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

doi:10.1021/jm400196q

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

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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 language	English (US)
Pages (from-to)	7804-7820
Number of pages	17
Journal	Journal of Medicinal Chemistry
Volume	56
Issue number	20
DOIs	https://doi.org/10.1021/jm400196q
State	Published - Oct 24 2013

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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Basudhar, D., Bharadwaj, G., Cheng, R. Y., Jain, S., Shi, S., Heinecke, J. L., Holland, R. J., Ridnour, L. A., Caceres, V. M., Spadari-Bratfisch, R. C., Paolocci, N., Velázquez-Martínez, C. A., Wink, D. A., & Miranda, K. M. (2013). Synthesis and chemical and biological comparison of nitroxyl- and nitric oxide-releasing diazeniumdiolate-based aspirin derivatives. Journal of Medicinal Chemistry, 56(20), 7804-7820. https://doi.org/10.1021/jm400196q

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

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title = "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.",

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AU - Jain, Sarthak

AU - Shi, Sa

AU - Heinecke, Julie L.

AU - Holland, Ryan J.

AU - Ridnour, Lisa A.

AU - Caceres, Viviane M.

AU - Spadari-Bratfisch, Regina C.

AU - Paolocci, Nazareno

AU - Velázquez-Martínez, Carlos A.

AU - Wink, David A.

AU - Miranda, Katrina M.

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N2 - 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.

AB - 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.

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

Abstract

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