Faculty of Pharmacy, Department of Pharmaceutical Chemistry, University of Ljubljana, Askerceva 7, Ljubljana 1000, Slovenia.
Bioconjug Chem. 2023 Jul 19;34(7):1271-1281. doi: 10.1021/acs.bioconjchem.3c00163. Epub 2023 Jun 24.
The binucleophilic properties of 1,2-aminothiol and its rare occurrence in nature make it a useful reporter for tracking molecules in living systems. The 1,2-aminothiol moiety is present in cysteine, which is a substrate for a biocompatible click reaction with heteroaromatic nitriles. Despite the wide range of applications for this reaction, the scope of nitrile substrates has been explored only to a limited extent. In this study, we expand the chemical space of heteroaromatic nitriles for bioconjugation under physiologically relevant conditions. We systematically assembled a library of 116 2-cyanobenzimidazoles, 1-methyl-2-cyanobenzimidazoles, 2-cyanobenzothiazoles, and 2-cyanobenzoxazoles containing electron-donating and electron-withdrawing substituents at all positions of the benzene ring. The compounds were evaluated for their stability, reactivity, and selectivity toward the N-terminal cysteine of model oligopeptides. In comparison to the benchmark 6-hydroxy-2-cyanobenzothiazole or 6-amino-2-cyanobenzothiazole, we provide highly selective and moderately reactive nitriles as well as highly reactive yet less selective analogs with a variety of enabling attachment chemistries to aid future applications in bioconjugation, chemical biology, and nanomaterial science.
1,2-氨硫醇的双亲核性质及其在自然界中的稀有性使其成为跟踪活体系中分子的有用报告分子。1,2-氨硫醇部分存在于半胱氨酸中，半胱氨酸是与杂芳族腈发生生物相容点击反应的底物。尽管该反应的应用范围很广，但腈底物的范围仅在有限的程度上得到了探索。在这项研究中，我们在生理相关条件下扩展了用于生物偶联的杂芳族腈的化学空间。我们系统地组装了一个包含电子供体和电子受体取代基的 116 个 2-氰基苯并咪唑、1-甲基-2-氰基苯并咪唑、2-氰基苯并噻唑和 2-氰基苯并恶唑的文库，这些取代基位于苯环的所有位置。评估了这些化合物在模型寡肽的 N 端半胱氨酸处的稳定性、反应性和选择性。与基准 6-羟基-2-氰基苯并噻唑或 6-氨基-2-氰基苯并噻唑相比，我们提供了高选择性和适度反应性的腈以及高反应性但选择性较低的类似物，这些类似物具有多种有效的连接化学，以辅助未来在生物偶联、化学生物学和纳米材料科学中的应用。
