Synthesis of novel 7-azaindole derivatives containing pyridin-3-ylmethyl dithiocarbamate moiety as potent PKM2 activators and PKM2 nucleus translocation inhibitors.
Synthesis of novel 7-azaindole derivatives containing pyridin-3-ylmethyl dithiocarbamate moiety as potent PKM2 activators and PKM2 nucleus translocation inhibitors.
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DOI：
10.1016/j.ejmech.2019.03.003
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发表时间：
2019-05
影响因子：
6.7
通讯作者：
Bingruo B. Liu;Xia Yuan;Boru Xu;Han Zhang;Ridong Li;Xin Wang;Z. Ge;Runtao Li
中科院分区：
文献类型：
--
作者：
Bingruo B. Liu;Xia Yuan;Boru Xu;Han Zhang;Ridong Li;Xin Wang;Z. Ge;Runtao Li
多项证据表明，丙酮酸激酶 M2 (PKM2) 在大多数癌细胞中表达上调，并且越来越多地被认为是肿瘤学中的潜在治疗靶点。在我们先导化合物5的发现和SAR研究的继续中，化合物5中的7-氮杂吲哚部分被系统地优化。结果表明，7-氮杂吲哚环上有二氟乙基取代的化合物6f对A375细胞系表现出高PKM2激活效力和抗增殖活性。在异种移植小鼠模型中，口服化合物6可使肿瘤显着消退，且无明显毒性。进一步的机制研究表明6f可能影响PKM2转入细胞核，并诱导A375细胞凋亡和自噬。更重要的是，compound6f以浓度依赖性方式显着抑制A375细胞的迁移。总的来说，6f 可能作为开发用于癌症治疗的有效 PKM2 激活剂的先导化合物。
Multiple lines of evidence have indicated that pyruvate kinase M2 (PKM2) is upregulated in most cancer cells and it is increasingly recognized as a potential therapeutic target in oncology. In a continuation of our discovery of lead compound5and SAR study, the 7-azaindole moiety in compound5was systematically optimized. The results showed that compound6f, which has a difluoroethyl substitution on the 7-azaindole ring, exhibited high PKM2 activation potency and anti-proliferation activities on A375 cell lines. In a xenograft mouse model, oral administration of compound6fled to significant tumor regression without obvious toxicity. Further mechanistic studies revealed that6fcould influence the translocation of PKM2 into nucleus, as well as induction of apoptosis and autophagy of A375 cells. More importantly, compound6fsignificantly inhibited migration of A375 cells in a concentration-dependent manner. Collectively,6fmay serve as a lead compound in the development of potent PKM2 activators for cancer therapy.