Examining the structure-activity relationship of benzopyran-based inhibitors of the hypoxia inducible factor-1 pathway.
Examining the structure-activity relationship of benzopyran-based inhibitors of the hypoxia inducible factor-1 pathway.
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DOI：
10.1016/j.bmcl.2017.02.073
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发表时间：
2017-04-15
影响因子：
2.7
通讯作者：
Wang B
中科院分区：
文献类型：
--
作者：
Ferguson J;De Los Santos Z;Devi N;Van Meir E;Zingales S;Wang B
许多形式的实体瘤都有一个被称为缺氧的特征，它描述了细胞微环境中低氧或不存在氧的存在。氧气的减少导致缺氧诱导因子（HIF）通路的激活，该通路激活许多基因的转录，导致细胞增殖、转移、糖酵解增加和血管生成。HIF表达增加与患者预后不良、恶性肿瘤增加和治疗耐药性有关。我们实验室之前的工作已经确定了1和2是HIF途径的抑制剂，特别是作为p300-HIF-1α复合物形成的干扰物。设计并合成了一个磺胺类似物文库，目的是检测该系列化合物的合成孔径（SAR），并与先导化合物1和2相比，提高其效价和理化性质。最后，我们对未来优化工作至关重要的结构特征有了透彻的了解。爱思唯尔有限公司版权所有。
Many forms of solid tumor have a characteristic feature known as hypoxia, which describes a low or non-existent presence of oxygen in the cellular microenvironment. This decrease in oxygen causes activation of the hypoxia inducible factor (HIF) pathway, which activates the transcription of many genes that cause cell proliferation, metastasis, increased glycolysis and angiogenesis. Increased HIF expression has been linked with poor patient prognosis, increased malignancy, and therapeutic resistance. Previous work in our lab has identified 1 and 2 as inhibitors of the HIF pathway, specifically as disrupters of the p300-HIF-1α complex formation. A library of sulfonamide analogs has been designed and synthesized with the intent of examining the SAR of this series of compounds and improving potency and physicochemical properties as compared with lead compounds 1 and 2. At the end, we have achieved a thorough understanding of the structural features critical for future optimization work. 2009 Elsevier Ltd. All rights reserved.