Abstract
Purpose. To investigate the effect of benzofusion on NO donor properties and related biological activities of the furoxan system. The biological properties considered were the ability to increase the cytosolic levels of cGMP in C6 cells and vasodilation.
Methods. NO donor properties were investigated either in the presence or the absence of cysteine by using the Griess reaction, chemiluminescence, and gas chromatography. Increase of cytosolic cGMP levels were evaluated by radioimmunoassay. Vasodilating activity was assessed on rat aorta strips precontracted with noradrenaline, in the presence and the absence of oxyhemoglobin (HbO2) and methylene blue (MB), respectively.
Results. Benzofuroxan and its methyl and cyano derivatives were unable to release NO under the experimental conditions. Generally these compounds displayed feeble vasodilating properties and were able to weakly stimulate soluble guanylate cyclase (sGC). By contrast, benzodifuroxan and benzotrifuroxan were able to produce both NO• and its reduced form NO−, the nitroxyl anion. They displayed potent vasodilating properties and were able to increase cytosolic levels of cGMP in a concentration-dependent manner.
Conclusions. The simple benzofuroxans considered here are devoid of the capability to release NO, they weakly stimulate sGC as well as manifest feeble vasodilating properties by a mechanism that does not involve a thiol-induced NO production. By contrast, benzodifuroxan and benzotrifuroxan behave as typical NO donor furoxans.
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REFERENCES
Methods in Nitric Oxide Research, M. Feelisch, J. S. Stamler (eds.), John Wiley, Chichester, 1996.
A. Gasco, R. Fruttero, and G. Sorba. NO-donors: an emerging class of compounds in Medicinal Chemistry. Il Farmaco. 51: 617–635 (1996).
R. Ferioli, G. C. Folco, C. Ferretti, A. M. Gasco, C. Medana, R. Fruttero, M. Civelli, and A. Gasco. A new class of furoxan derivatives as NO donors: mechanism of action and biological activity. Br. J. Pharmacol. 114: 816–820 (1995).
G. Sorba, C. Medana, R. Fruttero, C. Cena, A. Di Stilo, U. Galli, and A. Gasco. Water soluble furoxan derivatives as NO prodrugs. J Med. Chem. 40: 463–469 (1997). 40: 2288 (1997).
A. J. Boulton, P. J. Halls, and A. R. Katritzky. N-Oxides and related compounds J. Chem. Soc. (B). 636–640 (1970).
F. B. Mallory. Benzofurazan oxide. Org. Synth. 37:1–2 (1957).
T. Zincke, and P. Schwarz. Ueber o-dinitrosoverbindungen der benzolreihe. Liebigs Ann. Chem. 307:28–49 (1899).
A. J. Boulton, A. C. Gripper Gray, and A. R. Katritzky. Heterocyclic rearrangements. Part IV. Furoxano-and Furazano-benzofuroxan. J. Chem. Soc., 5958–5964 (1965).
A. S. Bailey, and J. R. Case. 4:6-Dinitrobenzofuroxan, nitrobenzodifuroxan and benzotrifuroxan: a new series of complex-forming reagents for aromatic hydrocarbons. Tetrahedron. 3:113–131 (1958).
A. M. Gasco, G. Ermondi, R. Fruttero, and A. Gasco. Benzofurazanyl-and benzofuroxanyl-1,4-dihydropyridines: synthesis, structure and calcium entry blocker activity. Eur. J. Med. Chem. 31:3–10 (1996).
P. B. Ghosh, B. Ternai, and M. W. Whitehouse. Potential antileukemic and immunosuppressive drugs. 3. Effects of homocyclic ring substitution on the in vitro drug activity of 4-Nitrobenzo-2,1,3-oxadiazoles (4-nitrobenzofurazans) and their N-oxides (4-nitrobenzofuroxans). J. Med. Chem. 15:255–260 (1972).
M. Witanowski, L. Stefaniak, S. Biernat, and G. A. Webb. Nitrogen and carbon NMR of some benzofuroxans. Org. Magn. Reson. 14:356–359 (1980).
S. Archer. Measurement of nitric oxide in biological models. FASEB J. 7:349–360 (1993).
V. Hampl, C. L. Walters, and S. L. Archer. Determination of nitric oxide by the chemiluminescence reaction with ozone. In M. Feelisch, J. S. Stamler (eds.), Methods in Nitric Oxide Research, John Wiley, Chichester, 1996, pp. 309–318.
H. T. Nagasawa, E. G. DeMaster, B. Redfern, F. N. Shirota, and D. J. W. Goon. Evidence for nitroxyl in the catalase-mediated bioactivation of the alcohol deterrent agent cyanamide. J. Med. Chem. 33:3120–3122 (1990).
P. Gosh, B. Ternai, and M. Whitehouse. Benzofurazans and benzofuroxans: biochemical and pharmacological properties. Med. Res. Rev. 1:159–187 (1981).
J. M. Fukuto, K. Chiang, R. Hszieh, P. Wong, and G. Chaudhuri. The pharmacological activity of nitroxyl: A potent vasodilator with activity similar to nitric oxide and/or endothelium-derived relaxing factor J. Pharmacol. Exp. Ther. 263:546–551 (1992).
M. Feelish, K. Schonafinger, and E. Noack. Thiol mediated generation of nitric oxide accounts for vasodilator action of furoxans. Biochem. Pharmacol. 44:1149–1157 (1992).
P. S. Y. Wong, J. Hyun, J. M. Fukuto, F. M. Shirota, E. G. DeMaster, D. W. Shoeman, and H. T. Nagasawa. Reaction between S-nitrosothiols and thiols: Generation of nitroxyl (HNO) and subsequent chemistry. Biochemistry 37:5362–5371 (1998).
R. Fruttero, D. Boschi, E. Fornatto, A. Serafino, A. Gasco, and O. Exner. Electronic substituent effects of furoxan and furazan systems. J. Chem. Res. (S) 495 (1998). Ibid. (M) 2545–2562 (1998).
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Medana, C., Di Stilo, A., Visentin, S. et al. NO Donor and Biological Properties of Different Benzofuroxans1. Pharm Res 16, 956–960 (1999). https://doi.org/10.1023/A:1018974409622
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DOI: https://doi.org/10.1023/A:1018974409622