Synthesis and Biological Evaluation of Alkylpiperidine Arenosclerin A.

项目摘要 烷基哌啶生物碱是一类从具有多种生物活性的海绵中分离得到的天然产物， 生物活性，包括肿瘤细胞毒性、抗疟疾、抗结核和抗菌特性。一 这类天然产物的成员是arenosclerin，其初步报道为 对几种耐药性临床分离株具有抗菌活性， 针对几种肿瘤细胞系。虽然arenosclerin和相关的家庭成员已初步 与临床相关的生物活性相关，进一步的评价受到限制，因为这些天然的 产品只能少量分离。提供一种获得arenosclerin的有效合成途径 以及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。本研究提出了一种有效的总量 arenosclerin的合成，其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，其将允许获得双- 哌啶环系统存在于几种生物活性天然产物中，包括arenosclerin。在目标2中， 提出了一种全合成arenosclerin的方法，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步骤将其进一步加工成arenosclerin 交叉偶联策略，以关闭剩余的两个大环。在目标3中，这项拟议的研究初步详细说明了 评价arenosclerin及其合成前体对敏感和敏感细胞的生长抑制作用， 耐药病原体这些目标将共同提供一个有效的途径，以获得arenosclerin，初步 研究arenosclerin独特生物活性的一个方面的数据，并允许未来访问和 相关烷基哌啶生物碱的评价。

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.