Synthesis and chemical and biological comparison of nitroxyl- and nitric oxide-releasing diazeniumdiolate-based aspirin derivatives

Structural modifications of nonsteroidal anti-inflammatory drugs (NSAIDs) have successfully reduced the side effect of gastrointestinal ulceration without affecting anti-inflammatory activity, but they may increase the risk of myocardial infarction with chronic use. the fact that nitroxyl (HNO) reduces platelet aggregation, preconditions against myocardial infarction, and enhances contractility led us to synthesize a diazeniumdiolate-based HNO-releasing aspirin and to compare it to an NO-releasing analogue. Here, the decomposition mechanisms are described for these compounds. in addition to protection against stomach ulceration, these prodrugs exhibited significantly enhanced cytotoxcity compared to either aspirin or the parent diazeniumdiolate toward nonsmall cell lung carcinoma cells (A549), but they were not appreciably toxic toward endothelial cells (HUVECs). the HNO-NSAID prodrug inhibited cylcooxgenase-2 and glyceraldehyde 3-phosphate dehydrogenase activity and triggered significant sarcomere shortening on murine ventricular myocytes compared to control. Together, these anti-inflammatory, antineoplasic, and contractile properties suggest the potential of HNO-NSAIDs in the treatment of inflammation, cancer, or heart failure.National Institutes of HealthIntramural Research Program of the National Institutes of HealthCenter for Cancer ResearchFaculty of Pharmacy and Pharmaceutical Sciences at the University of AlbertaNational Cancer InstituteUniv Arizona, Dept Chem & Biochem, Tucson, AZ 85721 USANIH, Radiat Biol Branch, Bethesda, MD 20892 USAUniv Alberta, Fac Pharm & Pharmaceut Sci, Edmonton, AB T6G 2E1, CanadaJohns Hopkins Med Inst, Dept Med, Div Cardiol, Baltimore, MD 21287 USAHarbin Med Univ, Dept Pathophysiol, Harbin 150081, Heilongjiang, Peoples R ChinaNCI, Biol Chem Lab, Frederick, MD 21702 USAFed Univ São Paulo UNIFESP, Dept Biosci, BR-04021001 Santos, SP, BrazilUniv Perugia, Dept Clin & Expt Med, I-06100 Perugia, ItalyFed Univ São Paulo UNIFESP, Dept Biosci, BR-04021001 Santos, SP, BrazilNational Institutes of Health: R01-GM076247Web of Scienc