Stereochemical promiscuity in artificial transcriptional activators
Stereochemical promiscuity in artificial transcriptional activators
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DOI：
10.1021/ja0536567
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发表时间：
2005-09-14
影响因子：
15
通讯作者：
Mapp, AK
中科院分区：
文献类型：
--
作者：
Buhrlage, SJ;Brennan, BB;Mapp, AK
转录激活结构域的小分子替代是非常理想的靶标，因为它们作为机械工具的实用性及其对多种人类疾病的长期治疗潜力。在这里，我们检查了两亲性异恶唑烷仅在组成侧链的位置上有所不同作为转录激活结构域的能力。结果表明，转录功能不需要在构象受限的小分子支架内精确定位功能基团；相反，支架内极性和疏水性的平衡是转录功能更重要的决定因素。这表明，许多不同的有机分子支架在适当功能化时应充当转录激活剂结构域，这一假设目前正在研究中。
Small molecule replacements of transcriptional activation domains are highly desirable targets due to their utility as mechanistic tools and their long-term therapeutic potential for a variety of human diseases. Here, we examine the ability of amphipathic isoxazolidines differing only in the placement of constituent side chains to function as transcriptional activation domains. The results reveal that precise positioning of functional groups within a conformationally constrained small molecule scaffold is not required for transcription function; rather, the balance of polarity and hydrophobicity within the scaffold is the more important determinant of transcription function. This suggests that a number of different organic molecule scaffolds should function as transcriptional activator domains when appropriately functionalized, a hypothesis currently under investigation.