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 language | English |
|---|---|
| Pages (from-to) | 203-216 |
| Number of pages | 14 |
| Journal | Drug Design and Discovery |
| Volume | 16 |
| Issue number | 3 |
| Publication status | Published - 1999 |
| Externally published | Yes |
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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 journal › Article
}
TY - JOUR
T1 - 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
AU - Yokokura, Hisayuki
AU - Osawa, Masanori
AU - Inoue, Tsutomu
AU - Umezawa, Isao
AU - Naito, Yasuhito
AU - Ikura, Mitsuhiko
AU - Hidaka, Hiroyoshi
PY - 1999
Y1 - 1999
N2 - 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.
AB - 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.
KW - Ca signaling
KW - CaM
KW - Covalently cross-linked derivatives of W-7
KW - Structure-activity relationship
KW - Structure-based drug design
UR - http://www.scopus.com/inward/record.url?scp=0032741423&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0032741423&partnerID=8YFLogxK
M3 - Article
C2 - 10624566
AN - SCOPUS:0032741423
VL - 16
SP - 203
EP - 216
JO - Drug Design and Discovery
JF - Drug Design and Discovery
SN - 1055-9612
IS - 3
ER -