ACS Chem Biol. 2011 Nov 18;6(11):1175-81. doi: 10.1021/cb2002686. Epub 2011 Sep 28.
Natural products are essential tools for basic cellular studies leading to the identification of medically relevant protein targets and the discovery of potential therapeutic leads. The development of methods that enable mild and selective derivatization of natural products continues to be of significant interest for mining their information-rich content. Herein, we describe novel diazo reagents for simultaneous arming and structure-activity relationship (SAR) studies of alcohol-containing natural products with a small steric footprint, namely, an α-trifluoroethyl (HTFB) substituted reagent. The Rh(II)-catalyzed O-H insertion reaction of several natural products, including the potent translation inhibitor lactimidomycin, was investigated, and useful reactivity and both chemo- and site (chemosite) selectivities were observed. Differential binding to the known protein targets of both FK506 and fumagillol was demonstrated, validating the advantage of the smaller steric footprint of α-trifluoroethyl derivatives. A p-azidophenyl diazo reagent is also described that will prove useful for photoaffinity labeling of low affinity small molecule protein receptors.
天然产物是基础细胞研究的重要工具，可用于鉴定与医学相关的蛋白质靶标和发现潜在的治疗先导化合物。开发温和、选择性的天然产物衍生化方法，继续挖掘其富含信息的内容，仍然是人们关注的焦点。本文描述了新型重氮试剂，用于含有小空间位阻的醇类天然产物的同时武装和构效关系（SAR）研究，即α-三氟乙基（HTFB）取代的试剂。研究了几种天然产物，包括强效翻译抑制剂乳霉素，的 Rh(II)催化的 O-H 插入反应，观察到了有用的反应性和化学及位点（化学位）选择性。对已知 FK506 和呋咱霉素的蛋白质靶标的差异结合进行了验证，证明了α-三氟乙基衍生物较小空间位阻的优势。还描述了一种对-叠氮苯重氮试剂，它将证明对低亲和力小分子蛋白质受体的光亲和标记有用。
