COMBINATORIAL CYCLODEPSIPEPTIDE LIBRARIES FROM DIDEMNINS

该项目的总体目标是优化固有的 didemnins的细胞毒性、抗病毒和免疫调节活性 并最终开发出治疗癌症的新药， 感染和免疫紊乱。 在第一阶段，新的固相 Didemnin A的合成及其环化-裂解的新方法 将从固体载体中开发该化合物。 这种方法 然后将用于合成小的环缩酚肽文库。 最终，这些组合化学技术将被用来 产生大量不同的环缩肽文库， 筛选有用的生物活性。 在这些微珠中识别的微珠 屏幕将用于设计后续的重点库，以便 进一步优化有用的生物活性。 合适的候选人将接受 与制药公司合作进行进一步的测试和开发 搭档 拟议的商业应用：治疗癌症的新疗法，病毒 感染和免疫紊乱的治疗。Didemnins代表 这些疾病类别中有价值的线索。拟议 技术将极大地促进活性化合物的研究， 结构上与didemnins相关。此外，这些方法 所开发的方法应适用于其他环肽和缩肽 不同的环大小和序列，用于识别药物， 其它疾病

The overall goal of this project is to optimize the inherent cytotoxicity, antiviral, and immunomodulatory activity of the didemnins and eventually develop new drugs for the treatment of cancer, viral infections, and immune disorders. In Phase I, a new solid-phase synthesis of didemnin A and a new method for the cyclization-cleavage of this compound from the solid support will be developed. This methodology will then be used to synthesize a small cyclodepsipeptide library. Eventually, these combinatorial chemistry techniques will be utilized to generate large diverse libraries of cyclodepsipeptides which will be screened for useful bioactivity. beads which are identified in these screens will be used to design subsequent focused libraries, so as to further optimize useful bioactivity. Suitable candidates would undergo further testing and development in collaboration with a pharmaceutical partner. PROPOSED COMMERCIAL APPLICATION: New therapies to treat cancer, viral infections, and immune disorders are urgently needed. Didemnins represent valuable leads in each of these disease categories. The proposed technology would greatly facilitate the search for active compounds structurally related to the didemnins. In addition, the methods being developed should be applicable to other cyclic peptides and depsipeptides of varying ring size and sequence for the identification of drugs for other diseases.