Molecular Hybridization Tools in the Development of Furoxan‐Based NO‐Donor Prodrugs

Abstract

The molecular hybridization of different compounds with known pharmacological activity is a particularly prominent approach for the design of potential drugs with improved pharmacokinetic profiles. Much attention over the last decade has been focused on the synthesis of hybrid structures with a nitric oxide (NO)-donor framework, as NO is a ubiquitous and crucial regulator of cellular metabolism, affecting various physiological and pathophysiological processes. 1,2,5-Oxadiazole 2-oxides (furoxans), which are capable of exogenous NO release in the presence of thiol cofactors, are an important class of prospective NO donors. As such, a wide range of hybrid compounds that combine a furoxan ring with various pharmacologically active structures have been created. This review focuses on recent results in the synthesis and pharmacological activity of furoxan-based hybrids. Special attention is given to chemo- and regioselective methods used in the preparation of these hybrid structures, and the role of synergistic effects on their pharmacological activity, associated with the furoxan fragment.

A Focused Library of NO‐Donor Compounds with Potent Antiproliferative Activity Based on Green Multicomponent Reactions

“…Among nitric oxide releasing moieties, furoxan has attracted considerable attention due to its stability under ambient conditions and ability to produce large fluxes of NO by a thiol‐dependent mechanism, thereby eliciting the cytotoxic effects associated with NO. Unlike organic nitrates, furoxans do not promote tolerance under continuous therapy . Organic nitrates are the oldest and structurally simplest NO‐donor with an important role in cardiovascular therapy but also have demonstrated anticancer properties in vitro and in vivo .…”

“…Unlike organic nitrates,f uroxansd on ot promote tolerance under continuous therapy. [31,41] Organicn itrates are the oldest and structurally simplest NO-donorw ith an important role in cardiovascular therapy but also have demonstrated anticancer properties in vitro and in vivo. [42] Many efforts have been made to fully elucidate the mechanism of NO generation by organic nitrates.…”

“…[28] Recently,t he role of NO in cancer has been studied and it hasbeen determined that at high concentrations, this free radical acts as an antineoplastic agent.I n this context, NO-donorh ybrid compoundsh ave been extensively investigated. [29,30] There is aw ide variety of chemical structures capable of releasing NO, such as organic nitrates and 1,2,5-oxadiazole N-oxides (furoxans), [31] which have been used as precursors for the synthesis of new potential anticancer agents. Therefore, the developmento fn ew and effective NO-donorh ybrid molecules remains ac urrent challenge in medicinal chemistry,e specially in the design of new probes to manipulate biochemical pathways involving this free radical.…”

Synthesis, structural characterization and cytotoxic activity of heterocyclic compounds containing the furoxan ring

“…It is well-known that furoxans behave as NO donors in presence of thiol cofactors. 5,10,11 At the same time, the formation of nitrite-anion as a result of NO oxidation may be quantified according to Griess assay and thus may serve as a reliable tool for measuring the amount of NO release. The amounts of NO 2 -produced of the selected hetarylfuroxan structures under physiological conditions (pH 7.4; 37 °C) after 1 h incubation were measured via the Griess reaction using a spectrophotometric technique.…”

“…Over thirty years ago it was established that NO is one of the crucial regulator molecules for cellular metabolism, affecting various physiological and pathophysiological processes. [4][5][6] Many different types of compounds have been synthesized and tested as NO donors (guanidines, nitramines, oximes, mesoionic systems, heterocyclic N-oxides, etc. ), [7][8][9] including the 1,2,5-oxadiazole 2-oxides (furoxans) which are capable of exogenous NO release at the presence of thiol cofactors.…”