Fenner Amanda M, Oppegard Lisa M, Hiasa Hiroshi, Kerns Robert J
Division of Medicinal and Natural Products Chemistry, Department of Pharmaceutical Sciences and Experimental Therapeutics, University of Iowa, Iowa City, IA 52242, USA.
ACS Med Chem Lett. 2013 May 9;4(5):470-474. doi: 10.1021/ml3004507.
Numerous therapeutic applications have been proposed for molecules that bind heparin-binding proteins. Development of such compounds has primarily focused on optimizing the degree and orientation of anionic groups on a scaffold, but utility of these polyanions has been diminished by their typically large size and non-specific interactions with many proteins. In this study -arylacyl sulfonated aminoglycosides were synthesized and evaluated for their ability to selectively inhibit structurally similar bacterial and human topoisomerases. It is demonstrated that the structure of the aminoglycoside and of the arylacyl moiety imparts selective inhibition of different topoisomerases and alters mechanism. The results here outline a strategy that will be applicable to identifying small, structurally defined oligosaccharides that bind heparin-binding proteins with a high degree of selectivity.
对于能够结合肝素结合蛋白的分子，人们已经提出了许多治疗应用。这类化合物的开发主要集中在优化支架上阴离子基团的程度和方向，但是这些聚阴离子的效用因其通常较大的尺寸以及与许多蛋白质的非特异性相互作用而降低。在本研究中，合成了-芳基酰基磺化氨基糖苷，并评估了它们选择性抑制结构相似的细菌和人类拓扑异构酶的能力。结果表明，氨基糖苷和芳基酰基部分的结构赋予了对不同拓扑异构酶的选择性抑制，并改变了作用机制。此处的结果概述了一种策略，该策略将适用于鉴定能够高度选择性结合肝素结合蛋白的结构明确的小寡糖。
