Design and Evaluation of Hydroxamate Derivatives as Metal-Mediated Inhibitors of a Protein Tyrosine Kinase
摘要:
Protein tyrosine kinases use two Mg2+ ions as cofactors in catalysis, one as the ATP-Mg complex (M1) and the other as an essential activator (M2). The M2-binding site has high affinity for transition metal cations such as cobalt and zinc. Taking advantage of this high affinity, we examined hydroxamates as metal-mediated inhibitors against C-terminal Src kinase (Csk), a protein tyrosine kinase. Of a small group of amino acid hydroxamates, tyrosine and phenylalanine hydroxamates inhibited Csk activity only in the presence of Co2+. Four classes of phenylalanine and tyrosine hydroxamate derivatives were synthesized and evaluated as metal-mediated inhibitors of Csk, leading to improved inhibition and a better understanding of the structure-activity relationships. This study suggests that hydroxamates may serve as a general scaffold for developing metal-mediated inhibitors against protein tyrosine kinases. To the best of our knowledge, this is the first report of designing metal-mediated inhibitors against a protein tyrosine kinase by targeting a metal binding site.
Hydroxamic Acid Derivative And Age Generation Inhibitor Containing The Derivative
申请人:Kakuchi Junji
公开号:US20080132539A1
公开(公告)日:2008-06-05
To provide a novel compound which inhibits the generation of AGE and an AGE generation inhibitor containing the compound. A compound represented by the following formula or a pharmaceutically acceptable salt thereof, a medicinal composition containing the compound or such a salt thereof, and an additive composition containing the compound.
HYDROXAMIC ACID DERIVATIVE AND AGE GENERATION INHIBITOR CONTAINING THE DERIVATIVE
申请人:Kureha Corporation
公开号:EP1707560A1
公开(公告)日:2006-10-04
To provide a novel compound which inhibits the generation of AGE and an AGE generation inhibitor containing the compound. A compound represented by the following formula or a pharmaceutically acceptable salt thereof, a medicinal composition containing the compound or such a salt thereof, and an additive composition containing the compound.
提供一种抑制 AGE 生成的新型化合物和一种含有该化合物的 AGE 生成抑制剂。一种由下式代表的化合物或其药学上可接受的盐、一种含有该化合物或其盐的药物组合物,以及一种含有该化合物的添加剂组合物。
Design and Evaluation of Hydroxamate Derivatives as Metal-Mediated Inhibitors of a Protein Tyrosine Kinase
作者:Xianfeng Gu、Yuehao Wang、Anil Kumar、Guofeng Ye、Keykavous Parang、Gongqin Sun
DOI:10.1021/jm061058c
日期:2006.12.1
Protein tyrosine kinases use two Mg2+ ions as cofactors in catalysis, one as the ATP-Mg complex (M1) and the other as an essential activator (M2). The M2-binding site has high affinity for transition metal cations such as cobalt and zinc. Taking advantage of this high affinity, we examined hydroxamates as metal-mediated inhibitors against C-terminal Src kinase (Csk), a protein tyrosine kinase. Of a small group of amino acid hydroxamates, tyrosine and phenylalanine hydroxamates inhibited Csk activity only in the presence of Co2+. Four classes of phenylalanine and tyrosine hydroxamate derivatives were synthesized and evaluated as metal-mediated inhibitors of Csk, leading to improved inhibition and a better understanding of the structure-activity relationships. This study suggests that hydroxamates may serve as a general scaffold for developing metal-mediated inhibitors against protein tyrosine kinases. To the best of our knowledge, this is the first report of designing metal-mediated inhibitors against a protein tyrosine kinase by targeting a metal binding site.