ChemInform Abstract: PROPERTIES OF 3‐BROM‐1,2‐DIAZETINE 1,2‐DIOXIDES

Tikhonova, L. A.; Володарский, Л. Б.

doi:10.1002/chin.197721151

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“…The reduction of these compounds was reported to lead to formation of 1,2-nitroso oximes. 4 However, neither hydroxyamino oxime 5a nor 3-methyl-3-nitrosobutan-2one oxime was found to release NO in the absence or presence of thiols. Formation of 5a was not detected after addition of 3-methyl-3-nitrosobutan-2-one oxime to cysteine solution in phosphate buffer at 25 °C.…”

Section: Resultsmentioning

confidence: 97%

“…Destruction of the diazetine ring of DD was suggested to proceed via N−N bond splitting with intermediate formation of vicinal bis-nitroso compounds. The reduction of these compounds was reported to lead to formation of 1,2-nitroso oximes . However, neither hydroxyamino oxime 5a nor 3-methyl-3-nitrosobutan-2-one oxime was found to release NO in the absence or presence of thiols.…”

Section: Resultsmentioning

confidence: 99%

“…The ratio of the decay rates of 2a and N-acetylcysteamine (d[2a]/d[RSH], formal stoichiometry of the process) increases at low thiol concentration, indicating either that the intermediate is accumulated or that the partition into different pathways is thiol-dependent. Formation of a vicinal bisnitroso derivative 4 seems to be unlikely because the plot of ln [DD] vs time was linear at various thiol concentrations (data not shown). Moreover, this dinitroso compound could hardly react with thiols in a reversible manner.…”

Section: Discussionmentioning

confidence: 99%

“…Diazetine dioxides are known to react with various nucleophilic and reducing agents. These reactions can proceed via diazetine ring opening and may be accompanied by a loss of one of the nitrogen atoms of the heterocycle . The ability of DD to react with thiols was questioned 2a and is not explicitly investigated.…”

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confidence: 99%

“…These reactions can proceed via diazetine ring opening and may be accompanied by a loss of one of the nitrogen atoms of the heterocycle. 4 The ability of DD to react with thiols was questioned 2a and is not explicitly investigated. This study was accomplished in order to elucidate the contradiction between the strong vasorelaxant effect of DD and its low rate of spontaneous decomposition.…”

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confidence: 99%

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Thiol-Induced Nitric Oxide Release from 3-Halogeno-3,4-dihydrodiazete 1,2-Dioxides

Kirilyuk¹,

Utepbergenov

Mazhukin³

et al. 1998

J. Med. Chem.

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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.

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Section: Resultsmentioning

confidence: 97%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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