Synthesis and Chemical Biology of Bioactive Guanidine Alkaloids

生物活性胍生物碱的合成及化学生物学

• 批准号: 9030257
• 负责人: Joshua G. Pierce
• 金额: $ 26.77万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9030257
• 关键词: Action Potentials; Alkaloids; Area; Biological; Biology; Biomimetics; Cancer cell line; Chemical Structure; Chemicals; Complex; Coupling; Development; Disease; Esters; Evaluation; Family; Fatty Acids; Goals; Guanidines; Health; Human; Lead; Methods; Mission; Modeling; Natural Products; Plug-in; Polyamines; Porifera; Post-Translational Protein Processing; Preparation; Property; Proteins; Public Health; Reaction; Recording of previous events; Reporting; Research; Role; Route; Scheme; Side; Signal Pathway; Signal Transduction; Source; Spermidine; Structure; Structure-Activity Relationship; Synthesis Chemistry; Therapeutic; Tumor Cell Line; United States National Institutes of Health; Ursidae Family; Work; analog; cancer therapy; chemical synthesis; cytotoxic; drug development; flexibility; follow-up; hemiketal; human disease; in vivo; interest; marine natural product; member; morpholine; novel; protein profiling; research study; scaffold; stereochemistry

 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.

 描述（由适用提供）：该提案描述了对海洋天然产品的蒙乔奇素家族的综合和进一步研究。 Monanchocidins具有新颖的化学结构和潜在的生物学活性，使其成为化学合成的理想靶标。此外，单鼠毒素对相关的人类癌细胞系有效，并且相关的天然产物活跃于多种疾病，从而充当化学问题和/或治疗的发展的铅化合物。尚未报道对Monanchocidins的合成通道，并且几乎没有了解其生物靶标。拟议的研究的目的是为五边形鸟选择生物碱开发一种可扩展且方便的方法，并将这种合成方案应用于Monanchocidins和相关的天然产品。我们计划通过将线性前体的简洁合成和不对称合成与仿生鸟嘌呤形成的级联反应相结合来实现这一目标。还针对了构成天然产物东部的大量氧化的吗啡杂环的立体选择性合成。与我们的合成努力同时，我们正在研究自然产品碎片的生物学活性，并且已经揭示了有趣的特性。我们计划将这些支架推向多胺信号通路和体内蛋白质修饰的潜在和选择性化学问题。我们预计我们的努力将在合成化学和化学生物学方面取得重大进步，并揭示了化学问题发展的理性途径。