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Thiol-induced nitric oxide release from 3-halogeno-3,4-dihydrodiazete 1,2-dioxides Full article

Journal Journal of Medicinal Chemistry
ISSN: 0022-2623
Output data Year: 1998, Volume: 41, Number: 7, Pages: 1027-1033 Pages count : 7 DOI: 10.1021/jm960737s
Authors Kirilyuk I.A. 1 , Utepbergenov D.I. 1 , Mazhukin D.G. 1 , Fechner K. 3 , Mertsch K. 3 , Khramtsov V.V. 2 , Blasig I.E. 3 , Haseloff R.F. 3
Affiliations
1 Novosibirsk Institute of Organic Chemistry, Novosibirsk 630090, Russia
2 Chemical Kinetics and Combustion, Novosibirsk 630090, Russia
3 Institute of Molecular Pharmacology, Alfred-Kowalke-Strasse 4, D-10315 Berlin, Germany

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-3,4-hexamethylene-DD (4), and their reactivity toward thiols 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 1a 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.
Cite: Kirilyuk I.A. , Utepbergenov D.I. , Mazhukin D.G. , Fechner K. , Mertsch K. , Khramtsov V.V. , Blasig I.E. , Haseloff R.F.
Thiol-induced nitric oxide release from 3-halogeno-3,4-dihydrodiazete 1,2-dioxides
Journal of Medicinal Chemistry. 1998. V.41. N7. P.1027-1033. DOI: 10.1021/jm960737s WOS Scopus РИНЦ OpenAlex
Dates:
Published print: Mar 1, 1998
Identifiers:
Web of science: WOS:000072852600004
Scopus: 2-s2.0-0032568421
Elibrary: 13297386
OpenAlex: W2043000798
Citing:
DB Citing
Web of science 17
Scopus 18
Elibrary 16
OpenAlex 15
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