Complex Heterocycles and Hybrid Strategies for Pilot Scale Libraries

描述（由申请人提供）：作为对RFA-RM-08-003的回应，我们计划使用液相策略合成几个中试规模的文库（总计1，900种化合物），提交给NIH分子库小分子储存库（MLSMR），以供后续分发用于各种生物测定。我们的目标是合成（1）440个不同的内酰胺，它们来自多组分反应和使用酸酐的形式环加成，（2）308个对映体纯的3-羟基-2-羟吲哚和螺环羟吲哚-恶唑啉，（R-和S-对映体的系列），中心（核心/骨架）和外围设备（3）384个不同的双杂环和吡唑子结构，其特征在于中心和中心结构都是（4）288个杂合分子，其使用采用目的1-3中制备的杂环核心支架（子文库）的会聚偶联策略。另外480种化合物将通过将来自目标1-3的杂环核心支架与一组共同的结构单元偶联来获得。如这里所描述的，我们计划的合成路线包括功能，如一个新的多组分反应，立体发散制备螺环内酰胺的模块化方法，一个新的螺环羟吲哚恶唑啉支架，合成新的双杂环和吡唑结构，和一个新的收敛耦合策略杂环混合库。文库将具有约20-200个成员，每个成员具有>95%纯度的非商业小分子，用于提交（10-20 mg量）给MLSMR。将通过HPLC分析各化合物的纯度，并通过质谱法确认其鉴别。制备型HPLC色谱法将用于化合物纯化。美国国立卫生研究院的PubChem数据库是美国国家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。 公共卫生相关性：NIH的“路线图”旨在通过支持将从不同科学领域借鉴的倡议来促进生物医学研究，以加快新药的发现。该提案将为筛选实验中使用的分子收集（MLSMR）提供新的化合物，以更好地了解生物过程，并可能最终导致人类疾病的新疗法。

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.