Synthesis, biological evaluation and structure-activity relationship of novel dichloroacetophenones targeting pyruvate dehydrogenase kinases with potent anticancer activity
Synthesis, biological evaluation and structure-activity relationship of novel dichloroacetophenones targeting pyruvate dehydrogenase kinases with potent anticancer activity
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具有有效抗癌活性的丙酮酸脱氢酶激酶新型二氯苯乙酮的合成、生物学评价及构效关系
DOI：
10.1016/j.ejmech.2021.113225
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发表时间：
2021
影响因子：
6.7
通讯作者：
He Yun
中科院分区：
文献类型：
--
作者：
Xu Biao;Wang Zhi-Peng;Liu Qingwang;Yang Xiaohong;Li Xuemin;Huang Ding;Qiu Yanfei;Tam Kin Yip;Zhang Shao-Lin;He Yun
丙酮酸脱氢酶激酶（PDKs）是肿瘤代谢中一个很有前途的治疗靶点，受到越来越多的关注。本文报道了一系列新型PDKs抑制剂二氯苯乙酮类化合物的合成及生物活性评价。构效关系分析表明，化合物6 u对PDKs有较强的抑制作用，其EC_（50）值为0.09 μM，对多种肿瘤细胞的抑制作用为1.1 ~ 3.8 μM，而对非癌细胞L02的抑制作用较弱（IC_（50）> 10 μM）。在A375异种移植瘤模型中，6 u在5 mg/kg剂量下显示出明显的抗肿瘤活性，但对小鼠体重无负面影响。分子对接表明，6 u与PDK 1中的Ser 75和Gln 61形成了直接的氢键作用，同时6 u中的苯胺骨架被保守的疏水残基Phe 78和Phe 65夹在中间，这有助于提高其生化活性。6 u可诱导A375细胞凋亡，使细胞阻滞于G1期，并抑制癌细胞的迁移。另外，6-FU通过减少乳酸的形成、增加ROS的产生和OCR的消耗，改变了A375细胞的葡萄糖代谢途径，可能是一种潜在的调节剂，可以对癌细胞的糖酵解途径进行重新编程。
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 compound6u, which inhibited PDKs with an EC50value of 0.09 μM, and reduced various cancer cells proliferation with IC50values ranging from 1.1 to 3.8 μM, while show weak effect against non-cancerous L02 cell (IC50> 10 μM). In the A375 xenograft model,6udisplayed an obvious antitumor activity at a dose of 5 mg/kg, but with no negative effect to the mice weight. Molecular docking suggested that6uformed direct hydrogen bond interactions with Ser75 and Gln61 in PDK1, and meanwhile the aniline skeleton in6uwas sandwiched by the conserved hydrophobic residues Phe78 and Phe65, which contribute to the biochemical activity improvement. Moreover,6uinduced A375 cell apoptosis and cell arrest in G1 phase, and inhibited cancer cell migration. In addition,6ualtered 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.