COMBINATORIAL CYCLODEPSIPEPTIDE LIBRARIES FROM DIDEMNINS

这个项目的总体目标是优化固有的 白粉菌素的细胞毒性、抗病毒和免疫调节活性 并最终开发出治疗癌症的新药，病毒 感染和免疫紊乱。在第一阶段，一种新的固相 白粉菌素A的合成及环化-裂解新方法 这种由固体载体制成的化合物将被开发出来。这种方法论 然后将其用于合成一个小的环磷酰胺多肽文库。 最终，这些组合化学技术将被用于 产生大量不同的环肽文库，这些文库将被 筛选出有用的生物活性。在这些中识别出的珠子 屏幕将用于设计后续的聚焦图库，以便 进一步优化有益生物活性。合适的候选人将经历 与一家制药公司合作进一步测试和开发 搭档。 拟议的商业应用：治疗癌症和病毒的新疗法 感染和免疫紊乱是迫切需要的。Didemnins代表 这些疾病类别中的每一种都有有价值的线索。建议数 技术将极大地便利寻找活性化合物 在结构上与敌百虫有关。此外，这些方法是 所开发的方法应适用于其他环肽和多肽。 不同的环大小和序列用于药物的鉴定 其他疾病。

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.