Total Synthesis/Chloropeptin l/Anti-HIV Natural Product

全合成/氯肽素l/抗HIV天然产物

• 批准号: 6740708
• 负责人: JEROMY J COTTELL
• 金额: $ 4.11万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-16 至 2006-07-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6740708
• 关键词: HIV envelope protein gp120; HIV infections; antiAIDS agent; biological products; chemical structure function; chemical synthesis; drug design /synthesis /production; enzyme inhibitors; human immunodeficiency virus; inhibitor /antagonist; integrase; oligopeptides; postdoctoral investigator; protein binding; stereoisomer

DESCRIPTION (provided by applicant): Chloropeptin I is a representative member of a class of macrocyclic peptides that show potent anti-HIV activity. Specifically, chloropeptin I shows micromolar inhibition of both gp120 binding and of HIV-integrase. Both of these actions represent underdeveloped areas in current HIV therapy, and therefore chloropeptin I warrants further investigation for possible drug development. This proposal outlines the enantioselective synthesis of chloropeptin I to unambiguously prove its structure and configuration. The approach will focus on the construction of the two macrocycles via macrolactamization, followed by radical cyclization, and by intramolecular nucleophilic aromatic substitution. Upon the completion of an efficient and scalable synthesis, chloropeptin analogs can be prepared with minimal alteration of the synthetic route. Access to these derivative will allow investigation of the structure activity relationship of chloropeptin I, in an effort to develop more effective inhibitors.

描述（由申请人提供）：氯肽素 I 是一类大环肽的代表成员，具有有效的抗 HIV 活性。具体而言，氯肽 I 对 gp120 结合和 HIV 整合酶均具有微摩尔抑制作用。这两种作用都代表了当前 HIV 治疗中尚未开发的领域，因此氯肽 I 值得进一步研究以进行可能的药物开发。 该提案概述了氯肽 I 的对映选择性合成，以明确证明其结构和构型。该方法将重点关注通过大环内酰胺化、随后自由基环化和分子内亲核芳香取代来构建两个大环。 在完成有效且可扩展的合成后，可以通过对合成路线进行最小的改变来制备氯肽素类似物。获得这些衍生物将有助于研究氯肽素 I 的结构活性关系，以开发更有效的抑制剂。