Pilot-Scale Libraries for High-throughput Screening

用于高通量筛选的中试规模文库

• 批准号: 7497036
• 负责人: Amos B Smith
• 金额: $ 36.4万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-17 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7497036
• 关键词: Alkaloids; Anions; Architecture; Area; Biological; Biological Factors; Carbon; Chemistry; Complex; DNA Sequence Rearrangement; Drug Kinetics; Electrons; Facility Construction Funding Category; Foundations; Goals; Laboratories; Libraries; Methods; Molecular; Molecular Bank; Polyenes; Property; Protocols documentation; Research; Research Personnel; Scientist; Series; System; Time; United States National Institutes of Health; base; cheminformatics; design; experience; high throughput screening; member; programs; repository; small molecule

DESCRIPTION (provided by applicant): The principal goal of this new research program is to design, synthesize and deliver a series of pilot-scale libraries comprised of structurally diverse "natural product-like" compounds to the NIH Molecular Libraries Small-Molecule Repository (MLSMR) for high throughput screening. Toward this end, the PI has assembled a highly experienced, interdisciplinary team of investigators, including synthetic, medicinal and chemical informatics scientists, to assure that members of the proposed pilot scale libraries will cover broad areas of structural diversity not currently found in the NIH Small-Molecule Repository (vide infra), while at the same time having the requisite physiochemical and pharmacokinetic properties to be of value as probes for the exploration of biological systems at the molecular level. Particular emphasis will be placed on carbon-based libraries comprised of enantio- and diastereomerically pure natural product-like compounds. The specific synthetic tactics to be employed have their foundation in three exciting, new and efficient synthetic protocols developed recently in our laboratory, which, when employed in conjunction with the powerful synthetic tactics of ring closing metathesis (RCM), macrolactonization, and/or macrodimerization, hold great promise for the ready construction of diverse organic molecules that mimic both the architecture of complex natural products and their important bio-regulatory properties. The synthetic methods include: (a) Anion Relay Chemistry (ARC), (b) the Petasis-Ferrier Union/Rearrangement, and (c) the Chemo- and Stereoselective Functionalization of Polyenes Possessing Electron-Withdrawing Termini. Using these methods, we propose the synthesis of eight pilot-scale "natural product-like" libraries including macrocarbacycles, macrolactones, tetrahydropyran-based, and alkaloid-like examples. When complete, the carefully designed libraries, exploiting the combined expertise of this consortium of scientists, should significantly augment the diversity of potential small probe molecules currently available to the NIH Small-Molecule Repository.

描述（由申请人提供）：该新研究计划的主要目标是设计，合成和提供一系列飞行员规模的库，这些库由NIH分子图书馆的结构多样性的“天然产品”化合物组成，用于小型分子库（MLSMR），以进行高透射率筛选。 为此，PI组装了一支经验丰富的跨学科研究团队，包括合成，药物和化学信息学科学家，以确保拟议的飞行员量表库中的成员将涵盖NIH小分子存储库中目前不建立的结构多样性的广泛领域，同时又具有庞大的物理型物理型物理学的物理学物质，并具有必要的物理学物质，并具有物理效果。分子水平生物系统的探索。 特别重点将放在基于碳的库中，该文库由对映异构体和纯天然产物样化合物组成。 要使用的具体合成策略在最近在我们的实验室中开发的三个令人兴奋的，新的和高效的合成协议中，当它与环节关闭元理解（RCM）的强大合成策略结合使用时，大量映射，和/或型号的生产既可以构造自然的构造，又可以自然地构造有机分子的生产力，使其具有良好的构造。生物调节特性。 合成方法包括：（a）阴离子继电器化学（ARC），（b）Petasis-Ferrier联合/重排，以及（c）具有电子吸引电子末端的多元的化学和立体选择性功能化。使用这些方法，我们提出了八个试验规模的“天然产物样”库的合成，包括大环甲环霉，大花生酯，基于四氢吡喃的基于四氢吡喃和生物碱样示例。完成后，精心设计的图书馆利用了该科学家联盟的组合专业知识，应显着增加NIH小分子存储库目前可用的潜在小探针分子的多样性。