Nanoscale-Natural Products Chemistry

描述(申请人提供)：天然产物(NP‘s)是药物发现和合成有机化学发展的重要来源。目前对NP的兴趣的复兴源于技术进步，这些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，以利用微量的天然化合物进行药物发现。与此同时，合成有机化学的进展已经证明，多步天然产物合成适用于‘克级’规模的复杂生物活性NP的采购，如用于临床前和临床试验的大环内酯类聚酮基膦口恶唑和盘状除草剂。微毛细管核磁共振和质谱学等分析方法适用于不适用于X射线结晶学的NP，但立体化学的测定方法仍然缺乏。为了利用抗肿瘤天然产物的亚纳摩尔结构解释与宏观合成的趋同性，并响应NIH路线图在分子发现方面的优先地位，我们提出了一套分离和阐明亚纳摩尔量天然产物立体化学的方法。目的1将我们最近描述的测定无环1，n-二醇(n大于或等于5)的相对和绝对构型的方法扩展到双跳四醇和五醇，使用纳米脂质体中的激子耦合圆二色谱来确定多元醇(例如卡洛内酯A)。目的2将开发CD方法用于含氯环丙烷的大环内酯类化合物的立体化学鉴定，例如在Callipeltoside A-C和新的类似物Phorbaside A-E中发现的亚纳米分子水平的方法。目标3将使用基于J的分析、半合成和‘通用核磁共振数据库’基序相结合的混合方法来阐明非环氨基多元醇和多元醇中的多个连续的立体中心，用于构型分析以两性霉素A和沙吉胺A为代表的两个非环聚酮家族，而目标4将致力于应用这些方法从海洋无脊椎动物中分离新的促细胞凋亡化合物。这项工作的结果将提供新的抗肿瘤化合物先导，解决关键NP的立体化学复杂性，改进分析工具，在亚纳米水平上对特定类别的天然产物进行立体化学关联，并向社会揭示用于全合成的新的立体定义的抗肿瘤NP靶标。

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.