NONOates

MAHMA/NO and SPER/NO. On the basis of these results it is dear that synthetic changes to the nudeophile, alter only the chemical kinetics of the dmg. This, in turn, alters the biological activity, due to the parallels, already mentioned, between rate of NO release and biological responsiveness. 

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 

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NO synthons, including the vasodilators sodium nitropmsside (SNP) (261) and nitroglycerin (262), have been in clinical use since the 1970s. Newer synthons include molsidomine (263) and the NONOates, prodmg dimers of NO. 

The 5-fluorouracil (5-FU) and NONOate conjugates (Fig. 1.7) were prepared and their cytotoxicity was tested [90]. The median effect doses of the conjugates for DU145 and HeLa cancer cell lines were 2-4-fold lower than that of 5-FU. In another study by Wink et al, the cytotoxicity of cisplatin was enhanced about 60-fold after NONOate pretreatment for 30 min [91]. The enhancement of cytotoxicity of 5-FU/NONOate conjugates and cisplatin-NONOate combination has shown that there is a synergistic effect between anticancer drugs and NO. Another study by Jia et al. demonstrated that the cytotoxicity of Taxol was enhanced by S-nitrosocaptopril (Fig. 1.7) [92]. This effect is primarily mediated via the increased influx of Taxol by NO into intracellular compartments, while NO-induced cytotoxicity cannot be excluded. 

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. 

Fig. 8.11 Comparing the chemical structure of DMAEP/NO and ethylputreanine NONOate.

Scheme 8.4 Nitrosation of secondary amines from NONOates.

Administration by inhalation has been explored by Brilli [124], mentioned previously for his work with NONOates. Here he uses one of these same NONOates, DMAEP/NO (see Fig. 8.11), in aerosol form. When administered in an aerosolized state, DMAEP/NO again shows selective pulmonary vasodilation in a porcine model. This is achieved without affecting the systemic vascular resistance index (SVRI) or the cardiac index (Cl). Work from the same year by Adrie et al. [125] compared aerosolized DEA/NO with aerosolized SNP and inhaled NO, in sheep. As the NONOate has a short half-life (2.1 min), it was predicted that this would be a selective pulmonary vasodilator. However, compared with inhaled NO this was not observed, though SNP... 

Drago, R. S., NONOates, in Free Radicals in Inorganic Chemistry, edited by Colburn, C. B., American Chemical Society, Washington, DC 1962, p. 143... 

DETA NONOate ((Z)-l-[N-(2-Aminoethyl)-(V-(2-ammonioethyl) amino]diazen-l-ium-l,2-diolate)... 

DETA/NO is a stable NO-donor with the longest NO generation half-life of approximately 20 h. Thrombelastography performed on rabbit blood showed that DETA NONOate-derived NO significantly decreased coagulation activity and platelet activation [48]. Monitoring by intravital microscopy showed that DETA/NO attenuated the platelets/endothelial cells adhesion response to endotoxins (e.g. lipopolysaccharides) in murine intestinal venules [49]. The main mechanism of the antiadhesive action of DETA/NO on platelets was activation of soluble guanylate cyclase [49]. 

MAHMA NONOate spontaneously dissociates in a pH-dependent, first-order process with a half-life of 1 min at 37 °C. In vivo, examination in anesthetised rats showed, that MAHMA NONOate had both platelet inhibitory and vasodepressor effects [50]. Like other NONOates, MAHMA NONOate inhibited collagen-induced and ADP-induced rat platelet aggregation in a concentration-dependent manner [51]. ODQ, a soluble GS inhibitor, caused only small influence on the concentration-response curve to MAHMA NONOate, indicating that cGMP-independent mechanisms play a crucial role. A potential target of MAHMA NONOate induced inhibition was the sarco-endoplasmic reticulum calcium-ATPase of the platelet dense tubular system... 

Hodgkin s lymphoma partial cds GI 9857752 Mus musculus anti-human transferrin IgGi light chain variable region (Ig VL) mRNA, partial cds GI 786586 PDB ID ICLY complexed with Lewis Y nonoate methyl ester... 

Average struture of Fab (human IgGi chimeric fragment (Cbr96) complexed with Lewis Y methyl ester nonoate PDB ID ICLY... 

J.B. Salom, M.D. Barbera, J.M. Centeno, M. Orti, G. Torregrosa and E. Alborch, Relaxant effects of sodium nitroprusside and NONOates in rabbit basilar artery, Pharmacology, 57 (1998) 79-87. 

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