Li Bohan, Zhang Zhenguo, Tio Raymond, Li Jinling, Loh Teck-Peng
College of Advanced Interdisciplinary Science and Technology, Henan University of Technology, Zhengzhou 450001, China.
Division of Chemistry and Biological Chemistry, School of Chemistry Chemical Engineering & Biotechnology, Nanyang Technological University, Singapore 637371, Singapore.
Proc Natl Acad Sci U S A. 2024 Dec 10;121(50):e2405337121. doi: 10.1073/pnas.2405337121. Epub 2024 Dec 3.
Metathesis reactions that operate cleanly and reversibly under biocompatible conditions are crucial in diverse fields such as drug development, chemical biology, and dynamic combinatorial chemistry. This paper introduces an innovative strategy using the commercially available and cost-effective hydroxy(tosyloxy)iodobenzene (HTIB) as a radical initiator, enabling clean and bidirectional disulfide metathesis under biocompatible conditions. Our method facilitates efficient forward reactions by utilizing an excess of one disulfide to shift the equilibrium toward unsymmetrical disulfides, while also ensuring clean reverse reactions by the removal of low boiling point dimethyl disulfide. Furthermore, an alternative intramolecular approach using a cyclic five- or eight-membered disulfide avoids the need for an excess of one disulfide, effectively yielding unsymmetrical disulfide molecules. The radical mechanism of this approach, validated through various control experiments and EPR analysis, enables selective and biocompatible modifications of carbohydrates, drugs, native amino acids, and proteins. This study represents a notable advancement in organic chemistry, with significant implications for biomedical sciences, especially in areas that require precise and gentle biomolecular manipulations, such as protein engineering and therapeutic development.
在生物相容性条件下能够顺利且可逆地进行的复分解反应在药物开发、化学生物学和动态组合化学等多个领域都至关重要。本文介绍了一种创新策略，使用市售且经济高效的羟基（对甲苯磺酰氧基）碘苯（HTIB）作为自由基引发剂，能够在生物相容性条件下实现干净且双向的二硫键复分解。我们的方法通过使用过量的一种二硫键来使平衡向不对称二硫键移动，从而促进高效的正向反应，同时通过去除低沸点的二甲基二硫来确保干净的逆向反应。此外，使用环状五元或八元二硫键的另一种分子内方法避免了对过量一种二硫键的需求，有效地生成了不对称二硫键分子。通过各种对照实验和电子顺磁共振分析验证的这种方法的自由基机制，能够对碳水化合物、药物、天然氨基酸和蛋白质进行选择性且生物相容性的修饰。这项研究代表了有机化学领域的一项显著进展，对生物医学科学具有重要意义，尤其是在需要精确且温和的生物分子操作的领域，如蛋白质工程和治疗开发。
