Nanoscale-Natural Products Chemistry

描述（由申请人提供）：天然产物（NP）是药物发现和合成有机化学发展的重要来源。当前对NP的兴趣复兴源于技术进步，允许高通量筛选，亚纳米分子分析技术和化学遗传学方法利用微量天然存在的化合物进行药物发现。与此同时，合成有机化学的进步已经证明了多步天然产物合成在“克级”采购复杂生物活性NP的适用性，例如大环内酯类聚酮苯甲唑和迪德莫内酯，用于临床前和临床测试。微毛细管核磁共振和质谱等分析方法适用于不适合x射线晶体学的NP，然而，立体化学的测定方法仍然缺乏。为了充分利用抗肿瘤天然产物的亚纳米分子结构解析与宏观尺度合成的融合，并根据美国国立卫生研究院分子发现路线图的优先事项，我们建议开发一套亚纳米分子量天然产物立体化学的分离和解析方法。目标1将扩展我们最近描述的方法，用于确定非环1，n-二醇（n大于或等于5）到双跳过四醇和五醇的相对和绝对构型，使用纳米级脂质体中的激子耦合圆二色性到多元醇（例如caylobolide A）。目的2将利用CD方法在亚纳米水平上对含氯环丙烷的大环内酯类化合物进行立体化学解析，例如在油梨苷A-C和新的类似物，磷基苷A-E中发现的大环内酯类化合物。AIM 3将采用混合方法阐明无环氨基多元醇和多元醇中多个连续的立体中心，使用J基分析、半合成和“通用核磁共振数据库”的组合，对以两性霉素a和saggitamide a为代表的两个无环聚酮家族进行构型分析，AIM 4将解决应用该方法从海洋无脊椎动物中分离新的促凋亡化合物的问题。这项工作将提供新的抗肿瘤化合物线索，解决关键NP的立体化学复杂性，完善亚纳米分子水平上特定类别天然产物立体化学相关性的分析工具，并为全合成提供新的立体定义的抗肿瘤NP靶点。

DESCRIPTION (provided by applicant): Natural products (NP's) are a significant source for both drug discovery and development of synthetic organic chemistry. The current renaissance of interest in NP's originates in technological advances that allow high-throughput screening, sub-nanomole analytical techniques and chemical genetics approaches to exploit minute quantities of naturally occurring compounds for drug discovery. Concurrently, advances in synthetic organic chemistry have demonstrated the applicability of multistep natural product synthesis to 'gram-scale' procurement of complex biologically active NP's, such as the macrolide polyketides phorboxazole and discodermolide, for preclinical and clinical testing. Analytical methods such as microcapillary NMR and mass spectrometry are amenable to NP's that are not suitable for X-ray crystallography, however, methods for determination of stereochemistry are still lacking. In order to capitalize on the convergence of sub-nanomole structure elucidation of anti-tumor natural products and macro-scale synthesis, and subscribe to priorities of the NIH Roadmap in molecular discovery, we propose development of a suite of methods for isolation and elucidation of stereochemistry of natural products at sub- nanomole amounts. Aim 1 will extend our recently-described method for determining relative and absolute configuration of acyclic 1,n-diols (n greater than or equal to 5) to double-skipped tetraols and pentaols using exciton coupling circular dichroism in nanoscale-liposomes to polyols (e.g. caylobolide A). Aim 2 will exploit CD methods for stereochemical elucidation of chlorocyclopropane-containing macrolides, such as that found in callipeltosides A-C and the new analogs, phorbasides A-E, at sub-nanomole levels. AIM 3 will apply a hybrid approach to elucidate multiple contiguous stereocenters in acyclic amino-polyols and polyols using a combination of J- based analysis, semi-synthesis and 'universal NMR database' motifs for configurational analysis of two acyclic polyketide families, represented by zwittermicin A and saggitamide A, and Aim 4 will address apply the methods to isolation of novel proapoptotic compounds from marine invertebrates. The outcome of this work will provide new antitumor compound leads, resolve stereochemical complexity of key NP's, refine analytical tools for stereochemical correlations of specific classes of natural products at sub-nanomole levels, and reveal to the community new stereo-defined antitumor NP targets for total synthesis.