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）：该新研究计划的主要目标是设计，综合和提供一系列由结构上多样的和独特的硼酸及其衍生物组成的飞行员规模的库及其对NIH分子库小型分子存储库（MLSMR）。虽然据报道硼酸通过模仿过渡态充当酶抑制剂，但它们用作生物系统的探针受到限制。最近将硼酸Velcade引入了批准用于治疗某些癌症的蛋白酶体抑制剂的引入使人们对在探针和药物开发工作中使用该非常规官能团的兴趣。为此，PI组装了一支经验丰富的合作者跨学科团队，包括合成，药物和计算化学家确保这些新颖化合物具有“铅状”或“毒品”或“药物般”的特性，并涵盖了当前在NIH MLSMR中未代表的结构空间的广泛领域，同时概述了所需的物理和药物的概念，并涉及所需的物理原理和药物的范围，并涵盖了物理原理和药物的范围。分子水平的生物系统。要采用的特定合成策略在我们的实验室中开发出令人兴奋的化学基础，这些化学是在我们的实验室中，涉及有机氟氟甲酸酯作为硼酸的受保护形式的利用。已证明有机氟氟甲酸酯对硼酸具有各种敏感性的氧化，酸，碱，亲核试剂和亚米诺离子化学性具有抗性。这种灵活性允许处理在有机氟氟化合物中纳入的辅助官能团，同时保留有价值的硼碳键。以这种方式，易于可用的有机氟氟甲植物可以 以高效的方式阐述，以与硼酸部分不相容的方式增加分子复杂性和多样性。随后，可以通过三氟核酸盐的简单脱保护方案揭示关键的硼酸官能团。这将有助于构建和组装精心设计的文库，这些文库在NIH MLSMR中绝对没有先例，因此显着扩大了小分子的多样性，有可能成为分子水平探索生物系统的有价值的探针。