Novel Boronic Acids for Pilot-Scale Screening

用于中试筛选的新型硼酸

• 批准号: 7684187
• 负责人: GARY A MOLANDER
• 金额: $ 36.67万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-05 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7684187
• 关键词: Acids; Area; Boron; Boronic Acids; Carbon; Chemistry; Drug Kinetics; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Esters; Ethanolamines; Foundations; Goals; Ions; Laboratories; Libraries; Malignant Neoplasms; Molecular; Molecular Bank; Pharmaceutical Preparations; Predisposition; Process; Property; Proteasome Inhibitor; Protocols documentation; Reporting; Research; Resistance; Screening procedure; Series; Time; United States National Institutes of Health; Velcade; analog; base; biological systems; design; drug development; experience; flexibility; functional group; interest; novel; oxidation; 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 composed of structurally diverse and unique boronic acids and their derivatives to the NIH Molecular Libraries Small-Molecule Repository (MLSMR). While boronic acids have been reported to act as enzyme inhibitors through mimicking transition states, their use as probes of biological systems has been limited. The recent introduction of the boronic acid Velcade as a proteasome inhibitor approved for treatment of certain cancers has renewed interest in using this unconventional functional group in probe and drug development efforts. Toward this end, the PI has assembled an experienced interdisciplinary team of collaborators, including synthetic, medicinal, and computational chemists to assure these novel compounds possess "lead-like" or "drug-like" properties and cover broad areas of structural space not currently represented in the NIH MLSMR, while at the same time possessing the requisite physicochemical and pharmacokinetic properties to be of value as probes for the exploration of biological systems at the molecular level. The specific synthetic tactics to be employed have their foundation in exciting chemistry being developed in our laboratory concerning the utilization of organotrifluoroborates as protected forms of boronic acids. Organotrifluoroborates have been demonstrated to be resistant to oxidation, acids, bases, nucleophiles, and iminium ion chemistry to which boronic acids have various susceptibilities. This flexibility allows processing of ancillary functional groups incorporated within the organotrifluoroborates, while retaining the valuable boron carbon bonds. In this manner, small, readily available organotrifluoroborates can be elaborated in a highly efficient manner, increasing molecular complexity and diversity in a manner that is incompatible with the boronic acid moiety. Subsequently, the key boronic acid functional group can be unveiled through a simple deprotection protocol of the trifluoroborate. This will facilitate the construction and assembly of carefully designed libraries that have absolutely no precedent in the NIH MLSMR, thus significantly expanding the diversity of small molecules with the potential to be valuable probes for the exploration of biological systems at the molecular level.

描述（由申请人提供）：这项新研究计划的主要目标是设计、合成一系列由结构多样且独特的硼酸及其衍生物组成的中试规模文库，并将其交付至 NIH 分子文库小分子存储库（MLSMR）。虽然据报道硼酸通过模仿过渡态充当酶抑制剂，但它们作为生物系统探针的用途受到限制。最近推出的硼酸 Velcade 作为一种蛋白酶体抑制剂被批准用于治疗某些癌症，这重新引起了人们对在探针和药物开发工作中使用这种非常规官能团的兴趣。为此，PI 组建了一支经验丰富的跨学科合作团队，包括合成化学家、药物化学家和计算化学家，以确保这些新型化合物具有“类先导”或“类药物”特性，并覆盖目前尚未覆盖的广泛结构空间领域。 NIH MLSMR 中的代表，同时具有必要的理化和药代动力学特性，作为在分子水平探索生物系统的探针有价值。所采用的具体合成策略以我们实验室正在开发的令人兴奋的化学为基础，该化学涉及利用有机三氟硼酸盐作为硼酸的受保护形式。有机三氟硼酸盐已被证明能够抵抗氧化、酸、碱、亲核试剂和亚胺离子化学，而硼酸对这些化学物质具有不同的敏感性。这种灵活性允许加工并入有机三氟硼酸盐中的辅助官能团，同时保留有价值的硼碳键。以这种方式，小的、容易获得的有机三氟硼酸盐可以 以高效的方式进行精心设计，以与硼酸部分不相容的方式增加分子的复杂性和多样性。随后，可以通过三氟硼酸盐的简单脱保护方案揭示关键的硼酸官能团。这将有助于精心设计的文库的构建和组装，这在 NIH MLSMR 中绝对没有先例，从而显着扩大小分子的多样性，有可能成为在分子水平上探索生物系统的有价值的探针。