Novel Boronic Acids for Pilot-Scale 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和独特的硼酸及其衍生物组成的中试规模文库到NIH分子文库小分子库（MLSMR）。虽然硼酸已经报道通过模拟过渡状态作为酶抑制剂，但它们作为生物系统探针的使用受到限制。最近，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，这重新引起了人们在探针和药物开发工作中使用这种非常规功能基团的兴趣。为此，PI组建了一个经验丰富的跨学科合作团队，包括合成、药物和计算化学家，以确保这些新化合物具有“类似铅”或“类似药物”的性质，并覆盖目前在NIH MLSMR中没有代表的广泛结构空间。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。将采用的具体合成策略基于我们实验室正在开发的令人兴奋的化学，即利用有机三氟硼酸盐作为硼酸的保护形式。有机三氟硼酸盐已被证明具有抗氧化、抗酸、抗碱、抗亲核试剂和抗硼酸具有不同敏感性的亚离子化学。这种灵活性允许在有机三氟硼酸盐中加入辅助官能团，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

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.