Synthesis and Chemical Biology of Bioactive Guanidine Alkaloids

 描述（由申请人提供）：本提案描述了海洋天然产物单胞杀菌素家族的合成和进一步研究。单胞菌素具有新颖的化学结构和强大的生物活性，使其成为化学合成的理想目标。此外，单胞菌素对相关的人癌细胞系具有活性，并且相关的天然产物对许多疾病具有活性，从而用作开发化学探针和/或治疗剂的先导化合物。尚未报道合成获得单胞菌素的途径，对其生物靶点了解甚少。 该研究的目的是开发一种可扩展的和方便的方法来合成五环胍生物碱，并将该合成方案应用于单胞菌素和相关天然产物。我们计划实现这一目标相结合的一个简洁和不对称的合成的线性前体与仿生胍形成级联。也有针对性的立体选择性合成的一个严重氧化的吗啉杂环，构成东半部的天然产物。 在我们的合成努力的同时，我们正在研究天然产物片段的生物活性，因为它们变得可用，并且已经揭示了有趣的特性。我们计划将这些支架推进到多胺信号通路和体内蛋白质修饰的有效和选择性化学探针。我们希望我们的努力将导致合成化学和化学生物学的重大进展，并揭示合理的化学探针的发展道路。

 DESCRIPTION (provided by applicant): This proposal describes the synthesis and further study of the monanchocidin family of marine natural products. The monanchocidins have novel chemical structures and potent biological activities making them ideal targets for chemical synthesis. Further, the monanchocidins are active against relevant human cancer cell lines, and related natural products active against a number of diseases, and thereby serve as lead compounds for the development of chemical probes and/or therapeutics. Synthetic access to the monanchocidins has not yet been reported and little is understood regarding their biological targets. The objective of the proposed research is to develop a scalable and expedient approach to the pentacyclic guanidine alkaloids and apply this synthetic scheme to the monanchocidins and related natural products. We plan to achieve this goal by combining a concise and asymmetric synthesis of a linear precursor with a biomimetic guanidine-forming cascade. A stereoselective synthesis of a heavily oxidized morpholine heterocycle that constitutes the eastern half of the natural products is also targeted. In parallel to our syntheti efforts we are investigating the biological activity of the natural product fragments as they become available and have already revealed interesting properties. We plan to advance these scaffolds to potent and selective chemical probes for polyamine signaling pathways and for in-vivo protein modification. We expect that our efforts will lead to significant advances in both synthetic chemistry and chemical biology and reveal rational paths forward for the development of chemical probes.