Yokomatsu Tsutomu
School of Pharmacy, Tokyo University of Pharmacy and Life Sciences.
Yakugaku Zasshi. 2017;137(9):1051-1086. doi: 10.1248/yakushi.17-00110.
Phosphonic and phosphinic acids, especially α-heteroatom-substituted ones, possess unique structural and physical features which enable them to act as hydrotically stable analogs to biological phosphates in biological processes. They also act as mimetics in the transition state of the protease-induced hydrolysis of dipeptides. The first half of this review focuses on selected new synthetic methods developed by our research group for the stereoselective synthesis of α-heteroatom-substituted phosphonic and phosphinic acid derivatives, including modified nucleotide analogs and phosphinyl dipeptide isosteres. In the latter half, this review summarizes the utility of difluoromethylenephosphonic acids and phosphonic acid esters in the development of enzyme inhibitors against protein tyrosine phosphatases, sphingomyelinases, purine nucleoside phosphorylases and thrombin. The enzyme inhibitors developed were used as probes to elucidate signal transductions and the mechanisms of enzyme actions. The findings of the studies are briefly described.
膦酸和次膦酸，尤其是α-杂原子取代的膦酸和次膦酸，具有独特的结构和物理特性，这使得它们在生物过程中能够作为生物磷酸盐的水解稳定类似物发挥作用。它们在蛋白酶诱导的二肽水解的过渡态中也起到模拟物的作用。本综述的前半部分重点介绍了我们研究小组开发的用于立体选择性合成α-杂原子取代的膦酸和次膦酸衍生物的选定新合成方法，包括修饰的核苷酸类似物和次膦酰二肽等电子体。在后半部分，本综述总结了二氟亚甲基膦酸和膦酸酯在开发针对蛋白酪氨酸磷酸酶、鞘磷脂酶、嘌呤核苷磷酸化酶和凝血酶的酶抑制剂方面的应用。所开发的酶抑制剂被用作探针来阐明信号转导和酶作用机制。简要描述了这些研究的结果。
