Pilot-Scale Libraries for High-throughput Screening

描述（由申请人提供）：这个新研究项目的主要目标是设计、合成和交付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，以供NIH分子文库小分子库（MLSMR）进行高通量筛选。为此，PI组建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，以确保拟议的中试规模文库的成员将涵盖目前在NIH小分子库（vide infra）中未发现的结构多样性的广泛领域。同时具有必要的物理化学和药代动力学性质，作为在分子水平上探索生物系统的探针有价值。特别强调的是由对映体和非对映体纯天然产物类化合物组成的碳基文库。所采用的具体合成策略基于我们实验室最近开发的三种令人兴奋的、新的、高效的合成方案，当它们与强大的环闭合复分解（RCM）、大内酯化和/或大二聚化合成策略结合使用时，对于模拟复杂天然产物的结构及其重要的生物调节特性的各种有机分子的现成构建具有很大的希望。合成方法包括：(a)阴离子接力化学（ARC）， (b) Petasis-Ferrier结合/重排，以及(c)具有电子退出末端的多烯的化学和立体选择功能化。利用这些方法，我们提出了8个中试规模的“天然产物样”文库的合成，包括大碳环、大内酯、基于四氢吡喃和类生物碱的例子。一旦完成，精心设计的文库，利用这个科学家联盟的综合专业知识，将显著增加目前可用于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.