Abstract
In this work we studied the mechanism of nitric oxide (NO) release underlying the vasorelaxant and antiaggregant effect of 3,4-dihydrodiazete 1,2-dioxides (DD). Six derivatives were included in the investigations, namely, 3-bromo- and 3-chloro-3,4,4-trimethyl-DD (1a,b), 3-bromo- and 3- chloro-4-methyl-3,4-hexamethylene-DD (2a,b), 3,3,4,4-tetramethyl-DD (3), and 3-methyl-3,4hexamethylene-DD (4), and their reactivity toward thioIs was analyzed. The 3-bromo- and 3-chloro-DD derivatives were found to react with thiols; this reaction can lead to NO formation, DD 2a being the most reactive compound. 2-(Hydroxyamino)-2-methylbutan-3-one oxime (5a) and 2-hydroxy-2- methylbutan-3-one oxime (6) were the main products isolated from the reaction of la with cysteine. Reaction rates of DD with thiols were dependent upon pH and concentration of the reagents. Maximum rates of NO release corresponded to thiol concentrations in the range of 1 mM. Consistent with reaction kinetics data and products isolated, a reaction mechanism was proposed. Addition of 2a to bovine aortic endothelial cells led to strong NO release indicating a reaction with endogenous thiols. In rat mesenterial arteries, the vasorelaxant action of 2a was only slightly influenced by addition of thiol to the incubation medium. For the most reactive DD derivatives, cytotoxic effects were observed at concentrations roughly 2 orders of magnitude higher than those inducing vasorelaxation.
| Original language | English |
|---|---|
| Pages (from-to) | 1027-1033 |
| Number of pages | 7 |
| Journal | Journal of Medicinal Chemistry |
| Volume | 41 |
| Issue number | 7 |
| DOIs | |
| Publication status | Published - Mar 26 1998 |
| Externally published | Yes |
Fingerprint
ASJC Scopus subject areas
- Organic Chemistry
Cite this
Thiol-induced nitric oxide release from 3-halogeno-3,4-dihydrodiazete 1,2-dioxides. / Kirilyuk, Igor A.; Utepbergenov, Darkhan I.; Mazhukin, Dmitrii G.; Fechner, Klaus; Mertsch, Katharina; Khramtsov, Valery V.; Blasig, Ingolf E.; Haseloff, Reiner F.
In: Journal of Medicinal Chemistry, Vol. 41, No. 7, 26.03.1998, p. 1027-1033.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Thiol-induced nitric oxide release from 3-halogeno-3,4-dihydrodiazete 1,2-dioxides
AU - Kirilyuk, Igor A.
AU - Utepbergenov, Darkhan I.
AU - Mazhukin, Dmitrii G.
AU - Fechner, Klaus
AU - Mertsch, Katharina
AU - Khramtsov, Valery V.
AU - Blasig, Ingolf E.
AU - Haseloff, Reiner F.
PY - 1998/3/26
Y1 - 1998/3/26
N2 - In this work we studied the mechanism of nitric oxide (NO) release underlying the vasorelaxant and antiaggregant effect of 3,4-dihydrodiazete 1,2-dioxides (DD). Six derivatives were included in the investigations, namely, 3-bromo- and 3-chloro-3,4,4-trimethyl-DD (1a,b), 3-bromo- and 3- chloro-4-methyl-3,4-hexamethylene-DD (2a,b), 3,3,4,4-tetramethyl-DD (3), and 3-methyl-3,4hexamethylene-DD (4), and their reactivity toward thioIs was analyzed. The 3-bromo- and 3-chloro-DD derivatives were found to react with thiols; this reaction can lead to NO formation, DD 2a being the most reactive compound. 2-(Hydroxyamino)-2-methylbutan-3-one oxime (5a) and 2-hydroxy-2- methylbutan-3-one oxime (6) were the main products isolated from the reaction of la with cysteine. Reaction rates of DD with thiols were dependent upon pH and concentration of the reagents. Maximum rates of NO release corresponded to thiol concentrations in the range of 1 mM. Consistent with reaction kinetics data and products isolated, a reaction mechanism was proposed. Addition of 2a to bovine aortic endothelial cells led to strong NO release indicating a reaction with endogenous thiols. In rat mesenterial arteries, the vasorelaxant action of 2a was only slightly influenced by addition of thiol to the incubation medium. For the most reactive DD derivatives, cytotoxic effects were observed at concentrations roughly 2 orders of magnitude higher than those inducing vasorelaxation.
AB - In this work we studied the mechanism of nitric oxide (NO) release underlying the vasorelaxant and antiaggregant effect of 3,4-dihydrodiazete 1,2-dioxides (DD). Six derivatives were included in the investigations, namely, 3-bromo- and 3-chloro-3,4,4-trimethyl-DD (1a,b), 3-bromo- and 3- chloro-4-methyl-3,4-hexamethylene-DD (2a,b), 3,3,4,4-tetramethyl-DD (3), and 3-methyl-3,4hexamethylene-DD (4), and their reactivity toward thioIs was analyzed. The 3-bromo- and 3-chloro-DD derivatives were found to react with thiols; this reaction can lead to NO formation, DD 2a being the most reactive compound. 2-(Hydroxyamino)-2-methylbutan-3-one oxime (5a) and 2-hydroxy-2- methylbutan-3-one oxime (6) were the main products isolated from the reaction of la with cysteine. Reaction rates of DD with thiols were dependent upon pH and concentration of the reagents. Maximum rates of NO release corresponded to thiol concentrations in the range of 1 mM. Consistent with reaction kinetics data and products isolated, a reaction mechanism was proposed. Addition of 2a to bovine aortic endothelial cells led to strong NO release indicating a reaction with endogenous thiols. In rat mesenterial arteries, the vasorelaxant action of 2a was only slightly influenced by addition of thiol to the incubation medium. For the most reactive DD derivatives, cytotoxic effects were observed at concentrations roughly 2 orders of magnitude higher than those inducing vasorelaxation.
UR - http://www.scopus.com/inward/record.url?scp=0032568421&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0032568421&partnerID=8YFLogxK
U2 - 10.1021/jm960737s
DO - 10.1021/jm960737s
M3 - Article
VL - 41
SP - 1027
EP - 1033
JO - Journal of Medicinal Chemistry
T2 - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 7
ER -