Department of Chemistry , University of Connecticut , 55 N. Eagleville Road, U3060 , Storrs , Connecticut 06269 , United States.
Department of Molecular & Cellular Biology , University of Connecticut , 91 N. Eagleville Road, U3125 , Storrs , Connecticut 06269 , United States.
ACS Comb Sci. 2019 Mar 11;21(3):192-197. doi: 10.1021/acscombsci.8b00139. Epub 2019 Jan 15.
Many small molecule natural products with antibiotic and antiproliferative activity are adorned with a carbohydrate residue as part of their molecular structure. The carbohydrate moiety can act to mediate key interactions with the target, attenuate physicochemical properties, or both. Facile incorporation of a carbohydrate group on de novo small molecules would enable these valuable properties to be leveraged in the evaluation of focused compound libraries. While there is no universal way to incorporate a sugar on small molecule libraries, techniques such as glycorandomization and neoglycorandomization have made signification headway toward this goal. Here, we report a new approach for the synthesis of glycosylated small molecule libraries. It puts the glycosylation early in the synthesis of library compounds. Functionalized aglycones subsequently participate in chemoselective diversification reactions distal to the carbohydrate. As a proof-of-concept, we prepared several desosaminyl glycosides from only a few starting glycosides, using click cycloadditions, acylations, and Suzuki couplings as diversification reactions. New compounds were then characterized for their inhibition of bacterial protein translation, bacterial growth, and in a T-cell activation assay.
许多具有抗生素和抗增殖活性的小分子天然产物都被碳水化合物残基所修饰，这些残基是其分子结构的一部分。碳水化合物部分可以介导与靶标的关键相互作用，降低物理化学性质，或者两者兼而有之。在从头合成的小分子中轻易地引入糖基，可以在评估靶向化合物文库时利用这些有价值的性质。虽然没有一种通用的方法可以将糖基引入小分子文库中，但糖随机化和新糖随机化等技术已经在朝着这个目标取得显著进展。在这里，我们报告了一种合成糖基化小分子文库的新方法。它将糖基化步骤提前到文库化合物的合成中。随后，经过功能化的糖苷配基参与远离碳水化合物的化学选择性多样化反应。作为概念验证，我们仅使用点击环加成、酰化和 Suzuki 偶联等多样化反应，从少数几个起始糖苷中制备了几种去甲糖基糖苷。然后，我们对新化合物进行了细菌蛋白翻译抑制、细菌生长和 T 细胞激活测定的表征。
