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Synthesis, biological evaluation and structure-activity relationship of novel dichloroacetophenones targeting pyruvate dehydrogenase kinases with potent anticancer activity
Xu, Biao1; Wang, Zhi-Peng2,4; Liu, Qingwang5; Yang, Xiaohong1; Li, Xuemin1; Huang, Ding1; Qiu, Yanfei1; Tam, Kin Yip3; Zhang, Shao-Lin1; He, Yun1
2021-03-15
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.
关键词Pyruvate dehydrogenase kinase Proliferation Cancer metabolism Structure-activity relationship
DOI10.1016/j.ejmech.2021.113225
发表期刊EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
ISSN0223-5234
卷号214页码:16
通讯作者Zhang, Shao-Lin(zhangsl@cqu.edu.cn) ; He, Yun(yun.he@cqu.edu.cn)
收录类别SCI
WOS记录号WOS:000629633800022
语种英语