Other NO Donors

OXINO (Sodium trloxd I nitrate or Angel s Salt) 

OXIN O partially inhibited ADP-induced platelet aggregation in vitro. Flow cytometry analysis of PRP showed that OXINO decreased ADP-induced CD62P expression and fibrinogen binding on platelets [45]. 

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As well as NONOates, other NO donors also showed anticancer activity independently. Sodium nitroprusside (SNP), a metal-NO complex, showed cytotoxic effects on the cells of some patients with malignant lymphoma (ML), acute myelocytic leukemia (AML) or chronic myelomonocytic leukemia (CMMoL), but not with multiple myeloma [109]. SNP and cytosine arabinoside (Ara-C) did not share the drug resistance. Interestingly, SNP had no effect on lymphocytes of healthy volunteers. These results suggest that SNP has an anti-tumor effect on human hematological malignant cells. 

Selectivity of this kind erases any fears of systemic hypotension and hypoxemia, which is usually associated with other NO donors applied to such model systems. Similar attempts at selective vasodilation have been reported by other groups [94, 95] and further work by Brilli et al. [96] in this field shows how aerosolized NONOates, in combination with surfactant, improve both oxygenation and PVRI in porcine lung... 

The phenomenon of tolerance is of lesser pharmacological significance for other NO donors including sodium nitroprusside, molsidomine and SIN-1. 

Their mechanism of action is proposed to be dependent on bioactivation once in the circulation, with consequent relaxation of the vessels to reduce the pressure on the heart during an attack of angina. Early work described the effect of nitrate drugs on dog and rabbit arteries [51] and further evidence of a mechanism came with the description of the guanylate cyclase enzymes and the effects of azide and other NO donors by Kimura et al. [52]. 

There have been suggestions that nitroglycerin can substitute for defective NO production in atherosclerosis. There are important differences, however, between nitroglycerin and endogenous, endothelium-derived NO. Whereas endogenous NO and a number of other NO-donor drugs dilate all classes of coronary microvessels, nitroglycerin has only minor effects on coronary microvessels less... 

However, other NO donors have also been shown in another recent study to inhibit growth of liver tumours in vivo (Chen et al. 2008). Treatment (15 mg/kg, i.p., daily for 35 days) of SCID miee bearing subeutaneous human hepatocellular carcinomas as xenografts, with two furoxan-based NO donor derivatives of oleano-lic acid resulted in a reduction in growth rate by about 70% compared with controls and again there was no liver-specific or systemic toxicity. 

This problem has been addressed recently197 with model reactions in which the nucleophile (viz. electron donor) is NO-. It has been found that outer-sphere transition states are easier to compute with NO- than with other electron donors, thus allowing a complete characterization of the competition between the various pathways. 

Since anaerobic azo dye reduction is an oxidation-reduction reaction, a liable electron donor is essential to achieve effective color removal rates. It is known that most of the bond reductions occurred during active bacterial growth [48], Therefore, anaerobic azo dye reduction is extremely depended on the type of primary electron donor. It was reported that ethanol, glucose, H2/CO2, and formate are effective electron donors contrarily, acetate and other volatile fatty acids are normally known as poor electron donors [42, 49, 50]. So far, because of the substrate itself or the microorganisms involved, with some primary substrates better color removal rates have been obtained, but with others no effective decolorization have been observed [31]. Electron donor concentration is also important to achieve... 

Nitrosonium (NO+) is a strong oxidant and the reduction potential to NO has been measured in non-aqueous media (1.67 V vs. SCE in CH3CN), and estimated for water (Eq. (3)) (12,15). NO+ is subject to rapid hydrolysis to nitrite (2H+ + N02 ), and therefore if formed in biological media would be short-lived. However, other less water-sensitive chemical species can act as NO+ donors in reactions leading to the nitrosation of various substrates. For example, the reactions of certain metal nitrosyl complexes with nucleophiles such as R SH can lead to the transfer of NO+ as illustrated in Eq. (4). Such reactions will be discussed in greater detail below. 

Different types of NO donors will be discussed in the other chapters except for the following two classes. 

On the other hand, insufficient NO production also causes serious medical problems. Many diseases such as hypertension, atherosclerosis and restenosis involve a deficiency of NO production. Therefore, a compound that can release NO under specific conditions can be used therapeutically to palliate NO underproduction. In fact, the best known NO donor, glyceryl trinitrate, has been used for over a century to relieve acute attacks of angina pectoris. 

Hydroxamic acid derivatives, which belong to a new class of NO donors, have been shown to inhibit the matrix metalloproteinases (MMPs) [112]. MMPs are a family of zinc-dependent endopeptidases, which play a critical role in multiple steps in the metastatic cascade and facilitate neoangiogenesis. Numerous hydroxamic acids, such as marimastat, have been developed, that bind the zinc atom in the active catalytic domain of MMPs. During a randomized Phase III trial, comparing marimastat with placebo in patients with metastatic breast cancer, marimastat was not associated with an improvement in progression-free survival or overall survival. Other studies also indicated no benefit for MMP inhibitors when used either in combination with chemotherapy or sequentially after first-line chemotherapy in a variety of cancers [113]. Currently, many pharmaceutical companies have suspended clinical development of this kind of agent. 

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 simple 3,4-dihydro-l,2-diazete 1,2-dioxide (1,2-diazetine 1,2-dioxide, DD) system 53 is unknown. 3,3,4,4-Tetramethyl derivative 54 was the first compound of the class to be synthesised [50]. It has an unusually low triplet energy and is a useful triple quencer [51, 52]. Many other derivatives of 53 have recently been prepared in view of their NO-donor properties. 

In vivo, some other heterocyclic systems behave as NO-donors. Typical examples are the 3-amino-4-alkyl or arylalkyl derivatives of l,2,4-oxadiazol-5(4H)one 133 [169, 170]. These products can be synthesised following Scheme 6.25. 

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