78.100.138/handle/2HOD01W0/13218]  
专题中国科学院重庆绿色智能技术研究院
通讯作者Zhang, Shao-Lin; He, Yun
作者单位1.Univ Macau, Fac Hlth Sci, Taipa, Macao, Peoples R China
2.Chinese Acad Sci, Inst Hlth & Med Technol, Hefei Inst Phys Sci, Hefei 230031, Anhui, Peoples R China
3.Chongqing Univ, Sch Pharmaceut Sci, Chongqing Key Lab Nat Prod Synth & Drug Res, Chongqing 401331, Peoples R China
4.Chinese Acad Sci, Chongqing Inst Green & Intelligent Technol, Chongqing, Peoples R China
5.Univ Chinese Acad Sci Chongqing, Chongqing Sch, Chongqing, Peoples R China
推荐引用方式
GB/T 7714		 Xu, Biao,Wang, Zhi-Peng,Liu, Qingwang,et al. Synthesis, biological evaluation and structure-activity relationship of novel dichloroacetophenones targeting pyruvate dehydrogenase kinases with potent anticancer activity[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2021,214:16.
APA Xu, Biao.,Wang, Zhi-Peng.,Liu, Qingwang.,Yang, Xiaohong.,Li, Xuemin.,...&He, Yun.(2021).Synthesis, biological evaluation and structure-activity relationship of novel dichloroacetophenones targeting pyruvate dehydrogenase kinases with potent anticancer activity.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,214,16.
MLA Xu, Biao,et al."Synthesis, biological evaluation and structure-activity relationship of novel dichloroacetophenones targeting pyruvate dehydrogenase kinases with potent anticancer activity".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 214(2021):16.

入库方式： OAI收割

来源：重庆绿色智能技术研究院

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