Design, synthesis and biological evaluation of regioisomers of 666-15 as inhibitors of CREB-mediated gene transcription.
Design, synthesis and biological evaluation of regioisomers of 666-15 as inhibitors of CREB-mediated gene transcription.
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DOI：
10.1016/j.bmcl.2016.12.078
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发表时间：
2017-02-15
影响因子：
2.7
通讯作者：
Xiao X
中科院分区：
文献类型：
--
作者：
Xie F;Li BX;Xiao X
cAMP-反应元件结合蛋白（CREB）是一种核转录因子，其与各种类型的人类癌症的发病机制和维持有关。CREB介导的基因转录的小分子抑制剂的鉴定已经作为开发癌症治疗剂的新策略而被追求。我们最近发现了一种有效的细胞渗透性CREB抑制剂666-15。666-15是一种双萘酰胺，已显示具有有效的抗乳腺癌活性，而在体内没有毒性。在本研究中，我们设计并合成了一系列666-15的类似物，以探索萘环B上区域化学的重要性。这些类似物的生物学评价表明，萘环B中烷氧基和羧酰胺的取代模式对于维持有效的CREB抑制活性是非常关键的，这表明666-15中可获得的独特生物活性构象是至关重要的。
cAMP-response element binding protein (CREB) is a nuclear transcription factor that has been implicated in the pathogenesis and maintenance of various types of human cancers. Identification of small molecule inhibitors of CREB-mediated gene transcription has been pursued as a novel strategy for developing cancer therapeutics. We recently discovered a potent and cell-permeable CREB inhibitor called 666-15. 666-15 is a bisnaphthamide and has been shown to possess efficacious anti-breast cancer activity without toxicity in vivo. In this study, we designed and synthesized a series of analogs of 666-15 to probe the importance of regiochemistry in naphthalene ring B. Biological evaluations of these analogs demonstrated that the substitution pattern of the alkoxy and carboxamide in naphthalene ring B is very critical for maintaining potent CREB inhibition activity, suggesting that the unique bioactive conformation accessible in 666-15 is critically important.