Shaw E, Angliker H, Rauber P, Walker B, Wikstrom P
Biomed Biochim Acta. 1986;45(11-12):1397-403.
The fluoromethyl ketone derivatives of peptides are now available through several synthetic approaches and can be examined with respect to their properties as protease inhibitors. It had been expected that the fluoro atom might be too inert for nucleophilic displacement and that irreversible inactivation might not be achievable by this type of derivative in contrast to chloromethyl ketones. However, with serine and cysteinyl proteases, alkylation of the enzyme does take place although the rates are not similar to those of the chloromethyl ketones. Of the two classes, thiol proteases are more readily inactivated and the fluoromethyl ketones are almost as effective as the chloromethyl ketones. Our observations confirm and extend those of Rasnick (Anal. Biochem. 149, 461-465 (1985)). The structure of the peptidyl portion of the reagent controls specificity of inhibition in the typical manner of affinity-labels for proteases. However, fluoromethyl ketones are considerably less reactive to nucleophiles such as the thiol group of glutathione, than chloromethyl ketones and, therefore, this new class of inhibitors may provoke fewer side reactions when used in biological studies.
现在可以通过几种合成方法获得肽的氟甲基酮衍生物，并可以对其作为蛋白酶抑制剂的性质进行研究。人们曾预期氟原子对于亲核取代可能过于惰性，与氯甲基酮相比，这类衍生物可能无法实现不可逆失活。然而，对于丝氨酸和半胱氨酸蛋白酶，酶的烷基化确实会发生，尽管反应速率与氯甲基酮不同。在这两类中，硫醇蛋白酶更容易失活，氟甲基酮几乎与氯甲基酮一样有效。我们的观察结果证实并扩展了拉斯尼克的观察结果（《分析生物化学》149, 461 - 465 (1985)）。试剂肽基部分的结构以蛋白酶亲和标记的典型方式控制抑制的特异性。然而，氟甲基酮对亲核试剂（如谷胱甘肽的硫醇基团）的反应性比氯甲基酮低得多，因此，这类新型抑制剂在生物学研究中使用时可能引发较少的副反应。
