Melville Laboratory for Polymer Synthesis, Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW Cambridge, U.K.
Bioconjug Chem. 2023 Dec 20;34(12):2302-2310. doi: 10.1021/acs.bioconjchem.3c00424. Epub 2023 Nov 23.
Thiolactones (TL) can be readily incorporated into polymeric materials and have been extensively used as a ligation strategy despite their limited reactivity toward amine-containing substrates. Comparatively, iminiumthiolactones (ITL) are much more reactive, yet to this day, only the nonsubstituted ITL known as Traut's reagent is commercially available and used. In this work, we advance current TL/ITL chemistry by introducing reactive side groups to the ITL heterocycle in the γ-position, which can be orthogonally modified without affecting the ITL heterocycle itself. To study the reactivity of γ-functional ITLs, we subject one of our derivatives (γ-allyl-functional ITL ) to model reactions with several peptides and a chosen protein (lysozyme C). Using mild reaction conditions, we successfully demonstrate that the γ-functional ITL exhibits orthogonal and enhanced reactivity in a single or double modification while introducing a new functional handle to the biological substrate. We believe that γ-functional ITLs will advance the original Traut chemistry and open promising opportunities for the bioconjugation of biological building blocks to existing functional molecules, polymers, and materials.
硫内酯 (TL) 可以很容易地掺入聚合物材料中，并被广泛用作连接策略，尽管它们对含胺的底物的反应性有限。相比之下，亚胺硫内酯 (ITL) 的反应性要强得多，但迄今为止，只有被称为 Traut 试剂的未取代 ITL 在商业上是可用的和使用的。在这项工作中，我们通过在 ITL 杂环的 γ-位引入反应性侧基来推进当前的 TL/ITL 化学，这些侧基可以在不影响 ITL 杂环本身的情况下进行正交修饰。为了研究 γ-功能化 ITL 的反应性，我们将我们的一种衍生物（γ-烯丙基功能化 ITL）用于与几种肽和一种选定的蛋白质（溶菌酶 C）的模型反应。使用温和的反应条件，我们成功地证明了 γ-功能化 ITL 在单或双修饰时表现出正交和增强的反应性，同时为生物底物引入了新的功能基团。我们相信，γ-功能化 ITL 将推进原始的 Traut 化学，并为将生物构建块与现有功能分子、聚合物和材料进行生物偶联开辟有希望的机会。
