N-(6-氨基己基)-5-氯-1-萘磺酰胺(W-7)的对称共价键导致对钙/钙调素复合物具有增强抑制活性的新型衍生物。

Drug design and discovery Pub Date : 1999-11-01
H Yokokura, M Osawa, T Inoue, I Umezawa, Y Naito, M Ikura, H Hidaka
{"title":"N-(6-氨基己基)-5-氯-1-萘磺酰胺(W-7)的对称共价键导致对钙/钙调素复合物具有增强抑制活性的新型衍生物。","authors":"H Yokokura,&nbsp;M Osawa,&nbsp;T Inoue,&nbsp;I Umezawa,&nbsp;Y Naito,&nbsp;M Ikura,&nbsp;H Hidaka","doi":"","DOIUrl":null,"url":null,"abstract":"<p><p>A useful calmodulin (CaM) antagonist, N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7), was invented by Hidaka et al. in 1978 (J. Pharmacol. Exp. Ther. 207, 8-15). Here, we have designed new CaM antagonists on the basis of the three-dimensional structure of Ca2+/CaM complexed with W-7. Eleven new compounds all share a similar architecture, in which two W-7 molecules are linked between their aminohexyl termini by a linker with different functionalities. A wide range of inhibitory activities against Ca2+/CaM-dependent protein kinase I (CaM kinase I) has been observed with these self-crosslinked W-7 analogs, (W-7)2. In vitro competitive CaM kinase I assays using CaM kinase I and nuclear magnetic resonance studies indicated that one (W-7)2 molecule binds to one CaM molecule as expected, with the two chloronaphthalene rings of (W-7)2 being anchored separately to the N- and C-terminal hydrophobic pockets of Ca2+/CaM. The most potent compound, N,N'-bis[6-(5-chloro-1-naphthalenesulfonyl)-amino-1-hexyl]-p-xylen e-diamine ((W-7)2 - 10), inhibits CaM kinase I activity at an IC50 value of 0.23 microM; about 75 times more effectively than W-7. The length and basicity of the linker sequence in (W-7)2 significantly contribute to inhibitory activity. The present study opens an avenue for developing powerful CaM antagonists that could be used at low doses in vivo.</p>","PeriodicalId":11297,"journal":{"name":"Drug design and discovery","volume":"16 3","pages":"203-16"},"PeriodicalIF":0.0000,"publicationDate":"1999-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Symmetric covalent linkage of N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7) results in novel derivatives with increased inhibitory activities against calcium/calmodulin complex.\",\"authors\":\"H Yokokura,&nbsp;M Osawa,&nbsp;T Inoue,&nbsp;I Umezawa,&nbsp;Y Naito,&nbsp;M Ikura,&nbsp;H Hidaka\",\"doi\":\"\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>A useful calmodulin (CaM) antagonist, N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7), was invented by Hidaka et al. in 1978 (J. Pharmacol. Exp. Ther. 207, 8-15). Here, we have designed new CaM antagonists on the basis of the three-dimensional structure of Ca2+/CaM complexed with W-7. Eleven new compounds all share a similar architecture, in which two W-7 molecules are linked between their aminohexyl termini by a linker with different functionalities. A wide range of inhibitory activities against Ca2+/CaM-dependent protein kinase I (CaM kinase I) has been observed with these self-crosslinked W-7 analogs, (W-7)2. In vitro competitive CaM kinase I assays using CaM kinase I and nuclear magnetic resonance studies indicated that one (W-7)2 molecule binds to one CaM molecule as expected, with the two chloronaphthalene rings of (W-7)2 being anchored separately to the N- and C-terminal hydrophobic pockets of Ca2+/CaM. The most potent compound, N,N'-bis[6-(5-chloro-1-naphthalenesulfonyl)-amino-1-hexyl]-p-xylen e-diamine ((W-7)2 - 10), inhibits CaM kinase I activity at an IC50 value of 0.23 microM; about 75 times more effectively than W-7. The length and basicity of the linker sequence in (W-7)2 significantly contribute to inhibitory activity. The present study opens an avenue for developing powerful CaM antagonists that could be used at low doses in vivo.</p>\",\"PeriodicalId\":11297,\"journal\":{\"name\":\"Drug design and discovery\",\"volume\":\"16 3\",\"pages\":\"203-16\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"1999-11-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Drug design and discovery\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Drug design and discovery","FirstCategoryId":"1085","ListUrlMain":"","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0

摘要

1978年,Hidaka等人发明了一种有用的钙调素(CaM)拮抗剂N-(6-氨基己基)-5-氯-1-萘磺酰胺(W-7)。Exp. Ther. 207,8 -15)。在此,我们基于Ca2+/CaM与W-7络合的三维结构设计了新的CaM拮抗剂。11种新化合物都有相似的结构,其中两个W-7分子通过具有不同功能的连接物连接在它们的氨基己基端。这些自交联的W-7类似物对Ca2+/CaM依赖性蛋白激酶I (CaM激酶I)具有广泛的抑制活性,(W-7)2。使用CaM激酶I和核磁共振研究进行的体外竞争性CaM激酶I分析表明,一个(W-7)2分子与一个CaM分子结合,(W-7)2的两个氯萘环分别锚定在Ca2+/CaM的N端和c端疏水袋上。最有效的化合物N,N'-双[6-(5-氯-1-萘磺基)-氨基-1-己基]-对二甲苯-二胺((W-7)2 - 10)抑制CaM激酶I活性的IC50值为0.23微米;效率是W-7的75倍。(W-7)2中连接子序列的长度和碱度对抑制活性有显著影响。目前的研究为开发低剂量的强效CaM拮抗剂开辟了一条道路。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Symmetric covalent linkage of N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7) results in novel derivatives with increased inhibitory activities against calcium/calmodulin complex.

A useful calmodulin (CaM) antagonist, N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7), was invented by Hidaka et al. in 1978 (J. Pharmacol. Exp. Ther. 207, 8-15). Here, we have designed new CaM antagonists on the basis of the three-dimensional structure of Ca2+/CaM complexed with W-7. Eleven new compounds all share a similar architecture, in which two W-7 molecules are linked between their aminohexyl termini by a linker with different functionalities. A wide range of inhibitory activities against Ca2+/CaM-dependent protein kinase I (CaM kinase I) has been observed with these self-crosslinked W-7 analogs, (W-7)2. In vitro competitive CaM kinase I assays using CaM kinase I and nuclear magnetic resonance studies indicated that one (W-7)2 molecule binds to one CaM molecule as expected, with the two chloronaphthalene rings of (W-7)2 being anchored separately to the N- and C-terminal hydrophobic pockets of Ca2+/CaM. The most potent compound, N,N'-bis[6-(5-chloro-1-naphthalenesulfonyl)-amino-1-hexyl]-p-xylen e-diamine ((W-7)2 - 10), inhibits CaM kinase I activity at an IC50 value of 0.23 microM; about 75 times more effectively than W-7. The length and basicity of the linker sequence in (W-7)2 significantly contribute to inhibitory activity. The present study opens an avenue for developing powerful CaM antagonists that could be used at low doses in vivo.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
自引率
0.00%
发文量
0
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信