Use of the furoxan (1,2,5-oxadiazole 2-oxide) system in the design of new NO-donor antioxidant hybrids

2006 ARKIVOC  
The design, the synthesis and the study of the antioxidant and vasodilating properties of new hybrids obtained by linking different antioxidant phenolic moieties to the furoxan substructure present in CHF2363, which can release nitric oxide, are described. All the final NO-phenols were endowed with both antioxidant and vasodilating properties. The antioxidant activities were assessed on the ferrous salt/ascorbate induced autooxidation of lipids present in microsomial membranes of rat
more » ... s of rat hepatocytes. The vasodilating activities were assessed on rat aorta strips precontracted with phenylephrine, in the presence and absence of ODQ. The antioxidant potencies (IC 50 values) and the vasodilating potencies (EC 50 values) were widely modulated into the series. Further in vivo studies should clarify whether these products may become preclinical candidates for the treatment of atherosclerosis and related disorders. ARKAT cellular targets to NO. Again the excess O 2 -• may be responsible for: 1) the trapping of nitric oxide to generate peroxynitrite (-OONO) which, in turn, can afford two very reactive and toxic radicals, the OH• and the nitrogen dioxide radical (NO 2 •); 2) reaction with thiol residues of proteins. The consequent inactivation of these residues, normally involved in S-nitrosylation, prevents this reaction from occurring, thus resulting in the perturbation of this signalling mechanism with the consequent decrease of vessel responsiveness to NO•. [18] [19] [20] By contrast there is experimental evidence that, at least in vitro, the responsiveness to the vasodilating action of exogenous NO released by NO-donors, such as glyceryl trinitrate and nitroprusside, is largely preserved and that the effects mediated by endogenous NO could be reconstituted/mimicked. This is most likely due to the relatively high doses of the compounds used in the experiments with respect to physiologically produced NO concentrations. 20 Issue ICHC-20 ARKIVOC 2006 (vii) 301-309 ARKAT furoxan chemistry emerges, which is worthy of additional investigation: the potential antioxidant activity of furoxan derivatives. CHF 2363 in fact displays both a potent vasodilating activity and a 2-3 fold higher antioxidant action than p-cresol. This may be due to the product's ability to directly scavenge radicals and/or to small amounts of NO released by the product under the experimental conditions used for the evaluation of the antioxidant activity. It is known that low concentrations of NO display antioxidant actions. 25 Indeed we were able to detect, using a NO selective electrode (WPI, ISO-NO Mark II, equipped with ISONOP200) a release of NO from CHF 2363 when the product was incubated with microsomial membranes, ascorbate and ferrous salt. Further investigations are necessary to clarify this point. Issue ICHC-20 ARKIVOC 2006 (vii) 301-309
doi:10.3998/ark.5550190.0007.722 fatcat:oqhvkdytbzdbbg73vm2fdggrsu