DIDEMNINS--SYNTHETIC STUDIES AND MECHANISM OF ACTION

Didemnins--综合研究和作用机制

• 批准号: 2683442
• 负责人: MADELEINE M JOULLIE
• 金额: $ 24.94万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-09-30 至 2000-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2683442
• 关键词: X ray crystallography; affinity chromatography; affinity labeling; antineoplastics; antiviral agents; biological products; circular dichroism; conformation; cyclic peptides; drug design /synthesis /production; drug receptors; immunosuppressive; molecular dynamics; oligopeptides; peptide analog; peptide chemical synthesis; photochemistry; protein structure function; receptor binding; stereochemistry

The didemnins are cyclic depsipeptides having immunosuppressive, antiviral and antitumor activities. The most potent congeners have exceptional antiproliferative potency (IC50 = 1-10nM) with intact cell viability. The mechanistic basis of the biological activities of didemnins is still uncertain; however, it is believed that didemnins exert their effects through a mechanism which is distinct from that of other immunosuppressive agents such as cyclosporin A, FK-506 or rapamycin. This project seeks to study and clarify the structural and mechanistic basis of the biological properties of the didemnins. The primary goal is the synthesis of novel didemnin analogs containing systematic structural modifications. Testing of these analogs will allow for the further development of a structure-activity relationship (SAR) profile. The second goal is the total synthesis of didemnin congeners which have been recently reported. Synthetic routes to these novel compounds will allow for biological testing and exploration of their potential as medicinal agents. The third goal is the preparation of synthetic didemnin for study by outside collaborators. These investigations will focus on conformational studies of biologically active didemnin analogs and derivatives, as well as interactions between didemnins and receptor proteins. In conclusion, this research is designed to investigate the biological activities of the didemnin cyclic depsipeptides through a program of chemical synthesis and biological evaluation. After the structural and mechanistic issues surround the potent antiproliferative and antitumor activities of didemnins have been clarified, it will be possible to evaluate more thoroughly the medicinal potential of this family of natural products.

白粉菌素是一种具有免疫抑制、抗病毒作用的环状多肽。 和抗肿瘤活性。最强大的同类者拥有特殊的 抗增殖能力(IC50=1-10 nm)，细胞活力完好。这个 粉尘草素生物活性的机制基础仍然是 不确定；然而，人们认为，敌百虫发挥其作用 通过一种与其他免疫抑制不同的机制 环孢素A、FK-506或雷帕霉素等药物。 本项目旨在研究和澄清结构和机制 了解敌百虫的生物学特性。主要目标是 含系统结构的新型白粉菌素类似物的合成 修改。对这些类似物的测试将允许进一步 开发结构-活性关系(SAR)简档。这个 第二个目标是完全合成已经被 最近报道的。通向这些新化合物的合成路线将使 用于生物测试和探索它们的药用潜力 探员们。第三个目标是制备用于研究的合成敌草胺。 由外部合作者提供。这些调查将集中在 具有生物活性的粉尘草素类似物的构象研究 衍生物以及二氢杨梅素与受体之间的相互作用 蛋白质。 综上所述，本研究旨在研究生物 通过一个程序研究二氢杨梅素环多肽的活性 化学合成和生物评价。在结构和 围绕着有效的抗增殖和抗肿瘤的机制问题 敌百虫的活性已被澄清，将有可能 更彻底地评估这种天然植物的药用潜力 产品。