Just-Baringo Xavier, Bruno Paolo, Pitart Cristina, Vila Jordi, Albericio Fernando, Álvarez Mercedes
Institute for Research in Biomedicine, Barcelona Science Park, University of Barcelona , Baldiri Reixac 10, 08028 Barcelona, Spain.
J Med Chem. 2014 May 22;57(10):4185-95. doi: 10.1021/jm500062g. Epub 2014 Apr 30.
Several analogues of baringolin (1) were prepared to evaluate the role of its characteristic thiazoline ring and pentapeptidic tail with the aim of defining structure-activity relationships for these moieties. The thiazoline ring appeared as a crucial moiety to maintain a broad scope of activities against different Gram-positive bacteria. Further modifications were performed to simplify the structure of the natural product and assess the role of its tail, resulting in an enhanced in vitro performance. Analogue 25, with the thiazole-containing macrocycle and a 4-aminocyclohexane-1-carboxylic acid moiety in place of the pentapeptidic tail, was identified as a much more potent analogue, capable of overcoming the absence of the thiazoline ring and performing extraordinarily well against all strains tested. This is the first library of thiopeptide analogues produced by chemical synthesis alone, which demonstrates the robustness and convenience of the synthetic strategy used.
制备了几种巴林戈林（1）的类似物，以评估其特征性噻唑啉环和五肽尾部的作用，目的是确定这些部分的构效关系。噻唑啉环似乎是维持对不同革兰氏阳性菌广泛活性的关键部分。进行了进一步的修饰以简化天然产物的结构并评估其尾部的作用，从而提高了体外性能。类似物25，含有含噻唑的大环和4-氨基环己烷-1-羧酸部分代替五肽尾部，被鉴定为一种更有效的类似物，能够克服噻唑啉环的缺失并对所有测试菌株表现出非凡的效果。这是第一个仅通过化学合成产生的硫肽类似物文库，证明了所使用合成策略的稳健性和便利性。
