Watanabe Takumi, Momose Isao
Institute of Microbial Chemistry, Tokyo.
Institute of Microbial Chemistry, Numazu.
Yakugaku Zasshi. 2022;142(2):145-153. doi: 10.1248/yakushi.21-00173-3.
The first medicine containing the boron element, bortezomib, was approved for clinical use just 18 years ago. The boronic acid substructure in bortezomib serves as an electrophilic functionality with high affinity for hydroxy groups, which are frequently found in catalytic sites of proteolytic enzymes, to create reversible covalent bonds with a slow dissociation rate. Today, boronic acid is considered an important molecule in the medicinal chemistry toolbox, which was promoted by the success of bortezomib and pioneering approaches to use boronic acid in the molecular design of serine protease inhibitors in the 1980s. In this review article, we first provide an overview of the development of bortezomib, and then summarize our achievements to construct boronic acid analogs of tyropeptin A, a naturally occurring proteasome inhibitor, with potent in vivo efficacy. Representative stereoselective synthetic methods of α-aminoboronic acid are also showcased.
第一种含硼元素的药物硼替佐米，18年前才被批准用于临床。硼替佐米中的硼酸亚结构作为一种对羟基具有高亲和力的亲电官能团，羟基在蛋白水解酶的催化位点中经常出现，可形成解离速率缓慢的可逆共价键。如今，硼酸被认为是药物化学工具库中的重要分子，这得益于硼替佐米的成功以及20世纪80年代在丝氨酸蛋白酶抑制剂分子设计中使用硼酸的开创性方法。在这篇综述文章中，我们首先概述硼替佐米的发展历程，然后总结我们在构建天然存在的蛋白酶体抑制剂酪蛋白A的硼酸类似物方面所取得的成果，这些类似物具有强大的体内疗效。还展示了α-氨基硼酸的代表性立体选择性合成方法。
