Abstract
Nitric oxide (NO) is a key signaling molecule that acts in various physiological processes such as cellular metabolism, vasodilation and transmission of nerve impulses. A wide number of vascular diseases as well as various immune and neurodegenerative disorders were found to be directly associated with a disruption of NO production in living organisms. These issues justify a constant search of novel NO-donors with improved pharmacokinetic profiles and prolonged action. In a series of known structural classes capable of NO release, heterocyclic NO-donors are of special importance due to their increased hydrolytic stability and low toxicity. It is no wonder that synthetic and biochemical investigations of heterocyclic NO-donors have emerged significantly in recent years. In this review, we summarized recent advances in the synthesis, reactivity and biomedical applications of promising heterocyclic NO-donors (furoxans, sydnone imines, pyridazine dioxides, azasydnones). The synthetic potential of each heterocyclic system along with biochemical mechanisms of action are emphasized.
Highlights
Nitric oxide (NO) is a key signaling molecule that acts in various physiological processes such as cellular metabolism, vasodilation and transmission of nerve impulses
This method is based on a general concept of bioorthogonal click-and-release reactions [36,38,39,40,52,53] due to the ability of sydnone imines to remove the mesoionic fragment through cycloaddition with alkyne triggers
A number of hybrid drug candidates comprising of a known pharmacologically active scaffold linked to the furoxan ring directly or via an appropriate spacer were synthesized from bromomethyl- orfuroxans using a nucleophilic substitution reaction
Summary
Nitric oxide (NO) ( known as an endothelium-derived relaxing factor) is an endogenous inorganic soluble gas produced in mammalians from L-arginine and molecular oxygen by the enzyme nitric oxide synthase (NOS) [1,2]. NO donor or overexpression of endothelial NO synthase fused to a green fluorescent protein (eNOS-GFP) has a protective effect against hypoxia-induced cellular deadhesion and greatly improves the redox balance by inhibiting the oxidative stress [14]. The progress made in the design, synthesis and biochemistry of heterocyclic NO-donors in the last decade unveiled an application potential of such organic nitrogen–oxygen molecular systems in medicinal chemistry and drug design. In this review, we summarized recent advances in the synthesis and reactivity of structurally diverse NO-donors incorporating nitrogen–oxygen-enriched heterocyclic scaffold: sydnone imines, furoxans, azasydnones and pyridazine dioxides (Figure 1). These heterocyclic subclasses were chosen due to an increased number of researches on their synthesis, functionalization and properties. NO-releasing properties, pharmacological activity and other biomedical applications along with an analysis of structure–property relationships are considered
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