Radical Ring Expansion Reactions on Solid support

固体支持物上的自由基扩环反应

• 批准号: 6340171
• 负责人: ULRICH ISERLOH
• 金额: $ 3.48万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-03-05 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6340171
• 关键词: ACE inhibitors; antineoplastics; antithrombins; carbopolycyclic compound; chemical registry /resource; chemical synthesis; combinatorial chemistry; drug design /synthesis /production; enzyme inhibitors; heterocyclic compounds; neprilysin

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.

本计画的目标是开发一种新的无痕连接子，以应用于组合化学。在建立了包括头孢菌素D的合成在内的一些基本化学之后，我们将寻求合成一个小的肽模拟物抑制剂库，该肽模拟物抑制剂库将针对各种酶靶标进行筛选，例如ras-法尼基转移酶（与癌症有关）、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）。合成中的关键事件将是固体载体上的自由基扩环反应，同时从树脂中释放出所需的抑制剂。自由基反应已经成为溶液相化学中的强有力的选择，但相对而言，对固体载体上的自由基反应知之甚少。我们的项目将在这一领域提供有益的见解。幸运的是，自由基裂解步骤中可能的副反应不应损害所需抑制剂的纯度，从而保证生物筛选中有意义的结果。