Complex Heterocycles and Hybrid Strategies for Pilot Scale Libraries

描述（由申请人提供）：为了响应RFA-RM-08-003，我们计划使用溶液相策略合成几个中试规模的文库（总共1,900种化合物），这些文库将提交给NIH分子文库小分子库（MLSMR），以便随后分发用于各种生物检测。我们的目标是合成(1)440种不同的内酰胺，这些内酰胺是由多组分反应和采用酸酐的形式环加成产生的；(2)308种对映体纯3-羟基-2-氧吲哚和螺环氧吲哚-恶唑啉具有立体化学（R-和s-对映体系列），中心（核心/骨架）和外周（附件）多样性；(3)384种不同的双杂环和吡唑亚结构具有中心（核心/骨架）和外周（附件）多样性。(4)利用Aims 1-3中制备的杂环核心支架（亚文库）采用收敛耦合策略的288个杂化分子。通过将Aims 1-3中的杂环核心支架与一组共同的构建块偶联，将获得另外480种化合物。如本文所述，我们计划的合成路线包括新的多组分反应，立体发散制备螺旋环内酰胺的模块化方法，新的螺旋环氧吲哚-恶唑啉支架，新的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。文库将有大约20-200个成员，每个成员的非商业小分子纯度为95%（10-20毫克），提交给MLSMR。每个化合物将用高效液相色谱法分析其纯度，并通过质谱法确认其身份。预备高效液相色谱法将用于化合物纯化。美国国立卫生研究院的PubChem数据库是美国国立卫生研究院知识库的一个组成部分，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。

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.