The Chemistry and Biology of Nitroxyl (HNO)
The Chemistry and Biology of Nitroxyl (HNO)

Author: Fabio Doctorovich

Publisher: Elsevier

Published: 2016-09-01

Total Pages: 425

ISBN-13: 0128011645

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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. Presents the first book on HNO (nitroxyl or azanone), an increasingly important molecule in biochemistry and pharmaceutical research Provides a valuable coverage of HNO’s chemical structure and significant reactions, including practical guidance on working with this highly reactive molecule Contains high quality content from recognized experts in both industry and academia

Development of Photoactivatable Nitroxyl (hno) Donor Molecules Using Photolabile Protecting Groups
Development of Photoactivatable Nitroxyl (hno) Donor Molecules Using Photolabile Protecting Groups

Author: Yang Zhou (Writer on chemistry and biochemistry)

Publisher:

Published: 2017

Total Pages: 0

ISBN-13:

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Nitroxyl (HNO) has attracted increasing attention because it has important and unique chemical and biological properties distinct from nitric oxide (NO). Especially, prodrugs of HNO show much promise in treating congestive heart failure. However, HNO is a very reactive molecule that rapidly dimerizes and spontaneously dehydrates to yield nitrous oxide (N2O) and H2O. Thus, precursor molecules named HNO donors are required to generate HNO in situ for chemical and biological studies. Current HNO donors release HNO with half-lives of minutes to hours. Due to the rapid reaction between HNO and biomolecules (k ~ 103-107 M-1s-1), the decomposition of current HNO donors to release HNO is invariably the rate-determining step during the mechanistic studies. Therefore, directly obtaining kinetic and mechanistic data for the reactions of HNO with biomolecules is not feasible because of the slow release of HNO (t1/2 ~ minutes to hours) from current available HNO donors. To address this limitation, we have sought to develop a novel family of photoactivatable HNO donors incorporating various photolabile protecting groups (PPG), which rapidly release HNO on demand. Initial work focused on the development of three N-alkoxysulfonamides incorporating the (3-hydroxy-2-naphthalenyl)methyl (3,2-HNM) phototrigger as HNO donors. Photochemical studies of these 3,2-HNM-based HNO donors revealed the presence of a photo-induced redox O-N cleavage pathway, in addition to the desired HNO generation pathway. Trifluoromethanesulfonyl-based donors maximally released ~ 70% HNO under optimal solvent conditions, and decomposed with a half-life ~ 7 s under a direct xenon light source. The HNO generation was found to occur via a concerted fashion rather than a stepwise mechanism. We also explored the role of 2-nitrobenzyl and 4,5-dimethoxy-2-nitrobenzyl phototriggers in these photoactivatable N-alkoxysulfonamides in an effort to improve the selectivity for the desired HNO generation pathway. However, the photo-induced redox O-N bond cleavage was observed as the major pathway even in the trifluoromethanesulfonyl-based donors. Then the (6-hydroxy-2-naphthalenyl)methyl (6,2-HNM) phototrigger was used to replace the isomeric 3,2-HNM-based moiety in these photoactivatable N-alkoxysulfonamides. The selectivity for the HNO generation pathway from the trifluoromethanesulfonyl-based donor was greatly increased up to ~ 98%. Upon irradiation by a direct xenon lamp, photodecomposition of the trifluoromethanesulfonyl-based donor proceeded rapidly with a half-life ~ 5 s. Finally, we investigated the impact on the selectivity of HNO generation of gem-disubstitution at the benzylic position of the 6,2-HNM-based HNO donor system. Relative to the desphenyl analog, the selectivity for the HNO generation pathway in the methanesulfonyl-based HNO donor was greatly increased up to ~ 42%, and the N-O bond cleavage was greatly suppressed (~ 17%).

Synthetic Explorations in the Pursuit of a Rapid, Photoactivatable, Nitroxyl Donor
Synthetic Explorations in the Pursuit of a Rapid, Photoactivatable, Nitroxyl Donor

Author: Mark Wesley Campbell

Publisher:

Published: 2017

Total Pages: 176

ISBN-13:

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Nitroxyl (HNO) is a biologically relevant small molecule with considerable clinical promise for the treatment of heart failure. However, studies of the chemistry and biology of nitroxyl are hampered by its instability in aqueous solution. To aid in biological and chemical studies, nitroxyl donors (molecules that degrade to release HNO) have been synthesized which utilize a 3-hydroxy-2-naphthyl methyl (HNM) OH protecting group. Our group0́9s focus is on the synthesis of nitroxyl donors that rapidly release HNO under physiological conditions through photoactivation. First generation HNO donors released HNO upon photoactivation, but competition was also observed from a redox side reaction. In this study, we are probing the impact of a methyl substituent at the benzylic position on these competing processes. The synthesis and photochemical anaylsis of such a donor are herein described.

Reactions of Biologically Important Thiols with Nitroxyl (HNO) and Development of a HNO Marker
Reactions of Biologically Important Thiols with Nitroxyl (HNO) and Development of a HNO Marker

Author: Biao Shen

Publisher:

Published: 2007

Total Pages: 0

ISBN-13:

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Biologically active nitroxyl (HNO) is one of the least understood nitrogen oxides. It may play a distinct role from NO in protecting the cardiovascular system, and thiols are suspected to be a major nitroxyl target. The major low-molecular-mass intracellular antioxidant, glutathione (GSH), is an important regulator of cellular homeostasis, and is the most likely biological target of HNO. Cysteine (Cys) and HCys (HCys) are naturally occurring thiol-containing amino acids with antioxidant properties and their levels have been linked to many diseases. Reactions of these thiols with Angeli's salt (AS), a HNO donor, were investigated here. N -acetyl-glutathione and N -acetyl-homocysteine were used in this study but are unavailable commercially. An efficient and simple method was developed to prepare N -acetylated low-mass thiols from the corresponding disulfides (e.g., GSSG, homocystine) in aqueous buffer using sulfosuccinimidyl acetate (NHSA) followed by disulfide reduction by immobilized tris (2-carboxyethyl)phosphine (TCEP). The pK a values of the low-mass thiols used here were determined by pH titration in 0.15 M KCl using the GLpKa instrument. GSH was incubated with AS for 30 min and room temperature, and the products were analyzed by ESI-MS. The sulfinamide (GSONH 2) and disulfide (GSSG) were formed at pH>5 but GSSG was the dominant product at higher pHs and GSH concentrations. Disulfides only were detected in the incubations of AS with Cys, N -AcCys, HCys, and penicillamine at pH>5. N -acetylation of penicillamine decreased its reactivity with HNO and led to sulfoxide disulfide (RSOSR) formation. Control experiments with NaNO 2 revealed that the products formed in the AS incubates are due to reaction with HNO at pH>5 but with HNO 2 at pH

Nitrosation Reactions and the Chemistry of Nitric Oxide
Nitrosation Reactions and the Chemistry of Nitric Oxide

Author: D.L.H. Williams

Publisher: Elsevier

Published: 2004-12-16

Total Pages: 281

ISBN-13: 0080473601

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Since 1988, there has been much literature published on the chemistry of nitric oxide, particularly in the field of S-nitrosation and the chemistry of S-nitroso compounds. Written by a chemist for the chemistry community, this book provides an update of the chemistry of nitrosation reactions, dealing with both the synthetic and mechanistic aspects of these reactions. It also looks at the chemistry of nitric oxide in relation to the amazing biological properties of this simple diatomic molecule, which were unknown until around 1990. * Provides an update on previously published literature on nitric oxide chemistry* Contains chapters on reagents for nitrosation, nitrosation at nitrogen, aliphatic and aromatic carbon, oxygen, sulfur and metal centres* Looks at hot research topics such as synthesis, properties and reactions of s-nitrosothiols

SYNTHESIS OF NEW PHOTOACTIVATABLE NITROXYL (HNO) DONORS BASED ON THE 6,2-HNM PHOTOTRIGGER
SYNTHESIS OF NEW PHOTOACTIVATABLE NITROXYL (HNO) DONORS BASED ON THE 6,2-HNM PHOTOTRIGGER

Author: Greggory C Brandle

Publisher:

Published: 2018

Total Pages: 101

ISBN-13:

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Nitroxyl (HNO) is a simple molecule that has been found to have high physiological relevance. HNO is a vasodilator, a positive lusitrope (increases myocardial relaxation), and a positive inotrope (increases the strength of a myocardial muscle contraction) that works independently of cAMP. It has been shown in recent studies to be useful for the treatment of patients with acute heart failure. A complication with HNO is that it rapidly dimerizes and, in order to study the chemistry and mechanisms of the reactions of HNO with biomolecules, there is a need for a rapidly releasing HNO donor. Our group is developing photoactivatable HNO donors that have promise for the rapid release of HNO "on demand". One system under investigation incorporates a hydroxy-2-naphthalenyl (HNM) phototrigger. Our first generation of HNO donors showed a competing photoredox side reaction pathway that did not lead to HNO generation. However, the use the 6,2-HNM phototrigger in compound 1 showed a better selectivity for HNO release. The impact of adding additional substituents at the C* position in 1 is being studied in order to increase HNO generation relative to the unwanted photoredox side reaction. Adding a methyl group to the C* in the first generation of HNO donors showed an increase in the selectivity for HNO generation. In the present work, the effect of the addition of a phenyl group at this position is under study.

Nitrosyl Complexes in Inorganic Chemistry, Biochemistry and Medicine II
Nitrosyl Complexes in Inorganic Chemistry, Biochemistry and Medicine II

Author: D. Michael P. Mingos

Publisher: Springer

Published: 2014-06-19

Total Pages: 266

ISBN-13: 3642411606

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The series Structure and Bonding publishes critical reviews on topics of research concerned with chemical structure and bonding. The scope of the series spans the entire Periodic Table and addresses structure and bonding issues associated with all of the elements. It also focuses attention on new and developing areas of modern structural and theoretical chemistry such as nanostructures, molecular electronics, designed molecular solids, surfaces, metal clusters and supramolecular structures. Physical and spectroscopic techniques used to determine, examine and model structures fall within the purview of Structure and Bonding to the extent that the focus is on the scientific results obtained and not on specialist information concerning the techniques themselves. Issues associated with the development of bonding models and generalizations that illuminate the reactivity pathways and rates of chemical processes are also relevant. The individual volumes in the series are thematic. The goal of each volume is to give the reader, whether at a university or in industry, a comprehensive overview of an area where new insights are emerging that are of interest to a larger scientific audience. Thus each review within the volume critically surveys one aspect of that topic and places it within the context of the volume as a whole. The most significant developments of the last 5 to 10 years should be presented using selected examples to illustrate the principles discussed. A description of the physical basis of the experimental techniques that have been used to provide the primary data may also be appropriate, if it has not been covered in detail elsewhere. The coverage need not be exhaustive in data, but should rather be conceptual, concentrating on the new principles being developed that will allow the reader, who is not a specialist in the area covered, to understand the data presented. Discussion of possible future research directions in the area is welcomed. Review articles for the individual volumes are invited by the volume editors. Readership: research scientists at universities or in industry, graduate students Special offer for all customers who have a standing order to the print version of Structure and Bonding, we offer free access to the electronic volumes of the Series published in the current year via SpringerLink.