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

Igor A. Kirilyuk, Darkhan I. Utepbergenov, Dmitrii G. Mazhukin, Klaus Fechner, Katharina Mertsch, Valery V. Khramtsov, Ingolf E. Blasig, Reiner F. Haseloff

Research output: Contribution to journalArticle

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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 languageEnglish
Pages (from-to)1027-1033
Number of pages7
JournalJournal of Medicinal Chemistry
Volume41
Issue number7
DOIs
Publication statusPublished - Mar 26 1998
Externally publishedYes

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Sulfhydryl Compounds
Nitric Oxide
Oximes
Derivatives
Vasodilator Agents
Endothelial cells
Vasodilation
Reaction kinetics
Reaction rates
Cysteine
Rats
Endothelial Cells
Arteries

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Kirilyuk, I. A., Utepbergenov, D. I., Mazhukin, D. G., Fechner, K., Mertsch, K., Khramtsov, V. V., ... Haseloff, R. F. (1998). Thiol-induced nitric oxide release from 3-halogeno-3,4-dihydrodiazete 1,2-dioxides. Journal of Medicinal Chemistry, 41(7), 1027-1033. https://doi.org/10.1021/jm960737s

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 journalArticle

Kirilyuk, IA, Utepbergenov, DI, Mazhukin, DG, Fechner, K, Mertsch, K, Khramtsov, VV, Blasig, IE & Haseloff, RF 1998, 'Thiol-induced nitric oxide release from 3-halogeno-3,4-dihydrodiazete 1,2-dioxides' Journal of Medicinal Chemistry, vol. 41, no. 7, pp. 1027-1033. https://doi.org/10.1021/jm960737s
Kirilyuk, Igor A. ; Utepbergenov, Darkhan I. ; Mazhukin, Dmitrii G. ; Fechner, Klaus ; Mertsch, Katharina ; Khramtsov, Valery V. ; Blasig, Ingolf E. ; Haseloff, Reiner F. / Thiol-induced nitric oxide release from 3-halogeno-3,4-dihydrodiazete 1,2-dioxides. In: Journal of Medicinal Chemistry. 1998 ; Vol. 41, No. 7. pp. 1027-1033.
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AU - Fechner, Klaus

AU - Mertsch, Katharina

AU - Khramtsov, Valery V.

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