通过释放应变的环丙烯酮共轭加成，快速不可逆地修饰半胱氨酸。
Fast, irreversible modification of cysteines through strain releasing conjugate additions of cyclopropenyl ketones.
机构信息
Brown Laboratories, Department of Chemistry and Biochemistry, University of Delaware, Newark, DE 19716, USA.
Departments of Chemical and Biomolecular Engineering and Materials Science and Engineering, University of Delaware, Newark, DE 19716, USA.
出版信息
Org Biomol Chem. 2018 Mar 28;16(12):2164-2169. doi: 10.1039/c8ob00166a. Epub 2018 Mar 9.
A method of cysteine alkylation using cyclopropenyl ketones is described. Due to the significant release of cyclopropene strain energy, reactions of thiols with cyclopropenyl ketones are both fast and irreversible and give rise to stable conjugate addition adducts. The resulting cyclopropenyl ketones have a low molecular weight and allow for simple attachment of amides via N-hydroxysuccinimide (NHS)-esters. While cyclopropenyl ketones do display slow background reactivity toward water, labeling by thiols is much more rapid. The reaction of a cyclopropenyl ketone with glutathione (GSH) proceeds with a rate of 595 M s in PBS at pH 7.4, which is considerably faster than α-halocarbonyl labeling reagents, and competitive with maleimide/thiol couplings. The method has been demonstrated in protein conjugation, and an arylthiolate conjugate was shown to be stable upon prolonged incubation in either GSH or human plasma. Finally, cyclopropenyl ketones were used to create PEG-based hydrogels that are stable to prolonged incubation in a reducing environment.
本文描述了一种利用环丙烯酮进行半胱氨酸烷基化的方法。由于环丙烯张力能的显著释放，硫醇与环丙烯酮的反应既快速又不可逆，并生成稳定的共轭加成加合物。所得的环丙烯酮具有低分子量，并允许通过 N-羟基琥珀酰亚胺（NHS）酯简单地连接酰胺。虽然环丙烯酮确实对水显示出缓慢的背景反应性，但硫醇的标记速度要快得多。环丙烯酮与谷胱甘肽（GSH）的反应在 pH 7.4 的 PBS 中的速率为 595 M s-1，这比α-卤代羰基标记试剂快得多，与马来酰亚胺/硫醇偶联相当。该方法已在蛋白质偶联中得到验证，芳基硫醇缀合物在 GSH 或人血浆中长时间孵育时表现出稳定。最后，环丙烯酮被用于构建 PEG 基水凝胶，该水凝胶在还原环境中长时间孵育时稳定。
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