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

Furoxan, 1,2,5-oxadiazole 2-oxide, 1 is an old heterocyclic system known to chemists thanks to an argument over its structure and its intriguing chemistry. Recently the ability of furoxan derivatives to activate the soluble guanylate cyclase (sGC) as a consequence of their capacity of releasing NO in vitro under the action of thiol cofactors was demonstrated.1,2 This finding generated a renewed interest toward the properties of this heterocycle, both from academia and industry.3 Nitric oxide is a physiological messenger involved in a wide range of biological functions.4 In particular NO exerts potent effects on vascular homeostasis, such as smooth muscle relaxation, inhibition of platelet adherence and aggregation, attenuation of monocyte infiltration. Atherosclerosis is the main cause of morbidity and mortality in the western society.5 Oxidative stress, consequent to an abnormal production of ROS (reactive oxygen species) when the correct balance between the prooxidant/antioxidant status in the organism is perturbed, is the main cause that triggers the atherosclerotic process. One of the first steps in this complex process is the oxidative modification of high levels of LDLs, leading to formation of foam cells.5,6 Experimental evidence supports the hypothesis that exogenous antioxidants can reduce LDL oxidation. In an atherosclerotic blood vessel endothelial dysfunction involves an impairment of NO mediated bioactions due to a reduced NO synthesis, a decreased responsiveness of target cells to NO and an increased NO inactivation by the action of oxygen free radicals. By contrast, vasodilation in response to appropriate concentrations of exogenous NO seems to be preserved.7 New therapeutic strategies for atherosclerosis could be aimed at improving the redox status by administration of antioxidants and at restoring NO functions via the administration of NO-donor molecules. Recently we started a project aimed at the design, synthesis and biological evaluation of a series of NO-donor antioxidants. In the first part of our work we developed a series of hybrid structures where some appropriately selected phenols, known for their antioxidant activity, were linked to substituted furoxan derivatives to yield NO-donor antioxidants. Herein we report on the chemistry, vasodilating properties and antioxidant activity of this series of compounds. The role of the parent furoxan heterocycle in the biological actions of these products is also investigated.