Novel Routes to Cyclic Peptide Cytochalasin Analogs

描述（由申请人提供）：拟议的研究围绕着一组环肽细胞松弛素类似物的合成，利用一种新颖的、非对对选择性的、硅系系的Diels-Alder环加成来构建该天然产物家族中普遍存在的异吲哚酮核心单元。细胞松弛素骨架的简易方法为细胞松弛素文库的合成提供了基础。为了证明这种方法的有效性，核心支架将首先被操纵到已知的生物活性物质，细胞松弛素B. .这将是本研究的最终目标，利用核心结构生产新的环状肽细胞松弛素类似物，使用多样性导向的方法。所产生的分子有能力作为细胞松弛素-细胞膜相互作用的探针，也有可能在癌症和艾滋病研究等领域成为具有重要生物学意义的化合物。这种方法也显示了合成的收敛性，因为从一个核心单元可以生成无数的细胞松弛素支架。最后，本研究适用于固相，将利用闭环烯烃复分解环释放策略在细胞松弛素库合成中得到利用。

DESCRIPTION (provided by applicant): The proposed research centers around the syntheses of an array of cyclic peptide cytochalasin analogs exploiting a novel, diastereoselective, silicon-tethered Diels-Alder cycloaddition toward the construction of the isoindolone core unit prevalent in this family of natural products. The facile approach to the cytochalasin skeleton provides the base for cytochalasin library synthesis. To prove the efficacy of this methodology, the core scaffold will initially be manipulated toward the known bioactive agent, cytochalasin B. It will be the ultimate goal of this research to utilize the core structure toward the production of novel cyclic peptide cytochalasin analogs using a diversity oriented approach. The molecules produced have the ability to serve as probes into cytochalasin-cell membrane interactions as well as have potential as biologically important compounds in areas such as cancer and AIDS research. This method also displays synthetic convergence, as a myriad of cytochalasin scaffolds can be generated from a single core unit. Finally, this research is amenable to the solid phase, which will be exploited in a cytochalasin library synthesis utilizing a ring-closing olefin metathesis cyclorelease strategy.