Complex Heterocycles and Hybrid Strategies for Pilot Scale Libraries

中试规模文库的复杂杂环化合物和混合策略

• 批准号: 8272695
• 负责人: MARK J. KURTH
• 金额: $ 36.6万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8272695
• 关键词: Anhydrides; Area; Biological Assay; Biological Process; Biomedical Research; Chromatography; Collection; Complex; Coupling; Data; Databases; High Pressure Liquid Chromatography; Hybrids; Lactams; Lead; Libraries; Mass Spectrum Analysis; Medicine; Molecular Bank; Peripheral; Phase; Preparation; PubChem; Pyrazoles; Reaction; Research Support; Route; Screening procedure; Series; Skeleton; Solutions; Speed; Structure; United States National Institutes of Health; appendage; cycloaddition; enantiomer; human disease; member; novel; oxindole; public health relevance; repository; research study; response; scaffold; small molecule

DESCRIPTION (provided by applicant): In response to RFA-RM-08-003, we plan to use solution-phase strategies to synthesize several pilot-scale libraries (totaling 1,900 compounds) to be submitted to the NIH Molecular Libraries Small-Molecule Repository (MLSMR) for subsequent distribution for various biological assays. Our aims are to synthesize (1) 440 diverse lactams that emanate from multicomponent reactions and formal cycloadditions employing anhydrides, (2) 308 enantiomerically-pure 3-hydroxy-2-oxindoles and spirocyclic oxindole-oxazolines featuring stereochemical (the series of both R- and S-enantiomers), central (core/skeleton), and peripheral (appendage) diversity, (3) 384 diverse bis-heterocycle and pyrazole substructures featuring both central (core/skeleton) and peripheral (appendage) diversity, and (4) 288 hybrid molecules using a convergent coupling strategy employing heterocycle core scaffolds (sub-libraries) prepared in Aims 1-3. An additional 480 compounds will be obtained by coupling the heterocycle core scaffolds from Aims 1-3 with a common set of building blocks. As described here, our planned synthetic routes include features such as a new multicomponent reaction, a modular approach for the stereo-divergent preparation of spirocyclic lactams, a new spirocyclic oxindole-oxazoline scaffold, syntheses of novel bis-heterocycle and pyrazole structures, and a new convergent coupling strategy for heterocycle hybrid libraries. Libraries will have ~20-200 members each with >95% purity of non-commercial small-molecules for submission (10-20 mg quantities) to the MLSMR. Each compound will be analyzed by HPLC for purity and its identity confirmed by mass spectroscopy. Preparatory HPLC chromatography will be used for compound purification. The NIH's PubChem database, a component of the National Institute of Health Repository, will be used for management of our various pilot libraries. PubChem interfaces substance information, compound structures, and bioactivity data. PUBLIC HEALTH RELEVANCE: The NIH "Roadmap" seeks to contribute biomedical research by supporting initiatives that will draw from different scientific areas to speed up the discovery of new medicines. This proposal will provide new compounds for the collection of molecules (MLSMR) used in screening experiments to develop a better understanding of biological processes and may ultimately lead to new cures for human diseases.

描述(由申请人提供)：响应RFA-RM-08-003，我们计划使用溶液阶段策略合成几个中试规模的文库(总计1900个化合物)，提交给NIH分子文库小分子资料库(MLSMR)，用于随后的各种生物分析。我们的目标是合成(1)440种不同的内酰胺，它们来自多组分的反应和使用酸酐的形式环加成，(2)308个具有立体化学(R-和S-对映体系列)、中心(核心/骨架)和外围(附件)多样性的对映体纯3-羟基-2-氧吲哚和螺环噁唑类化合物，(3)384个具有中心(核心/骨架)和外围(附件)多样性的双杂环和吡唑亚结构，以及(4)288个采用聚合耦合策略的杂化分子。通过将来自AIMS 1-3的杂环核心支架与一组共同的构建块偶联，将获得额外的480个化合物。如本文所述，我们计划的合成路线包括新的多组分反应，用于立体发散制备螺环内酰胺的模块化方法，新的螺环氧吲哚-恶唑啉支架，新型双杂环和吡唑结构的合成，以及杂环杂化文库的新的收敛耦合策略。图书馆将有大约20-200名成员，每个成员的非商业小分子纯度为95%，提交给MLSMR(10-20毫克数量)。每一种化合物都将通过高效液相色谱进行纯度分析，并通过质谱学确认其身份。化合物的提纯将采用高效液相色谱预分离。NIH的PubChem数据库是国家卫生研究院的一个组成部分，将用于管理我们的各种试点图书馆。PubChem接口物质信息、化合物结构和生物活性数据。 与公共卫生相关：美国国立卫生研究院“路线图”寻求通过支持将从不同科学领域吸收的倡议来促进生物医学研究，以加快新药的发现。这项提议将为筛选实验中使用的分子(MLSMR)收集提供新的化合物，以更好地了解生物过程，并最终可能导致治疗人类疾病的新方法。

项目成果

Catalytic stereoselective synthesis of diverse oxindoles and spirooxindoles from isatins.

• DOI: 10.1021/co300003c
• 发表时间: 2012-04-09
• 期刊: ACS combinatorial science
• 作者: MacDonald JP;Badillo JJ;Arevalo GE;Silva-García A;Franz AK
• 通讯作者: Franz AK

Nucleophilic substitution of oxazino-/oxazolino-/benzoxazin [3,2-b]indazoles: an effective route to 1H-indazolones.

• DOI: 10.1021/ol100751n
• 发表时间: 2010-06-04
• 期刊: ORGANIC LETTERS
• 影响因子: 5.2
• 作者: Donald, Michael B.;Conrad, Wayne E.;Oakdale, James S.;Butler, Jeffrey D.;Haddadin, Makhluf J.;Kurth, Mark J.
• 通讯作者: Kurth, Mark J.

Synthesis of substituted chromanones: an organocatalytic aldol/oxa-Michael reaction.

• DOI: 10.1021/ol101221c
• 发表时间: 2010-08-06
• 期刊: ORGANIC LETTERS
• 影响因子: 5.2
• 作者: Butler, Jeffrey D.;Conrad, Wayne E.;Lodewyk, Michael W.;Fettinger, James C.;Tantillo, Dean J.;Kurth, Mark J.
• 通讯作者: Kurth, Mark J.

A one-pot-three-step route to triazolotriazepinoindazolones from oxazolino-2H-indazoles.

• DOI: 10.1021/ol3015804
• 发表时间: 2012-08-03
• 期刊: ORGANIC LETTERS
• 影响因子: 5.2
• 作者: Conrad, Wayne E.;Rodriguez, Kevin X.;Nguyen, Huy H.;Fettinger, James C.;Haddadin, Makhluf J.;Kurth, Mark J.
• 通讯作者: Kurth, Mark J.

The Davis-Beirut reaction: N1,N2-disubstituted-1H-indazolones via 1,6-electrophilic addition to 3-alkoxy-2H-indazoles.

• DOI: 10.1021/ol2010424
• 发表时间: 2011-06-17
• 期刊: ORGANIC LETTERS
• 影响因子: 5.2
• 作者: Conrad, Wayne E.;Fukazawa, Ryo;Haddadin, Makhluf J.;Kurth, Mark J.
• 通讯作者: Kurth, Mark J.