The Chemistry and Biology of Nitroxyl (HNO)

1st Edition - September 1, 2016
Editors: Fabio Doctorovich, Patrick J. Farmer, Marcelo A. Marti
Language: English
Hardback ISBN:
9 7 8 - 0 - 1 2 - 8 0 0 9 3 4 - 5
eBook ISBN:
9 7 8 - 0 - 1 2 - 8 0 1 1 6 4 - 5

The Chemistry and Biology of Nitroxyl (HNO) provides first-of-its-kind coverage of the intriguing biologically active molecule called nitroxyl, or azanone per IUPAC nomenclat… Read more

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The Chemistry and Biology of Nitroxyl (HNO) provides first-of-its-kind coverage of the intriguing biologically active molecule called nitroxyl, or azanone per IUPAC nomenclature, which has been traditionally elusive due to its intrinsically high reactivity.

This useful resource provides the scientific basis to understand the chemistry, biology, and technical aspects needed to deal with HNO. Building on two decades of nitric oxide and nitroxyl research, the editors and authors have created an indispensable guide for investigators across a wide variety of areas of chemistry (inorganic, organic, organometallic, biochemistry, physical, and analytical); biology (molecular, cellular, physiological, and enzymology); pharmacy; and medicine.

This book begins by exploring the unique molecule’s structure and reactivity, including important reactions with small molecules, thiols, porphyrins, and key proteins, before discussing chemical and biological sources of nitroxyl. Advanced chapters discuss methods for both trapping and detecting nitroxyl by spectroscopy, electrochemistry, and fluorescent inorganic cellular probing.

Expanding on the compound’s foundational chemistry, this book then explores its molecular physiology to offer insight into its biological implications, pharmacological effects, and practical issues.

List of Contributors
Introduction: A Bit of History and General Facts About Nitroxyl: From Interstellar Molecule to Biological Gasotransmitter
1. HNO: Redox Chemistry and Interactions With Small Inorganic Molecules
- Abstract
- 1.1 Introduction
- 1.2 Dimerization
- 1.3 Reaction with molecular oxygen
- 1.4 Reaction with NO
- 1.5 Reaction with H₂S
- 1.6 Redox-related reactions
- References
2. HNO Donors: Angeli’s Salt and Related Diazeniumdiolates
- Abstract
- 2.1 Introduction
- 2.2 Angeli’s salt
- 2.3 Diazeniumdiolates
- 2.4 Diazeniumdiolate-based HNO-releasing prodrugs
- 2.5 Acyl nitroso compounds as HNO donors
- 2.6 Conclusions
- Acknowledgments
- Abbreviations
- References
3. Hydroxylamines With Organic-Based Leaving Groups as HNO Donors
- Abstract
- 3.1 Introduction
- 3.2 Synthesis
- 3.3 Piloty’s acid and its derivatives
- 3.4 Cyanamide
- 3.5 Hydroxylamines with carbon-bound leaving groups
- 3.6 Summary
- Acknowledgment
- References
4. Mechanistic Aspects of HNO Production from Hydroxylamine and Derivatives
- Abstract
- 4.1 Hydroxylamine in chemical reactions
- 4.2 Hydroxylamine derivatives and related compounds
- References
5. HNO Generation From NO, Nitrite, Inorganic or Organic Nitrosyls, and Crosstalk With H₂S
- Abstract
- 5.1 HNO generation from NO and {MNO}ⁿ
- 5.2 HNO generation from nitrite and nitroso, NO⁺, species through the interplay with H₂S and HSNO formation
- 5.3 Conclusion
- References
6. HNO–Thiol Relationship
- Abstract
- 6.1 Reaction of HNO with thiols: biochemical foundations
- 6.2 Specific thiolates as targets for HNO-induced physiological/pharmacological effects
- 6.3 Thiol-based HNO generation
- 6.4 Conclusions
- References
7. Non-Heme Transition Metal Complexes of HNO
- Abstract
- 7.1 Synthetic methods
- 7.2 Binding mode of HNO. Characterization by NMR, IR, and UV-vis spectroscopies, X-ray diffraction, and DFT calculations
- 7.3 Electronic structure of metallonitroxyl complexes containing diatomic NO⁻
- 7.4 Structural and spectroscopic changes in {MX₅L} complexes (L=HNO, NO₂⁻, and diatomic nitrosyls: NO⁺, NO, NO⁻) in a common MX₅ platform. Spectroelectrochemical (UV–vis, IR) measurements
- 7.5 Stability and reactivity in HNO complexes
- References
8. The Interaction of HNO With Transition Metal Centers and Its Biological Significance. Insight Into Electronic Structure From Theoretical Calculations
- Abstract
- 8.1 Introduction
- 8.2 HNO and hemes: electronic structure and relevance for soluble guanylate cyclase
- 8.3 Calculation of accurate binding constants using DFT methods: application to soluble guanylate cyclase activation by NO, HNO, and CO
- 8.4 The pK_a’s of transition metal HNO complexes
- 8.5 Conclusions
- Acknowledgment
- References
9. Interactions of HNO With Metallated Porphyrins, Corroles, and Corrines
- Abstract
- 9.1 General reactivity of Fe, Mn, and Co porphyrins with HNO
- 9.2 Metallocorroles and metallocorrines
- 9.3 Conclusions
- References
10. Fluorescent Probes for HNO Detection
- Abstract
- 10.1 Introduction
- 10.2 Copper-based fluorescent HNO probes
- 10.3 TEMPO-based fluorescent HNO probes
- 10.4 Phosphine-based fluorescent HNO probes
- 10.5 Conclusions
- Acknowledgments
- References
11. Phosphine-Based HNO Detection
- Abstract
- 11.1 Introduction
- 11.2 Reactions of phosphines with nitroso compounds
- 11.3 Reactions of phosphines with HNO
- 11.4 Reductive ligation
- 11.5 Fluorescent HNO probes
- 11.6 Conclusion
- Acknowledgments
- References
12. Electrochemical Detection of Azanone
- Abstract
- 12.1 Background
- 12.2 Design of an amperometric HNO sensor
- 12.3 Analytical properties of the azanone detecting electrode
- 12.4 Applications of the HNO sensor
- References
13. Detection of HNO by Membrane Inlet Mass Spectrometry
- Abstract
- 13.1 Introduction
- 13.2 Membrane inlet design and methods
- 13.3 Detection of HNO by MIMS
- 13.4 Differentiating HNO and NO MIMS signals
- 13.5 HNO donor comparison
- 13.6 Detection of HNO from HOCl-mediated oxidation of N-Hydroxyarginine (NOHA)
- 13.7 Conclusions and future directions
- Acknowledgment
- References
14. Spectroscopic NMR Characterizations of HNO Adducts of Ferrous Heme Proteins
- Abstract
- 14.1 Introduction
- 14.2 Solution structure determination
- 14.3 Characterization of isoform mixtures
- 14.4 Conclusions
- References
15. Global Kinetic Analysis and Singular Value Decomposition Methods Applied to Complex Multicomponent Reactions of HNO
- Abstract
- 15.1 Introduction
- 15.2 Experimental
- 15.3 Results
- 15.4 Discussion
- Acknowledgments
- Abbreviations
- References
16. HNO as an Oxygen Substitute in Enzymes
- Abstract
- 16.1 Introduction
- 16.2 Nitroxygenase activity
- 16.3 Results
- 16.4 Discussion
- 16.5 Conclusions
- 16.6 Materials and methods
- 16.7 Kinetic measurements
- Acknowledgments
- Abbreviations
- References
17. The Reactions of HNO With Nonheme Proteins: An Emphasis on Thiol-Containing Proteins
- Abstract
- 17.1 Introduction
- 17.2 The chemistry of HNO with thiols
- 17.3 Examining HNO in biological systems
- 17.4 Reaction of HNO with thiol-containing proteins
- 17.5 HNO versus NO
- 17.6 Summary
- References
18. Is Azanone Endogenously Produced in Mammals?
- Abstract
- 18.1 The newest small molecule signaling agent
- 18.2 Possible routes for enzymatic HNO production
- 18.3 Biochemical spontaneous “reducing” pathways leading to HNO
- 18.4 Physiological context and effects of endogenous HNO production
- References
19. From Heaven to Heart: Nitroxyl (HNO) in the Cardiovascular System and Beyond
- Abstract
- 19.1 Introduction
- 19.2 Possible pathways of endogenous HNO production in the cardiovascular system
- 19.3 The cardiovascular actions of HNO donors
- 19.4 Studies with the novel HNO donors, CXL-1020 and CXL-1427
- 19.5 HNO and systemic and coronary vasodilation
- 19.6 HNO’s mechanisms of action in the heart and in the vasculature: “nitroxylation”
- 19.7 Myocardial ischemia and HNO
- 19.8 Additional pharmacological effects of HNO in the cardiovascular system and on other pathophysiological conditions
- 19.9 HNO impact on the central nervous system
- 19.10 HNO donors and human ADHF
- 19.11 Questions to ponder and future perspectives
- 19.12 Concluding remarks
- 19.13 Disclosures
- 19.14 Sources of funding
- Abbreviations
- References
Index

Fabio Doctorovich

Prof. Fabio Doctorovich earned his PhD in Organic Chemistry from the University of Buenos Aires (Argentina) in 1990. He was a postdoctoral fellow at the Georgia Institute of Technology working with Prof. E.C. Ashby and K. Barefield, first on single electron transfer and then on chemical reactions taking place in nuclear waste tanks. Back in Argentina, he started to work on nitric oxide (NO), including organic nitrosocompounds, inorganic iron, ruthenium and iridium nitrosyl complexes, and reactivity of metalloporphyrins towards HNO. He also worked on CO complexes, catalytic reactions, and other topics. Nowadays, his research focus is on reactions involving HNO as well as catalytic production of hydrogen from water. Prof. Doctorovich has published over 100 works in international journals such as Accounts of Chemical Research, Journal of the American Chemical Society, Inorganic Chemistry, Journal of Organic Chemistry, and Nature Communications. He has supervised more than 10 PhD students. In 2011, he received the Guggenheim Fellowship. Since 1996, Prof. Doctorovich has been a member of CONICET.

Affiliations and expertise

University of Buenos Aires, Buenos Aires, Argentina

Patrick J. Farmer

Professor and Chair of Chemistry and Biochemistry, Baylor University

Affiliations and expertise

Baylor University, Waco, TX, USA

Marcelo A. Marti

Dr. Marcelo A. Martí earned his PhD in Biophysical Chemistry from the University of Buenos Aires (Argentina) in 2006 working with Prof. D.A. Estrín and F. Doctorovich. In this period, he pioneered the use of hybrid QM/MM based methods to study metalloprotein reactivity with Reactive Nitrogen and Oxygen Species (RNOS), while performing the first studies on HNO reactions with metallporphyrins. After his PhD, he worked on heme protein Raman spectroscopy in the field of protein electron transfer. In 2010, he accepted a professorship in the Department of Biological Chemistry at the University of Buenos Aires where he leads the protein structure biophysics and bioinformatics group. As a scientist in the triple frontier of chemistry, informatics, and biology, his research is focused on the comprehension of the underlying chemical basis of protein function. This approach has allowed for the construction of a detailed atomic picture of several biological processes, in particular metalloprotein reactions with RNOS. Prof. Martí has published over 100 works in international Journals such as Plos Comp. Biol., J. Am. Chem. Soc., PNAS, and Nat. Comm. He received the Technology Review Argentina Innovators Under 35 Award in 2012, and the Young Scientist Award in Chemistry from the Argentinean National Academy of Sciences in 2013. Since 2008, Dr. Martí has been a member of CONICET.

Affiliations and expertise

University of Buenos Aires, Buenos Aires, Argentina

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The Chemistry and Biology of Nitroxyl (HNO)

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Fabio Doctorovich

Patrick J. Farmer

Marcelo A. Marti