Nanoscale-Natural Products Chemistry

纳米级天然产物化学

• 批准号: 7130987
• 负责人: Tadeusz F Molinski
• 金额: $ 20.21万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-22 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7130987
• 关键词: biological products; diol; family; neoplasm /cancer; stereochemistry

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.

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开发的重要来源。目前对NP的兴趣的复兴起源于技术进步，这些技术进步允许高通量筛选、亚纳摩尔分析技术和化学遗传学方法来利用微量的天然存在的化合物用于药物发现。同时，在合成有机化学的进展已经证明了多步天然产物合成的适用性，以“克级”采购复杂的生物活性NP的，如大环内酯聚酮phorboxazole和discodermolide，用于临床前和临床试验。分析方法如微毛细管NMR和质谱法适用于不适合X射线晶体学的NP，然而，仍然缺乏用于确定立体化学的方法。为了利用抗肿瘤天然产物的亚纳摩尔结构解析和宏观尺度合成的融合，并订阅NIH路线图在分子发现中的优先事项，我们提出开发一套用于分离和解析亚纳摩尔量的天然产物的立体化学的方法。目的1将我们最近描述的用于确定非环状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过的四醇和五醇，其使用纳米尺度脂质体中的激子耦合圆二色性到多元醇（例如cylobaldeA）。目标2将利用CD方法在亚纳摩尔水平上对含氯环丙烷的大环内酯进行立体化学解析，例如在callipeltosides A-C和新类似物phorbasides A-E中发现的大环内酯。目的3将应用混合方法来阐明非环状氨基多元醇和多元醇中的多个连续立体中心，使用基于J的分析、半合成和“通用NMR数据库”基序的组合来对以zwittermicin A和saggitamide A为代表的两个非环状聚酮家族进行构型分析，目的4将解决将该方法应用于从海洋无脊椎动物中分离新的促凋亡化合物。这项工作的结果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，在亚纳摩尔水平上改进特定类别天然产物的立体化学相关性的分析工具，并向社区揭示新的立体定义的抗肿瘤NP靶点用于全合成。