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

Abstract
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.
AuthorsDebashree Basudhar, Gaurav Bharadwaj, Robert Y Cheng, Sarthak Jain, Sa Shi, Julie L Heinecke, Ryan J Holland, Lisa A Ridnour, Viviane M Caceres, Regina C Spadari-Bratfisch, Nazareno Paolocci, Carlos A Velázquez-Martínez, David A Wink, Katrina M Miranda
JournalJournal of medicinal chemistry (J Med Chem) Vol. 56 Issue 20 Pg. 7804-20 (Oct 24 2013) ISSN: 1520-4804 [Electronic] United States
PMID24102516 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Anti-Inflammatory Agents, Non-Steroidal
  • Azo Compounds
  • Enzyme Inhibitors
  • Nitrogen Oxides
  • Prodrugs
  • diazeniumdiolate
  • Nitric Oxide
  • Cyclooxygenase 2
  • Glyceraldehyde 3-Phosphate Dehydrogenase (NADP+)
  • nitroxyl
  • Aspirin
Topics
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal (chemical synthesis, chemistry, pharmacology)
  • Aspirin (chemical synthesis, chemistry, pharmacology)
  • Azo Compounds (chemistry)
  • Carcinoma, Non-Small-Cell Lung (pathology)
  • Cell Line, Tumor
  • Cell Survival (drug effects)
  • Cells, Cultured
  • Cyclooxygenase 2 (metabolism)
  • Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
  • Glyceraldehyde 3-Phosphate Dehydrogenase (NADP+) (metabolism)
  • Humans
  • Lung Neoplasms (pathology)
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Models, Chemical
  • Molecular Structure
  • Myocytes, Cardiac (cytology, drug effects, metabolism)
  • Nitric Oxide (chemistry)
  • Nitrogen Oxides (chemistry)
  • Prodrugs (chemical synthesis, chemistry, pharmacology)
  • Sarcomeres (drug effects, metabolism)

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