The biology of nitric oxide (NO) is 1 of the most prolific fields in biomedical science and has impacted our understanding of both basic physiology and disease etiology. NO is a unique endogenous signaling agent since its chemistry is the single most important determinant of its biological function. Research efforts in this field have primarily focused on NO and related oxidized species; however, recent attention has been devoted to the reduced species nitroxyl (HNO). Comparative studies have demonstrated that the chemistry and thus the biological responses to NO and HNO donors are often discrete. Our long-term goal is to utilize this diversity in conjunction with a thorough understanding of the chemical biology of nitrogen oxides to provide disease treatments. The relevance of HNO to endogenous signaling is still a matter of debate, in part due to a poor understanding of its basic chemistry and to limited techniques to define its role in biology. Further, due to rapid self-consumption, HNO must be produced in situ. The most common donor is a nitrogen oxide salt, Na2N2O3, which has proven to be invaluable in the initiation of the study of the unique chemical properties and pharmacological effects of HNO. However, therapeutic exploitation of HNO will only be possible with development of donors with adaptable backbones to complement those that already exist for NO.
The specific aims of this proposal are 1) to design, synthesize and characterize novel HNO donors based on organic backbones; 2) to utilize this donor library and existing HNO donors to elucidate fundamental aspects of the chemical biology of HNO; and 3) to identify specific biological targets. Completion of these aims will expand our understanding of the chemistry of HNO and its roles in biology and may have direct implications for the treatment of heart failure, myocardial infarct and stroke. Additionally, new biological targets, such as zinc fingers and non-heme iron centers, are likely to be revealed, which may suggest other therapeutic interventions. ? ? ?
| Longhi-Balbinot, Daniela T; Rossaneis, Ana C; Pinho-Ribeiro, Felipe A et al. (2016) The nitroxyl donor, Angeli's salt, reduces chronic constriction injury-induced neuropathic pain. Chem Biol Interact 256:1-8 |
| Thomas, Douglas D; Heinecke, Julie L; Ridnour, Lisa A et al. (2015) Signaling and stress: The redox landscape in NOS2 biology. Free Radic Biol Med 87:204-25 |
| Basudhar, Debashree; Cheng, Robert C; Bharadwaj, Gaurav et al. (2015) Chemotherapeutic potential of diazeniumdiolate-based aspirin prodrugs in breast cancer. Free Radic Biol Med 83:101-14 |
| Bharadwaj, Gaurav; Benini, Patricia G Z; Basudhar, Debashree et al. (2014) Analysis of the HNO and NO donating properties of alicyclic amine diazeniumdiolates. Nitric Oxide 42:70-8 |
| Staurengo-Ferrari, Larissa; Zarpelon, Ana C; Longhi-Balbinot, Daniela T et al. (2014) Nitroxyl inhibits overt pain-like behavior in mice: role of cGMP/PKG/ATP-sensitive potassium channel signaling pathway. Pharmacol Rep 66:691-8 |
| Cheng, Robert Y S; Basudhar, Debashree; Ridnour, Lisa A et al. (2014) Gene expression profiles of NO- and HNO-donor treated breast cancer cells: insights into tumor response and resistance pathways. Nitric Oxide 43:17-28 |
| Basudhar, Debashree; Bharadwaj, Gaurav; Cheng, Robert Y et al. (2013) Synthesis and chemical and biological comparison of nitroxyl- and nitric oxide-releasing diazeniumdiolate-based aspirin derivatives. J Med Chem 56:7804-20 |
| Zarpelon, Ana C; Souza, Guilherme R; Cunha, Thiago M et al. (2013) The nitroxyl donor, Angeli's salt, inhibits inflammatory hyperalgesia in rats. Neuropharmacology 71:1-9 |
| Flores-Santana, Wilmarie; Salmon, Debra J; Donzelli, Sonia et al. (2011) The specificity of nitroxyl chemistry is unique among nitrogen oxides in biological systems. Antioxid Redox Signal 14:1659-74 |
| Kumar, Murugaeson R; Fukuto, Jon M; Miranda, Katrina M et al. (2010) Reactions of HNO with heme proteins: new routes to HNO-heme complexes and insight into physiological effects. Inorg Chem 49:6283-92 |
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