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

Hisayuki Yokokura, Masanori Osawa, Tsutomu Inoue, Isao Umezawa, Yasuhito Naito, Mitsuhiko Ikura, Hiroyoshi Hidaka

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

A useful calmodulin (CaM) antagonist, N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7), was invented by Hidaka et al. in 1978. 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-xylene-diamine ((W-7)2- 10), inhibits CaM kinase I activity at an IC50 value of 0.23 μM; 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.

Original languageEnglish
Pages (from-to)203-216
Number of pages14
JournalDrug Design and Discovery
Volume16
Issue number3
Publication statusPublished - 1999
Externally publishedYes

Fingerprint

Calmodulin
Calcium
Calcium-Calmodulin-Dependent Protein Kinases
Calcium-Calmodulin-Dependent Protein Kinase Type 1
W 7
Diamines
Inhibitory Concentration 50
Magnetic Resonance Spectroscopy

Keywords

  • Ca signaling
  • CaM
  • Covalently cross-linked derivatives of W-7
  • Structure-activity relationship
  • Structure-based drug design

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

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. / Yokokura, Hisayuki; Osawa, Masanori; Inoue, Tsutomu; Umezawa, Isao; Naito, Yasuhito; Ikura, Mitsuhiko; Hidaka, Hiroyoshi.

In: Drug Design and Discovery, Vol. 16, No. 3, 1999, p. 203-216.

Research output: Contribution to journalArticle

Yokokura, Hisayuki ; Osawa, Masanori ; Inoue, Tsutomu ; Umezawa, Isao ; Naito, Yasuhito ; Ikura, Mitsuhiko ; Hidaka, Hiroyoshi. / 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. In: Drug Design and Discovery. 1999 ; Vol. 16, No. 3. pp. 203-216.
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