Pilot-Scale Libraries for High-throughput Screening

描述(申请人提供)：这项新研究计划的主要目标是设计、合成一系列中试规模的文库，这些文库由结构多样的“天然产物类”化合物组成，并提供给美国国立卫生研究院分子文库小分子资料库(MLSMR)进行高通量筛选。为此，PI组建了一支经验丰富的跨学科调查团队，其中包括合成、医学和化学信息学科学家，以确保拟议的试点规模文库的成员将涵盖目前在NIH小分子资料库中找不到的广泛领域的结构多样性，同时具有必要的物理化学和药代动力学特性，对于在分子水平上探索生物系统具有价值。将特别强调由对映体和非对映异构体纯天然产物类化合物组成的碳基库。我们实验室最近开发了三种令人兴奋的、新的和高效的合成方案，这些方案与闭环歧化(RCM)、大内酯和/或大二聚等强大的合成策略结合使用，为模拟复杂天然产物的结构和重要的生物调节特性而随时构建各种有机分子提供了基础。合成方法包括：(A)阴离子接力化学(ARC)，(B)Petsis-Ferrier联盟/重排，(C)具有吸电子末端的聚烯的化学和立体选择性官能化。利用这些方法，我们提出了八个中试规模的“类天然产物”文库的合成，包括大碳环、大内酯、四氢吡喃类和生物碱类实例。当完成后，精心设计的文库，利用这个科学家联盟的综合专业知识，应该会显著增加目前NIH小分子储存库可用的潜在小探测分子的多样性。

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.