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

doi:10.1016/j.ejmech.2021.113225

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	Synthesis, biological evaluation and structure-activity relationship of novel dichloroacetophenones targeting pyruvate dehydrogenase kinases with potent anticancer activity
	Xu, Biao 1; Wang, Zhi-Peng 2,4; Liu, Qingwang 5; Yang, Xiaohong 1; Li, Xuemin 1; Huang, Ding 1; Qiu, Yanfei 1; Tam, Kin Yip 3; Zhang, Shao-Lin 1; He, Yun 1
	2021-03-15
发表期刊	EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
ISSN	0223-5234
通讯作者	Zhang, Shao-Lin(zhangsl@cqu.edu.cn) ; He, Yun(yun.he@cqu.edu.cn)
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
DOI	10.1016/j.ejmech.2021.113225
收录类别	SCI
语种	英语
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]
项目资助者	National Natural Science Foundation of China ; Chongqing Science and Technology Bureau ; Science and Technology Development Fund, Macau SAR ; University of Macau
WOS研究方向	Pharmacology & Pharmacy
WOS类目	Chemistry, Medicinal
WOS记录号	WOS:000629633800022
出版者	ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
引用统计	被引频次：8[WOS] [WOS记录] [WOS相关记录]
文献类型	期刊论文
条目标识符	http://ir.hfcas.ac.cn:8080/handle/334002/121228
专题	中国科学院合肥物质科学研究院
通讯作者	Zhang, Shao-Lin; He, Yun
作者单位	1.Chongqing Univ, Sch Pharmaceut Sci, Chongqing Key Lab Nat Prod Synth & Drug Res, Chongqing 401331, Peoples R China 2.Chinese Acad Sci, Chongqing Inst Green & Intelligent Technol, Chongqing, Peoples R China 3.Univ Macau, Fac Hlth Sci, Taipa, Macao, Peoples R China 4.Univ Chinese Acad Sci Chongqing, Chongqing Sch, Chongqing, Peoples R China 5.Chinese Acad Sci, Inst Hlth & Med Technol, Hefei Inst Phys Sci, Hefei 230031, Anhui, 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.
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.
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).