Pilot-Scale Libraries for High-throughput Screening

描述（由申请人提供）：这项新研究计划的主要目标是设计、合成并向NIH分子库小分子库（MLSMR）提供一系列由结构多样的“天然产物样”化合物组成的中试规模文库，以进行高通量筛选。 为此，PI组建了一个经验丰富的跨学科研究团队，包括合成、医药和化学信息学科学家，以确保拟议中试规模文库的成员将涵盖NIH小分子库中目前未发现的广泛结构多样性领域。（参见下文），同时具有作为用于在分子水平上探索生物系统的探针的价值所必需的生理化学和药代动力学性质。 特别强调将放在碳基库组成的对映体和非对映体纯天然产物样化合物。 所采用的具体合成策略以我们实验室最近开发的三种令人兴奋的、新的和有效的合成方案为基础，当与闭环复分解（RCM）、大环内酯化和/或大环二聚化的强大合成策略结合使用时，具有很大的希望，为准备建设不同的有机分子，模仿结构复杂的天然产品和他们的重要的生物调节特性。 合成方法包括：（a）阴离子中继化学（ARC），（B）Petasis-Ferrier联合/重排，和（c）具有吸电子末端的多烯的化学选择性和立体选择性官能化。使用这些方法，我们提出了8个试点规模的“天然产物样”库，包括macrocarbacycles，macrolactones，基于四氢吡喃，和类黄酮的例子的合成。当完成时，精心设计的库，利用这个科学家联盟的综合专业知识，应该显着增加目前可用于NIH小分子库的潜在小探针分子的多样性。

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.