DIDEMNINS--SYNTHETIC STUDIES AND MECHANISM OF ACTION

Didemnins--综合研究和作用机制

• 批准号: 2894635
• 负责人: MADELEINE M JOULLIE
• 金额: $ 25.9万
• 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/2894635
• 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.

地德明是具有免疫抑制、抗病毒和抗肿瘤活性的环缩酚肽。 和抗肿瘤活性。 最有效的同源物具有特殊的 抗增殖效力（IC 50 = 1- 10 nM），具有完整的细胞活力。 的 生物活性的机制基础仍然是 不确定;然而，据信，didemnins发挥其作用， 通过与其他免疫抑制剂不同的机制， 药物如环孢菌素A、FK-506或雷帕霉素。 该项目旨在研究和澄清结构和机制 生物学特性的基础上。 主要目标是 具有系统结构新颖的地德明类似物的合成 修改. 这些类似物的测试将允许进一步的 建立构效关系（SAR）谱。 的 第二个目标是全合成didemnin同系物， 最近报道。 这些新化合物的合成路线将允许 进行生物学测试和探索其药用潜力 剂. 第三个目标是制备供研究用的合成地德明 外部合作者。 这些调查将集中在 生物活性的地德明类似物的构象研究， 衍生物，以及didemnins和受体之间的相互作用 proteins. 总之，这项研究旨在研究生物学 活性的didemnin环缩酚酸肽通过一个程序， 化学合成和生物学评价。 在结构和 围绕有效抗增殖和抗肿瘤的机制问题 didemnins的活动已经澄清，将有可能 更彻底地评估这个天然家族的药用潜力 产品.