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

Debashree 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

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)7804-7820
Number of pages17
JournalJournal of Medicinal Chemistry
Volume56
Issue number20
DOIs
StatePublished - 2013

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Aspirin
Nitric Oxide
Anti-Inflammatory Agents
Prodrugs
Myocardial Infarction
Pharmaceutical Preparations
Sarcomeres
Glyceraldehyde-3-Phosphate Dehydrogenases
Poisons
Platelet Aggregation
Muscle Cells
Stomach
Endothelial Cells
Heart Failure
diazeniumdiolate
nitroxyl
Inflammation
Carcinoma
Lung
Neoplasms

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Synthesis and chemical and biological comparison of nitroxyl- and nitric oxide-releasing diazeniumdiolate-based aspirin derivatives. / Basudhar, Debashree; Bharadwaj, Gaurav; Cheng, Robert Y.; Jain, Sarthak; Shi, Sa; Heinecke, Julie L.; Holland, Ryan J.; Ridnour, Lisa A.; Caceres, Viviane M.; Spadari-Bratfisch, Regina C.; Paolocci, Nazareno; Velázquez-Martínez, Carlos A.; Wink, David A.; Miranda, Katrina M.

In: Journal of Medicinal Chemistry, Vol. 56, No. 20, 2013, p. 7804-7820.

Research output: Contribution to journalArticle

Basudhar, D, Bharadwaj, G, Cheng, RY, Jain, S, Shi, S, Heinecke, JL, Holland, RJ, Ridnour, LA, Caceres, VM, Spadari-Bratfisch, RC, Paolocci, N, Velázquez-Martínez, CA, Wink, DA & Miranda, KM 2013, 'Synthesis and chemical and biological comparison of nitroxyl- and nitric oxide-releasing diazeniumdiolate-based aspirin derivatives', Journal of Medicinal Chemistry, vol. 56, no. 20, pp. 7804-7820. https://doi.org/10.1021/jm400196q
Basudhar, Debashree ; Bharadwaj, Gaurav ; Cheng, Robert Y. ; Jain, Sarthak ; Shi, Sa ; Heinecke, Julie L. ; Holland, Ryan J. ; Ridnour, Lisa A. ; Caceres, Viviane M. ; Spadari-Bratfisch, Regina C. ; Paolocci, Nazareno ; Velázquez-Martínez, Carlos A. ; Wink, David A. ; Miranda, Katrina M. / Synthesis and chemical and biological comparison of nitroxyl- and nitric oxide-releasing diazeniumdiolate-based aspirin derivatives. In: Journal of Medicinal Chemistry. 2013 ; Vol. 56, No. 20. pp. 7804-7820.
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