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

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.

Reaction of Nitric Oxide at the β-Carbon of Enamines. A New Method of Preparing Compounds Containing the Diazeniumdiolate Functional Group

“…While there certainly are compounds whose solid-state X-ray crystal structures resemble 16 that do not release NO spontaneously (Cupferron, X = Ph, is one example) and the mechanism of NO release from 16 is not yet fully understood, the literature to date suggests that if 15 is favored over 16 dissociation to NO is inhibited. We note that both enamine diazeniumdiolate 5 (in one tautomeric form) and the previously known NO donor N -( p -methoxybenzyl)- N -nitrosohydroxyguanidine 18 exhibit the conjugated double-bond system shown in 17 while zwitterions 8 − 14 do not, and that this system is also the proposed NO-releasing intermediate arising from the dihydrodiazete 1,2-dioxides . This suggests that future efforts to produce spontaneous NO releasers should be directed toward this type of system.…”

Nitric Oxide-Releasing Molecules for Cancer Therapy and Chemoprevention

“…They can also be considered to be highly strained intramolecular C-NO dimers that decompose in aqueous solutions to liberate two moles of NO per mole of compound, at physiological temperature and pH. Intracellularly, the rate of NO release from these compounds or their halogenated derivatives depends upon the concentration of thiolate anions (Kirilyuk et al 1998). Diazetine dioxides exhibit strong vasorelaxant and anti-aggregative properties, attributable to the activation of sGC to release NO (Severina et al 1994(Severina et al , 1996.…”

Construction of 3,4‐dihydro‐1,2‐diazete ring through 4π electron cyclization of 4‐hydroxy‐2‐oxo‐2H chromene‐3‐carbaldehyde [(1E)‐arylmethylene] hydrazone

“…1,2‐Diazetine N , N ‐dioxides (diazetine dioxides) are a class of strained four‐membered ring azo dioxide heterocycles. Although the first report of a diazetine dioxide was as early as 1971, only a handful of such compounds are currently known [5–9]. Diazetine dioxides have been used as highly effective low‐energy triplet quenchers in photochemical reactions [10] and have been recently investigated for their biological activity as potent vasorelaxant and antiaggregant agents [7–9, 11].…”

“…Although the first report of a diazetine dioxide was as early as 1971, only a handful of such compounds are currently known [5–9]. Diazetine dioxides have been used as highly effective low‐energy triplet quenchers in photochemical reactions [10] and have been recently investigated for their biological activity as potent vasorelaxant and antiaggregant agents [7–9, 11]. One of the more intriguing aspects of the reactivity of diazetine dioxides is their tendency to liberate 2 equiv of nitric oxide (NO) upon decomposition to yield the corresponding alkene [5, 7].…”