Synthesis and Biological Evaluation of Alkylpiperidine Arenosclerin A.

项目总结 烷基哌啶生物碱是从海洋海绵中分离出来的一类天然产物，具有多种 生物活性，包括肿瘤细胞毒性、抗疟疾、抗结核和抗菌特性。一 这类天然产物中的这种成员就是芳香素，初步报道为 对几种抗生素耐药的临床分离株具有抗菌活性和较强的细胞毒性 对几种肿瘤细胞株的作用。而芦荟素及其相关家族成员已初步被 与临床相关的生物活性有关，进一步的评估受到限制，因为这些天然的 产品只能少量隔离。提供一条有效的合成路线来获取芳香油苷 以及相关的生物碱将使进一步的生物学研究成为可能。芳香果苷的四环结构包括 一个双胡椒碱核心附加到两个17元的外围大环上。这项研究提出了一个有效的总体 芳香素的合成，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-裂解策略的发展，其将允许获得双- 几种具有生物活性的天然产物中存在的哌啶环系统，包括芳香素。在目标2中， 本文提出了一种全合成芳烃类化合物的方法，即环加成-碎裂反应策略。 目标双-哌啶核，然后可以使用灵活的后期阶段进一步精制成花生四氢叶苷 交叉耦合策略，关闭剩余的两个宏观周期。在目标3中，这项拟议研究详细说明了初步情况 花生四烯醇苷及其合成前体对敏感型和多发性骨髓瘤生长抑制作用的评价 抗药性病原体。这些目标结合在一起将提供一条有效的途径来获得arenosicin，初步 数据用于研究花生球蛋白独特的生物活性的一个方面，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.