Nanoscale-Natural Products Chemistry

纳米级天然产物化学

• 批准号: 7647175
• 负责人: Tadeusz F Molinski
• 金额: $ 20.37万
• 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 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7647175
• 关键词: Address; Adriamycin PFS; Antitumor Natural Products; Apoptotic; Biological Factors; Circular Dichroism; Colonic Neoplasms; Communities; Complex; Coupling; Databases; Dependence; Development; Evaluation; Exciton; Exhibits; Family; Glycols; Gossypium; Human; Hybrids; Liposomes; Macrolides; Mammary Neoplasms; Marine Invertebrates; Mass Spectrum Analysis; Methods; Modeling; Molecular; Natural Products Chemistry; Organic Chemistry; Outcome; Polyketide Macrolides; Prostatic Neoplasms; Relative (related person); Renaissance; Resistance; Sampling; Solvents; Source; Structure; Techniques; Temperature; Tumor Cell Line; United States National Institutes of Health; Work; X-Ray Crystallography; analog; analytical method; analytical tool; base; callipeltoside A; caylobolide A; chemical genetics; discodermolide; drug discovery; high throughput screening; hydroxyl group; interest; marine organism; nanoscale; neoplastic cell; novel; polyol; pre-clinical; research clinical testing; stereochemistry; tumor; zwittermicin A

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的开发的重要来源。当前对NP的兴趣复兴起源于技术进步，允许高通量筛选，亚纳米摩尔分析技术和化学遗传学方法来利用大量的天然化合物进行药物发现。同时，合成有机化学的进步证明了多步天然产物合成对复杂的生物活性NP的“革兰氏尺度”采购的适用性，例如大花环多酮化合物phorboxazole和discodermolide，用于陶醉和临床测试。分析方法（例如微毛细血管NMR）和质谱法与不适合X射线晶体学的NP相应，但是，仍然缺乏确定立体化学的方法。为了利用抗肿瘤天然产物和宏观统计合成的亚纳米尔结构的收敛，并订阅了分子发现中NIH路线图的优先级，我们建议开发一套用于隔离和阐明自然产物降低天然含量纳米尔量的方法的方法。 AIM 1将将我们最近描述的方法扩展为确定无环1，N-二醇（N大于或等于5）的相对和绝对构型，以使用纳米级 - 糖体中的纳米级 - 二色体对多醇（例如cayloboliide a）中的纳米级 - 丝体中的激子偶联二色性二色性二色性二色性二甲醇。 AIM 2将利用CD方法来立体化化学阐明含有氯丙烷的大环内酯类，例如在callipeltosides a-c和新的类似物A-e中发现的氯丙烷A-e，在亚纳米尔水平上。 AIM 3将采用混合方法来阐明在循环氨基 - 多聚元素和多元醇中使用J-基于J-基于分析的组合，半合成和“通用NMR数据库”基序的多个连续的立体式，用于对两个新闻界面的Acyclotation acyplication acyplication forsifation a acyclication ai Nomplantation Alignation aimation aimation acytibation a i Inlogation to Zwittermicin a和sagimicin agitmicin agimicin a和saggitamide aimide aimide aimide Aimide Aimide Aimide agipigietamide agipi。海洋无脊椎动物的凋亡化合物。这项工作的结果将提供新的抗肿瘤化合物铅，解决Key NP的立体化学复杂性，精炼分析工具，用于在亚纳米尔水平上特定的天然产品的立体化学相关性，并向社区揭示新的立体定义的抗肿瘤NP NP NP NP目标。

项目成果

Hemi-phorboxazole a: structure confirmation, analogue design and biological evaluation.

半佛波唑a：结构确认、类似物设计和生物学评价。

• DOI: 10.1021/ol9014317
• 发表时间: 2009
• 期刊: Organic letters
• 影响因子: 5.2
• 作者: Smith3rd,AmosB;Liu,Zhuqing;Hogan,Anne-MarieL;Dalisay,DoralynS;Molinski,TadeuszF
• 通讯作者: Molinski,TadeuszF

Liposomal Circular Dichroism (L-CD) of Arenoyl Derivatives of Sphingolipids. Amplification of Cotton Effects in Ordered Lipid Bilayers.

• DOI: 10.3390/md15120352
• 发表时间: 2017-12-20
• 期刊: Marine drugs
• 影响因子: 5.4
• 作者: Molinski TF;Broaddus CD;Morinaka BI
• 通讯作者: Morinaka BI