Synthesis and Biological Evaluation of Alkylpiperidine Arenosclerin A.

烷基哌啶Arenosclerin A的合成及生物学评价。

• 批准号: 10183273
• 负责人: Jade Charmaine Williams
• 金额: $ 2万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10183273
• 关键词: Acids; Agar; Alkaloids; Anti-Bacterial Agents; Antibiotic Resistance; Antifungal Agents; Antimalarials; Biological; Biological Models; Cancer cell line; Clinical; Coupling; Data; Development; Diels Alder reaction; Diffusion; Evaluation; Family; Family member; Future; Genomics; Goals; Gram-Negative Bacteria; Growth; Investigation; Lead; Mediating; Methodology; Methods; Natural Products; Peripheral; Porifera; Property; Reaction; Reporting; Reproducibility; Resistance; Route; Staphylococcus aureus; Structure; System; Tumor Cell Line; cellular targeting; clinically relevant; colon cancer cell line; cycloaddition; cytotoxicity; design; drug resistant pathogen; experimental study; family structure; fibrosarcoma; flexibility; improved; innovation; insight; leukemia; melanoma; member; neoplastic cell; piperidine; scaffold; success

PROJECT SUMMARY The alkylpiperidine alkaloids are a class of natural products isolated from marine sponges possessing diverse biological activity, including tumor cell cytotoxicity, antimalarial, antitubercular, and antibacterial properties. One such member of this class of natural products is arenosclerin, which has preliminarily been reported as possessing antibacterial activity against several antibiotic-resistant clinical isolates and potent cytotoxicity against several tumor cell lines. While arenosclerin and related family members have preliminarily been associated with clinically-relevant biological activity, further evaluation has been limited given that these natural products can only be isolated in small quantities. Providing an efficient synthetic route to access arenosclerin and related alkaloids would enable further biological study. The tetracyclic structure of arenosclerin consists of a bis-piperdine core appended to two 17-member peripheral macrocycles. This study proposes an efficient total synthesis of arenosclerin, which could also be used to synthesize related members of the alkylpiperidine family. In Aim 1, development of a cycloaddition-fragmentation strategy is described, which would allow access to bis- piperidinyl ring systems present in several biologically active natural products, including arenosclerin. In Aim 2, a total synthesis of arenosclerin is proposed whereby a cycloaddition-fragmentation strategy would afford the target bis-piperidine core, which could then be further elaborated to arenosclerin using a flexible late-stage cross-coupling strategy to close the two remaining macrocycles. In Aim 3, this proposed study details preliminary evaluation of the effect of arenosclerin and its synthetic precursors on the growth inhibition of both sensitive and drug-resistant pathogens. These aims together will provide an efficient route to access arenosclerin, preliminary data toward investigating one facet of arenosclerin's unique biological activity, and allow for future access and evaluation of related alkylpiperidine alkaloids.

项目概要 烷基哌啶生物碱是从海绵中分离出来的一类天然产物，具有多种活性。 生物活性，包括肿瘤细胞的细胞毒性、抗疟、抗结核和抗菌特性。一 这类天然产物的成员是 arenosclerin，初步报道为 对多种抗生素耐药的临床分离株具有抗菌活性和有效的细胞毒性 对抗多种肿瘤细胞系。虽然沙石硬化素和相关家族成员已初步被 与临床相关的生物活性相关，鉴于这些天然物质，进一步的评估受到限制 只能少量分离产品。提供一种有效的合成路线来获取沙石硬化素 和相关的生物碱将使进一步的生物学研究成为可能。 arenosclerin 的四环结构由以下组成 一个双哌啶核心附加到两个 17 元外围大环化合物上。本研究提出了一种有效的总 合成沙粒硬化素，也可用于合成烷基哌啶家族的相关成员。 在目标 1 中，描述了环加成-断裂策略的开发，该策略将允许获得双- 哌啶基环系统存在于几种具有生物活性的天然产物中，包括沙粒硬化素。在目标 2 中， 提出了一种全合成的 arenosclerin，其中环加成-断裂策略将提供 靶向双哌啶核心，然后可以使用灵活的后期将其进一步加工成 arenosclerin 交叉耦合策略来关闭剩余的两个宏周期。在目标 3 中，本拟议研究详细介绍了初步 评估沙石硬化素及其合成前体对敏感和敏感细胞生长抑制的影响 耐药病原体。这些目标共同将为获取 arenosclerin 提供有效的途径，初步 用于研究沙石硬化素独特生物活性的一方面的数据，并允许将来访问和 相关烷基哌啶生物碱的评价。