Novel Boronic Acids for Pilot-Scale Screening

描述(由申请人提供)：这一新研究计划的主要目标是设计、合成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，并将其交付给NIH分子文库小分子文库(MLSMR)。虽然有报道称，硼酸通过模拟过渡态作为酶抑制剂，但它们作为生物体系探针的用途一直受到限制。最近，作为一种被批准用于治疗某些癌症的蛋白酶体抑制剂，硼酸VELCADE的推出重新引起了人们在探针和药物开发工作中使用这种非传统官能团的兴趣。为此，PI组建了一支经验丰富的跨学科合作者团队，其中包括合成、药物和计算化学家，以确保这些新化合物具有“类铅”或“类药物”性质，并覆盖目前NIH MLSMR中没有的广泛结构空间，同时具有必要的物理化学和药代动力学性质，对于在分子水平上探索生物系统具有价值。我们实验室正在开发的关于有机三氟硼酸盐作为受保护形式的硼酸的使用的激动人心的化学，有其特定的合成策略的基础。有机三氟硼酸盐已被证明对氧化、酸、碱、亲核试剂和亚胺离子化学具有不同的敏感性。这种灵活性允许加工有机三氟硼酸盐中包含的辅助官能团，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 以一种高效的方式进行阐述，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，关键的硼酸官能团可以通过三氟硼酸盐的简单脱保护方案揭开面纱。这将促进精心设计的文库的构建和组装，这些文库在NIH MLSMR中完全没有先例，从而显著扩大了小分子的多样性，有可能成为在分子水平上探索生物系统的有价值的探测器。

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.