BIOLOGICALLY ACTIVE CYCLIC PEPTIDES

生物活性环肽

• 批准号: 6095263
• 负责人: DALE L BOGER
• 金额: $ 35.9万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-07-01 至 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6095263
• 关键词: DNA binding protein; alkylation; antineoplastic antibiotics; chemical binding; chemical structure function; crosslink; cyclic peptides; cyclization; cytotoxicity; drug design /synthesis /production; enzyme inhibitors; glycopeptides; peptide analog; peptide chemical synthesis; peptide library; quinoline analog; reverse transcriptase inhibitors; stereochemistry; telomerase; tyrosine; vancomycin

Studies on the total synthesis of the glycopeptide antibiotics vancomycin, teicoplanin, chloropeptins, RP-66453, ramoplanin, and their key partial structures, analogs, and analog libraries are detailed. Their comparative examination may shed further light on the subtle aspects of their site and mechanism of action, identify the role and importance of their structural features, probe engineered structural changes introduced to address the emerging clinical resistance (binding to L-Lys-D-Ala-D-Lac vs L-Lys-D- Ala-D-Ala), and should identify simpler structures with improved properties. Similarly, details of proposed total syntheses of thiocoraline and BE-22179, C2- symmetric cyclic octadepsipeptides possessing two pendant heterocyclic chromophores which are related to sandramycin, the luzopeptins, and quinoxapeptins and which derive their properties through sequence selective DNA bisintercalation, are presented. The definition of the DNA binding properties and biological properties of thiocoraline and BE-22179, key partial structures, and analogs will be conducted as will be a continuation of analogous studies on the luzopeptins and quinoxapeptins. Additionally, plans for the preparation of libraries of analogs of HUN-7293 are detailed to probe and optimize its structural features responsible for inhibition of cell adhesion molecule expression (VCAM-1) and the resultant anti-inflammatory activity and activity in autoimmune diseases.

详细介绍了糖肽抗生素万古霉素、替考拉宁、氯肽、RP-66453、雷莫拉宁的全合成及其关键部分结构、类似物和类似物库。他们的比较检查可能会进一步阐明其位点和作用机制的微妙方面，确定其结构特征的作用和重要性，探测为解决新出现的临床耐药性而引入的工程结构变化（与 L-Lys-D-Ala 结合） -D-Lac 与 L-Lys-D-Ala-D-Ala），并且应该识别具有改进性能的更简单的结构。类似地，提出了硫珊瑚啉和 BE-22179 的全合成细节，BE-22179 是具有两个悬垂杂环发色团的 C2-对称环状八缩肽，与沙霉素、luzopeptins 和 quinoxapeptins 相关，并通过序列选择性 DNA 双嵌入获得其特性。将进行 thiocoraline 和 BE-22179 的 DNA 结合特性和生物特性、关键部分结构和类似物的定义，这将是对 luzopeptins 和 quinoxapeptins 的类似研究的延续。此外，还详细制定了​​ HUN-7293 类似物文库的制备计划，以探测和优化其负责抑制细胞粘附分子表达（VCAM-1）以及由此产生的抗炎活性和自身免疫性疾病活性的结构特征。