Structure-based design of a selective heparanase inhibitor as an antimetastatic agent.
Structure-based design of a selective heparanase inhibitor as an antimetastatic agent.
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DOI：
10.1158/1535-7163.1069.3.9
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发表时间：
2004-09
影响因子：
5.7
通讯作者：
K. Ishida;Go Hirai;K. Murakami;T. Teruya;S. Simizu;M. Sodeoka;H. Osada
中科院分区：
文献类型：
--
作者：
K. Ishida;Go Hirai;K. Murakami;T. Teruya;S. Simizu;M. Sodeoka;H. Osada
肝素酶是一种内切β - d -葡萄糖醛酸酶，可降解细胞外基质和基底膜中的硫酸肝素糖胺聚糖，并参与肿瘤细胞侵袭和血管生成。我们已经将肝素酶作为抗肿瘤药物，特别是抗转移药物的靶点。(R)-3-hexadecanoyl-5-hydroxymethyltetronic acid （RK-682）在筛选天然来源时发现对肝素酶具有抑制活性。由于RK-682已被报道对几种酶具有抑制活性，我们尝试用合理的药物设计方法开发选择性肝素酶抑制剂。根据肝素酶/RK-682配合物的结构，我们推测对肝素酶的选择性抑制活性可以通过芳基烷基化，即通过RK-682的4位苄基化获得。在合理设计的4-烷基- rk -682衍生物中，发现4-苄基- rk -682对肝素酶具有选择性抑制活性（对肝素酶的IC50为17微mol/L，对其他酶的IC50为100微mol/L）。4-Benzyl-RK-682对人纤维肉瘤HT1080细胞的侵袭和迁移也有抑制作用（侵袭IC50为1.5 micromol/L，迁移IC50为3.0 micromol/L）。另一方面，RK-682在高达100微mol/L的剂量下对HT1080细胞的侵袭和迁移没有抑制作用。
Heparanase is an endo-beta-D-glucuronidase that degrades heparan sulfate glycosaminoglycans in the extracellular matrix and the basement membrane and is well known to be involved in tumor cell invasion and angiogenesis. We have focused on heparanase as a target for antitumor agents, especially antimetastatic agents. (R)-3-hexadecanoyl-5-hydroxymethyltetronic acid (RK-682) was found to display an inhibitory activity against heparanase in our screening of natural sources. Because RK-682 has been reported to show inhibitory activities against several enzymes, we have tried to develop selective heparanase inhibitors using the method of rational drug design. Based on the structure of the heparanase/RK-682 complex, we speculated that selective inhibitory activity against heparanase could be acquired by arylalkylation, namely, by benzylation of the 4-position of RK-682. Among the rationally designed 4-alkyl-RK-682 derivatives, 4-benzyl-RK-682 has been found to possess a selective inhibitory activity for heparanase (IC50 for heparanase, 17 micromol/L; IC50 for other enzymes, >100 micromol/L). 4-Benzyl-RK-682 also inhibited the invasion and migration of human fibrosarcoma HT1080 cells (IC50 for invasion, 1.5 micromol/L; IC50 for migration, 3.0 micromol/L). On the other hand, RK-682 had no inhibitory effect on the invasion and migration of HT1080 cells at doses of up to 100 micromol/L.