Radical Ring Expansion Reactions on Solid support

该项目的目标是开发一种用于组合化学的新型无迹连接体。在建立一些基础化学包括头孢菌素D的合成之后，我们将寻求合成一个小的拟肽抑制剂文库，这些抑制剂将针对各种酶靶点进行筛选，如ras-法尼基转移酶（涉及癌症）、组织蛋白酶D（肿瘤转移）、血管紧张素转换酶（高血压）、中性内肽酶（充血性心力衰竭）和凝血酶（止血和凝血）。合成过程中的关键事件是在固体载体上发生自由基扩环反应，同时从树脂中释放出所需的抑制剂。自由基反应在溶液化学中已成为一种强有力的选择，但相对而言，人们对固体载体上的自由基反应知之甚少。我们的项目将在这方面提供有用的见解。幸运的是，自由基裂解步骤中可能出现的副反应不会影响所需抑制剂的纯度，从而保证了生物学筛选中有意义的结果。

The goal of this project is to develop a novel traceless linker for use in combinatorial chemistry. Afer establishing some basic chemistry including the synthesis of cephalosporolide D, we will seek to synthesize a small library of peptidomimetic inhibitors that will be screened against a variety of enzyme targets, such as ras-farnesyl transferase (involved in cancer), cathepsin D (tumor metastasis), angiotensin converting enzyme (hypertension), neutral endopeptidase (congestive heart failure) and thrombin (hemostasis and blood clotting). The key event in the synthesis will be a radical ring-expansion reaction on solid support that simultaneously releases the desired inhibitors from the resin. Radical reactions have emerged as powerful options in solution-phase chemistry, but comparatively little is known about radical reactions on solid support. Our project will provide useful insights in this area. Fortunately, possible side reactions in the radical cleavage step should not compromise the purity of the desired inhibitors, thus guaranteeing meaningful results in the biological screening.