Donors 5-nitrosothiols

S-nitrosothiols (RSNO) have emerged as important species in the storage and transport of nitric oxide. As NO donors these S-N compounds have potential medical applications in the treatment of blood circulation problems. 

Recently, it has been found that NO donors inhibit HIV-1 replication in acutely infected human peripheral blood mononuclear cells (PBMCs), and have an additive inhibitory effect on HIV-1 replication in combination with 3 -azido-3 -deoxythymisylate (AZT) [139, 140]. S-nitrosothiols (RSNOs) inhibit HIV-1 replication at a step in the viral replicative cycle after reverse transcription, but before or during viral protein expression through a cGMP-independent mechanism. In the latently infected U1 cell line, NO donors and intracellular NO production stimulate HIV-1 reactivation. These studies suggest that NO both inhibits HIV-1 replication in acutely infected cells and stimulates HIV-1 reactivation in chronically infected cells. Thus, NO donors may be useful in the treatment of HIV-1 disease by inhibiting acute infection, or reactivating a latent virus. 

Type II nitrosamines have two reaction pathways. One pathway involves nucleophilic attack at the carbon of C=0 to generate a tetrahedral intermediate which decomposes to an active diazotate ion (R-N=N-0 ). The other pathway involves the nucleophililc attack on the nitrogen of the nitroso group resulting in denitrosation (Scheme 3.5). The nucleophile can be a biologically prevalent thiol, therefore type II compounds are often used as NO donors for the formation of S-nitrosothiols [67, 68]. 

The capacity of furoxan derivatives to behave as NO-donors was first demonstrated by Feelisch et al. [19], who showed that furoxan derivatives produce nitric oxide when dissolved in physiological solution in the presence of thiols. Among the reaction products, they isolated nitrite and, in lesser amounts, nitrate, which are the final oxidation products of nitric oxide in aerobic water solution, as well as dioxime derivatives, which are the reduction products of the furoxans. They also evidenced a marked p H -dependent production of S-nitrosothiols. Working with N, AF-diisopropylfuroxan-3,4-dicarboxamide (29, Ipramidil) and an excess of glutathione (GSH), the amount of S-nitrosoglutathione formed increased with increasing pH until pH 9, above which it... 

Despite intense study of the chemical reactivity of the inorganic NO donor SNP with a number of electrophiles and nucleophiles (in particular thiols), the mechanism of NO release from this drug also remains incompletely understood. In biological systems, both enzymatic and non-enzymatic pathways appear to be involved [28]. Nitric oxide release is thought to be preceded by a one-electron reduction step followed by release of cyanide, and an inner-sphere charge transfer reaction between the ni-trosonium ion (NO+) and the ferrous iron (Fe2+). Upon addition of SNP to tissues, formation of iron nitrosyl complexes, which are in equilibrium with S-nitrosothiols, has been observed. A membrane-bound enzyme may be involved in the generation of NO from SNP in vascular tissue [35], but the exact nature of this reducing activity is unknown. 

Since the discovery that nitric oxide is crucially involved in a range of physiological processes and indeed that it is synthesized in vivo from L-arginine (for review articles see References 19-22), there has been intense interest in a range of compounds which might act as NO donors. Consequently, the most studied reaction of nitrosothiols is that where decomposition to nitric oxide occurs. 

Figure 8.2 Proposed mode of action of the organic nitrates, nitroglycerin and nitroprusside. Note that nitroprusside acts as a direct donor of nitric oxide (NO), whereas the nitrates require the presence of nitrosothiols to produce NO.

Due to the potential of NO as a therapeutic, the synthesis and biological applications of synthetic NO donors have been the focus of intense study.33 34 Despite the enormous variety among NO donors, diazeniumdiolates and nitrosothiols have emerged as the most widely studied systems. With respect to glucose sensor membranes, diazeniumdiolates have been used exclusively as NO release sources.7,17,24... 

Iron complexes are involved in various steps of NO metabolism most of these complexes also contain various sulfur ligands. Iron nitrosyls and nitrosothiols are the most relevant agents responsible for storage and transport of NO and related compounds nitrosothiols and metal nitrosyl complexes belong to the most important external sources of NO (NO-donors) (42). 

In 1980 Ignarro and colleagues [53] published a possible mechanism requiring the reduction of nitrates intracellularly by sulphydryl donors to form an S-nitrosothiol active intermediate that in turn directly, or by degrading to nitric oxide, activated guanylate cyclase. As discussed above, these and other experiments led to the description of the EDRF and NOS enzyme systems. 

Nitrosothiols such as cysteine-NO, glutathione-NO, and S-nitroso-N-acetylpenicillamine (SNAP) are often used a nitric oxide donors. The biological effects of these compounds suggest that they do, in fact, release significant amounts of nitric oxide, but the mechanism of release is not at... 

Shaffer et al. (1992) also confirmed our observations in normal rabbits. Taken together, the sydnonimine and S-nitrosothiol data suggest that the hemodynamic tolerance so often observed with nitrate therapy is not a general phenomenon for all NO donors. Further studies are needed to determine whether replacement of traditional NO donors with these or other novel agents can lead to therapeutic improvements. 

In 2010 S. Sortino reviewed the state-of-the-art on light-triggered NO donors. There are mainly two classes of organic compounds acting as light-triggered NO donors the first class is based on p-trifluoro-y-nitro-aniline (NA) and S-nitrosothiols (SNT), the second class contains d-metal complexes. Only the first class has been studied in combination with CD-based nanosystems. 

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