Design, synthesis and biological evaluation of selective boron-containing thrombin inhibitors
Design, synthesis and biological evaluation of selective boron-containing thrombin inhibitors
复制标题
DOI：
10.1016/s0968-0896(99)00069-3
复制
发表时间：
1999-07-01
影响因子：
3.5
通讯作者：
Tapparelli, C
中科院分区：
文献类型：
--
作者：
Wienand, A;Ehrhardt, C;Tapparelli, C
在比较不同胰蛋白酶样丝氨酸蛋白酶S-l袋结构的基础上，合成了一系列boc - d -三甲基硅丙氨酸-脯氨酸-硼- x蒎二醇衍生物，其中硼- x为不同的氨基硼酸，作为凝血酶抑制剂。研究了这些抑制剂P-1侧链上不同残基的氢供体/受体性质对选择性谱的影响。本研究证实了基于结构的工作假设：凝血酶（Ala/Val）、胰蛋白酶（Ser/Val）和纤溶酶（Ser/Thr） S-1袋中Asp 189邻近氨基酸残基190和213的疏水/亲水性决定了抑制剂与不同P-1残基相互作用的特异性。许多合成的化合物显示出强大的抗凝血酶活性，boc - d -三甲基硅丙氨酸-脯氨酸-硼-甲氧基丙基甘氨酸蒎二醇(9)是该系列中最具选择性的凝血酶抑制剂。1999爱思唯尔科学有限公司版权所有。
Based on the structural comparison of the S-l pocket in different trypsin-like serine proteases, a series of Boc-D-trimethylsilylalanine-proline-boro-X pinanediol derivatives, with boro-X being different amino boronic acids, have been synthesised as inhibitors of thrombin. The influence of hydrogen donor/acceptor properties of different residues in the P-1 side chain of these inhibitors on the selectivity profile has been investigated. This study confirmed the structure-based working hypothesis: The hydrophobic/hydrophilic character of amino acid residues 190 and 213 in the neighbourhood of Asp 189 in the S-1 pocket of thrombin (Ala/Val), trypsin (Ser/Val) and plasmin (Ser/Thr) define the specificity for the interaction with different P-1 residues of the inhibitors. Many of the synthesised compounds demonstrate potent antithrombin activity with Boc-D-trimethylsilylalanine-proline-boro-methoxypropylglycine pinanediol (9) being the most selective thrombin inhibitor of this series. (C) 1999 Elsevier Science Ltd. All rights reserved.