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Nitric Oxide Donors for Biomedical Applications: A Themed Issue Dedicated to Professor Alberto Gasco

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (31 August 2022) | Viewed by 37662

Special Issue Editors


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Guest Editor
Department of Drug Science and Technology, University of Turin, Via Giuria 9, 10125 Turin, Italy
Interests: nitric oxide; drug design; multi-target drugs; cancer multidrug resistance

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Guest Editor
Department of Life Sciences and Systems Biology, University of Turin, Via Accademia Albertina 13, 10123 Turin, Italy
Interests: nanoparticles; nitric oxide; cancer multidrug resistance; anticancer drugs

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Guest Editor
Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy Department of Drug Science and Technology, University of Turin, Via Giuria 9, 10125 Turin, Italy
Interests: NO-donor; prodrug strategy; molecular hybrid design; drug design; drug delivery; drug targeting
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Special Issue Information

Dear Colleagues,

Molecules is pleased to announce a Special Issue dedicated to Professor Alberto Gasco of the University of Turin, Italy, for his outstanding contributions to research on nitric oxide (NO)-donors.

NO is a ubiquitous and pleiotropic messenger that is involved in many physiological and pathophysiological processes in nearly every organ system. It is a free radical with protective and regulatory functions in the cardiovascular and central/peripheral nervous systems. NO also plays a key role in innate immunity and inflammation since it is a necessary component of nonspecific defence mechanisms for several pathogens, including bacteria, viruses, parasites and fungi.

The difficulties inherent in handling NO, due to its gaseous nature and reactivity, have led to the development of a number of NO donors, namely, compounds that can release NO under physiological conditions. NO donors have shown broad therapeutic potential against cardiovascular pathologies, tumours, bacterial and microbial infections, and in the maintenance of homeostasis in gastrointestinal and respiratory tracts. In recent years, the combination of NO donors and cytotoxic agents has also been proposed as a valid strategy for reversing the multidrug resistance (MDR) that is often encountered in conventional anticancer therapies.

Since the biological effects of NO are strictly dependent on its concentration, NO delivery should be controlled with great accuracy, in terms of space, time and dosage. Light-triggered NO donors and suitable nanosystems have recently been developed for regulated spatiotemporal release and are promising new therapeutic devices. In fact, light and nanocarriers are the most finely tuneable approach for the non-invasive delivery of NO to the desired biological environments.

This Special Issue is dedicated to Professor Alberto Gasco for his research on NO-donor pro-drugs, and, specifically, the 1,2,5-oxadiazole 2-oxide (furoxan) system. His work in this field has led to pioneering studies, beginning in the early 1990s, on the design of NO donors and NO-donor hybrid molecules and on their physico-chemical and biological profile. Of great importance is his research in the field of multitarget-drug design that he performed with passionate dedication, in collaboration with scientists of international renown, until very recently. His studies on cardiovascular, non-steroidal anti-inflammatory agents and, more recently, antitumor drugs are particularly worthy of attention. These studies have led to numerous publications in prestigious international journals and several patents in collaboration with companies in the pharmaceutical sector.

As Guest Editors, we aim to collect both original papers and up-to-date reviews that focus on the design, synthesis and biological effects of new and previously described NO donors. We encourage researchers working in this area to contribute to “Nitric Oxide Donors for Biomedical Applications: A Themed Issue Dedicated to Professor Alberto Gasco”.

Prof. Dr. Roberta Fruttero
Dr. Elena Gazzano
Dr. Federica Sodano
Guest Editors

Manuscript Submission Information

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Keywords

  • Nitric oxide
  • NO donors
  • NO photodonors
  • Controlled release systems
  • Nanocarriers
  • Biomedical applications
  • Antimicrobial activity
  • Anticancer activity

Published Papers (12 papers)

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Editorial

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4 pages, 195 KiB  
Editorial
“Nitric Oxide Donors for Biomedical Applications: A Themed Issue Dedicated to Professor Alberto Gasco”: Special Issue Editorial Overview
by Federica Sodano, Elena Gazzano and Roberta Fruttero
Molecules 2023, 28(23), 7870; https://doi.org/10.3390/molecules28237870 - 30 Nov 2023
Viewed by 713
Abstract
The Guest Editors Federica Sodano, Elena Gazzano, and Roberta Fruttero are pleased to present this editorial overview of the Special Issue entitled “Nitric Oxide Donors for Biomedical Applications: A Themed Issue Dedicated to Professor Alberto Gasco” [...] Full article

Research

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30 pages, 4137 KiB  
Article
Proteomics Studies Suggest That Nitric Oxide Donor Furoxans Inhibit In Vitro Vascular Smooth Muscle Cell Proliferation by Nitric Oxide-Independent Mechanisms
by Loretta Lazzarato, Laura Bianchi, Annapaola Andolfo, Agnese Granata, Matteo Lombardi, Matteo Sinelli, Barbara Rolando, Marina Carini, Alberto Corsini, Roberta Fruttero and Lorenzo Arnaboldi
Molecules 2023, 28(15), 5724; https://doi.org/10.3390/molecules28155724 - 28 Jul 2023
Cited by 1 | Viewed by 1061
Abstract
Physiologically, smooth muscle cells (SMC) and nitric oxide (NO) produced by endothelial cells strictly cooperate to maintain vasal homeostasis. In atherosclerosis, where this equilibrium is altered, molecules providing exogenous NO and able to inhibit SMC proliferation may represent valuable antiatherosclerotic agents. Searching for [...] Read more.
Physiologically, smooth muscle cells (SMC) and nitric oxide (NO) produced by endothelial cells strictly cooperate to maintain vasal homeostasis. In atherosclerosis, where this equilibrium is altered, molecules providing exogenous NO and able to inhibit SMC proliferation may represent valuable antiatherosclerotic agents. Searching for dual antiproliferative and NO-donor molecules, we found that furoxans significantly decreased SMC proliferation in vitro, albeit with different potencies. We therefore assessed whether this property is dependent on their thiol-induced ring opening. Indeed, while furazans (analogues unable to release NO) are not effective, furoxans’ inhibitory potency parallels with the electron-attractor capacity of the group in 3 of the ring, making this effect tunable. To demonstrate whether their specific block on G1-S phase could be NO-dependent, we supplemented SMCs with furoxans and inhibitors of GMP- and/or of the polyamine pathway, which regulate NO-induced SMC proliferation, but they failed in preventing the antiproliferative effect. To find the real mechanism of this property, our proteomics studies revealed that eleven cellular proteins (with SUMO1 being central) and networks involved in cell homeostasis/proliferation are modulated by furoxans, probably by interaction with adducts generated after degradation. Altogether, thanks to their dual effect and pharmacological flexibility, furoxans may be evaluated in the future as antiatherosclerotic molecules. Full article
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12 pages, 2503 KiB  
Article
Use of Nitric Oxide Donor-Loaded Microbubble Destruction by Ultrasound in Thrombus Treatment
by Ricardo Corro, Carlos Franco Urquijo, Oscar Aguila, Elisa Villa, Jesus Santana, Amelia Rios and Bruno Escalante
Molecules 2022, 27(21), 7218; https://doi.org/10.3390/molecules27217218 - 25 Oct 2022
Cited by 4 | Viewed by 1388
Abstract
In the presence of a vascular thrombus, the recovery of blood flow and vascular recanalization are very important to prevent tissue damage. An alternative procedure to thrombolysis is required for patients who are unable to receive surgery or thrombolytic drugs due to other [...] Read more.
In the presence of a vascular thrombus, the recovery of blood flow and vascular recanalization are very important to prevent tissue damage. An alternative procedure to thrombolysis is required for patients who are unable to receive surgery or thrombolytic drugs due to other physical conditions. Recently, the performance of thrombolysis combined with microbubbles has become an attractive and effective therapeutic procedure. Indeed, in a recent study, we demonstrated that, upon exposure to ultrasound, liposomes loaded with nitric oxide release agonists conjugated to microbubbles; therefore, there is potential to release the agonist in a controlled manner into specific tissues. This means that the effect of the agonist is potentiated, decreasing interactions with other tissues, and reducing the dose required to induce nitric-oxide-dependent vasodilation. In the present study, we hypothesized that a liposome microbubble delivery system can be used as a hydrophilic agonist carrier for the nitric oxide donor spermine NONOate, to elicit femoral vasodilation and clot degradation. Therefore, we used spermine-NONOate-loaded microbubbles to evaluate the effect of ultrasound-mediated microbubble disruption (UMMD) on thromboembolic femoral artery recanalization. We prepared spermine NONOate-loaded microbubbles and tested their effect on ex vivo preparations, hypothesizing that ultrasound-induced microbubble disruption is associated with the vasorelaxation of aortic rings. Thrombolysis was demonstrated in aorta blood-flow recovery after disruption by spermine NONOate-loaded microbubbles via ultrasound application in the region where the thrombus is located. Our study provides an option for the clinical translation of NO donors to therapeutic applications. Full article
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13 pages, 2906 KiB  
Article
Enhancing the Anticancer Activity of Sorafenib through Its Combination with a Nitric Oxide Photodelivering β-Cyclodextrin Polymer
by Francesca Laneri, Adriana C. E. Graziano, Mimimorena Seggio, Aurore Fraix, Milo Malanga, Szabolcs Béni, Giuseppe Longobardi, Claudia Conte, Fabiana Quaglia and Salvatore Sortino
Molecules 2022, 27(6), 1918; https://doi.org/10.3390/molecules27061918 - 16 Mar 2022
Cited by 5 | Viewed by 2688
Abstract
In this contribution, we report a strategy to enhance the therapeutic action of the chemotherapeutic Sorafenib (SRB) through its combination with a multifunctional β-cyclodextrin-based polymer able to deliver nitric oxide (NO) and emit green fluorescence upon visible light excitation (PolyCDNO). The basically water-insoluble [...] Read more.
In this contribution, we report a strategy to enhance the therapeutic action of the chemotherapeutic Sorafenib (SRB) through its combination with a multifunctional β-cyclodextrin-based polymer able to deliver nitric oxide (NO) and emit green fluorescence upon visible light excitation (PolyCDNO). The basically water-insoluble SRB is effectively encapsulated in the polymeric host (1 mg mL−1) up to a concentration of 18 μg mL−1. The resulting host-guest supramolecular complex is able to release SRB in sink conditions and to preserve very well the photophysical and photochemical properties of the free PolyCDNO, as demonstrated by the similar values of the NO release and fluorescence emission quantum efficiencies found. The complex PolyCDNO/SRB internalizes in HEP-G2 hepatocarcinoma, MCF-7 breast cancer and ACHN kidney adenocarcinoma cells, localizing in all cases mainly at the cytoplasmic level. Biological experiments have been performed at SRB concentrations below the IC50 and with light doses producing NO at nontoxic concentrations. The results demonstrate exceptional mortality levels for PolyCDNO/SRB upon visible light irradiation in all the different cell lines tested, indicating a clear synergistic action between the chemotherapeutic drug and the NO. These findings can open up exciting avenues to potentiate the anticancer action of SRB and, in principle, to reduce its side effects through its use at low dosages when in combination with the photo-regulated release of NO. Full article
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18 pages, 1956 KiB  
Article
Greener Synthesis of Antiproliferative Furoxans via Multicomponent Reactions
by Mariana Ingold, Victoria de la Sovera, Rosina Dapueto, Paola Hernández, Williams Porcal and Gloria V. López
Molecules 2022, 27(6), 1756; https://doi.org/10.3390/molecules27061756 - 8 Mar 2022
Cited by 1 | Viewed by 1906
Abstract
Prostate and bladder cancers are commonly diagnosed malignancies in men. Several nitric oxide donor compounds with strong antitumor activity have been reported. Thus, continuing with our efforts to explore the chemical space around bioactive furoxan moiety, multicomponent reactions were employed for the rapid [...] Read more.
Prostate and bladder cancers are commonly diagnosed malignancies in men. Several nitric oxide donor compounds with strong antitumor activity have been reported. Thus, continuing with our efforts to explore the chemical space around bioactive furoxan moiety, multicomponent reactions were employed for the rapid generation of molecular diversity and complexity. We herein report the use of Ugi and Groebke–Blackburn–Bienaymé multicomponent reactions under efficient, safe, and environmentally friendly conditions to synthesize a small collection of nitric-oxide-releasing molecules. The in vitro antiproliferative activity of the synthesized compounds was measured against two different human cancer cell lines, LNCaP (prostate) and T24 (bladder). Almost all compounds displayed antiproliferative activity against both cancer cell lines, providing lead compounds with nanomolar GI50 values against the cancer bladder cell line with selectivity indices higher than 10. Full article
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19 pages, 4690 KiB  
Article
Acidified Nitrite Accelerates Wound Healing in Type 2 Diabetic Male Rats: A Histological and Stereological Evaluation
by Hamideh Afzali, Mohammad Khaksari, Sajad Jeddi, Khosrow Kashfi, Mohammad-Amin Abdollahifar and Asghar Ghasemi
Molecules 2021, 26(7), 1872; https://doi.org/10.3390/molecules26071872 - 26 Mar 2021
Cited by 4 | Viewed by 2654
Abstract
Impaired skin nitric oxide production contributes to delayed wound healing in type 2 diabetes (T2D). This study aims to determine improved wound healing mechanisms by acidified nitrite (AN) in rats with T2D. Wistar rats were assigned to four subgroups: Untreated control, AN-treated control, [...] Read more.
Impaired skin nitric oxide production contributes to delayed wound healing in type 2 diabetes (T2D). This study aims to determine improved wound healing mechanisms by acidified nitrite (AN) in rats with T2D. Wistar rats were assigned to four subgroups: Untreated control, AN-treated control, untreated diabetes, and AN-treated diabetes. AN was applied daily from day 3 to day 28 after wounding. On days 3, 7, 14, 21, and 28, the wound levels of vascular endothelial growth factor (VEGF) were measured, and histological and stereological evaluations were performed. AN in diabetic rats increased the numerical density of basal cells (1070 ± 15.2 vs. 936.6 ± 37.5/mm3) and epidermal thickness (58.5 ± 3.5 vs. 44.3 ± 3.4 μm) (all p < 0.05); The dermis total volume and numerical density of fibroblasts at days 14, 21, and 28 were also higher (all p < 0.05). The VEGF levels were increased in the treated diabetic wounds at days 7 and 14, as was the total volume of fibrous tissue and hydroxyproline content at days 14 and 21 (all p < 0.05). AN improved diabetic wound healing by accelerating the dermis reconstruction, neovascularization, and collagen deposition. Full article
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Review

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18 pages, 2045 KiB  
Review
Biological Assessment of the NO-Dependent Endothelial Function
by Hasnae Boughaleb, Irina Lobysheva, Flavia Dei Zotti, Jean-Luc Balligand and Virginie Montiel
Molecules 2022, 27(22), 7921; https://doi.org/10.3390/molecules27227921 - 16 Nov 2022
Cited by 7 | Viewed by 1869
Abstract
Nitric oxide (NO) is implicated in numerous physiological processes, including vascular homeostasis. Reduced NO bioavailability is a hallmark of endothelial dysfunction, a prequel to many cardiovascular diseases. Biomarkers of an early NO-dependent endothelial dysfunction obtained from routine venous blood sampling would be of [...] Read more.
Nitric oxide (NO) is implicated in numerous physiological processes, including vascular homeostasis. Reduced NO bioavailability is a hallmark of endothelial dysfunction, a prequel to many cardiovascular diseases. Biomarkers of an early NO-dependent endothelial dysfunction obtained from routine venous blood sampling would be of great interest but are currently lacking. The direct measurement of circulating NO remains a challenge due by its high reactivity and short half-life. The current techniques measure stable products from the NO signaling pathway or metabolic end products of NO that do not accurately represent its bioavailability and, therefore, endothelial function per se. In this review, we will concentrate on an original technique of low temperature electron paramagnetic resonance spectroscopy capable to directly measure the 5-α-coordinated heme nitrosyl-hemoglobin in the T (tense) state (5-α-nitrosyl-hemoglobin or HbNO) obtained from fresh venous human erythrocytes. In humans, HbNO reflects the bioavailability of NO formed in the vasculature from vascular endothelial NOS or exogenous NO donors with minor contribution from erythrocyte NOS. The HbNO signal is directly correlated with the vascular endothelial function and inversely correlated with vascular oxidative stress. Pilot studies support the validity of HbNO measurements both for the detection of endothelial dysfunction in asymptomatic subjects and for the monitoring of such dysfunction in patients with known cardiovascular disease. The impact of therapies or the severity of diseases such as COVID-19 infection involving the endothelium could also be monitored and their incumbent risk of complications better predicted through serial measurements of HbNO. Full article
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17 pages, 1511 KiB  
Review
NO in Viral Infections: Role and Development of Antiviral Therapies
by Federica Sodano, Elena Gazzano, Roberta Fruttero and Loretta Lazzarato
Molecules 2022, 27(7), 2337; https://doi.org/10.3390/molecules27072337 - 5 Apr 2022
Cited by 8 | Viewed by 3240
Abstract
Nitric oxide is a ubiquitous signaling radical that influences critical body functions. Its importance in the cardiovascular system and the innate immune response to bacterial and viral infections has been extensively investigated. The overproduction of NO is an early component of viral infections, [...] Read more.
Nitric oxide is a ubiquitous signaling radical that influences critical body functions. Its importance in the cardiovascular system and the innate immune response to bacterial and viral infections has been extensively investigated. The overproduction of NO is an early component of viral infections, including those affecting the respiratory tract. The production of high levels of NO is due to the overexpression of NO biosynthesis by inducible NO synthase (iNOS), which is involved in viral clearance. The development of NO-based antiviral therapies, particularly gaseous NO inhalation and NO-donors, has proven to be an excellent antiviral therapeutic strategy. The aim of this review is to systematically examine the multiple research studies that have been carried out to elucidate the role of NO in viral infections and to comprehensively describe the NO-based antiviral strategies that have been developed thus far. Particular attention has been paid to the potential mechanisms of NO and its clinical use in the prevention and therapy of COVID-19. Full article
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38 pages, 2087 KiB  
Review
Recent Developments in Nitric Oxide Donors and Delivery for Antimicrobial and Anti-Biofilm Applications
by Wee Han Poh and Scott A. Rice
Molecules 2022, 27(3), 674; https://doi.org/10.3390/molecules27030674 - 20 Jan 2022
Cited by 41 | Viewed by 8003
Abstract
The use of nitric oxide (NO) is emerging as a promising, novel approach for the treatment of antibiotic resistant bacteria and biofilm infections. Depending on the concentration, NO can induce biofilm dispersal, increase bacteria susceptibility to antibiotic treatment, and induce cell damage or [...] Read more.
The use of nitric oxide (NO) is emerging as a promising, novel approach for the treatment of antibiotic resistant bacteria and biofilm infections. Depending on the concentration, NO can induce biofilm dispersal, increase bacteria susceptibility to antibiotic treatment, and induce cell damage or cell death via the formation of reactive oxygen or reactive nitrogen species. The use of NO is, however, limited by its reactivity, which can affect NO delivery to its target site and result in off-target effects. To overcome these issues, and enable spatial or temporal control over NO release, various strategies for the design of NO-releasing materials, including the incorporation of photo-activable, charge-switchable, or bacteria-targeting groups, have been developed. Other strategies have focused on increased NO storage and delivery by encapsulation or conjugation of NO donors within a single polymeric framework. This review compiles recent developments in NO drugs and NO-releasing materials designed for applications in antimicrobial or anti-biofilm treatment and discusses limitations and variability in biological responses in response to the use of NO for bacterial eradiation. Full article
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11 pages, 554 KiB  
Review
The Application of Nitric Oxide for Ocular Hypertension Treatment
by Binze Han, Maomao Song, Liping Li, Xinghuai Sun and Yuan Lei
Molecules 2021, 26(23), 7306; https://doi.org/10.3390/molecules26237306 - 1 Dec 2021
Cited by 5 | Viewed by 2927
Abstract
Despite of various therapeutic methods for treating ocular hypertension and glaucoma, it still remains the leading cause of irreversible blindness. Intraocular pressure (IOP) lowering is the most effective way to slow disease progression and prevent blindness. Among the ocular hypotensive drugs currently in [...] Read more.
Despite of various therapeutic methods for treating ocular hypertension and glaucoma, it still remains the leading cause of irreversible blindness. Intraocular pressure (IOP) lowering is the most effective way to slow disease progression and prevent blindness. Among the ocular hypotensive drugs currently in use, only a couple act on the conventional outflow system, which is the main pathway for aqueous humor outflow and the major lesion site resulting in ocular hypertension. Nitric oxide (NO) is a commendable new class of glaucoma drugs that acts on the conventional outflow pathway. An increasing number of nitric oxide donors have been developed for glaucoma and ocular hypertension treatment. Here, we will review how NO lowers IOP and the types of nitric oxide donors that have been developed. And a brief analysis of the advantages and challenges associated with the application will be made. The literature used in this review is based on Pubmed database search using ‘nitric oxide’ and ‘glaucoma’ as key words. Full article
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16 pages, 1047 KiB  
Review
Glyceryl Trinitrate: History, Mystery, and Alcohol Intolerance
by Russell Pearson and Anthony Butler
Molecules 2021, 26(21), 6581; https://doi.org/10.3390/molecules26216581 - 30 Oct 2021
Cited by 7 | Viewed by 5987
Abstract
Glyceryl trinitrate (GTN) is one of the earliest known treatments for angina with a fascinating history that bridges three centuries. However, despite its central role in the nitric oxide (NO) story as a NO-donating compound, establishing the precise mechanism of how GTN exerts [...] Read more.
Glyceryl trinitrate (GTN) is one of the earliest known treatments for angina with a fascinating history that bridges three centuries. However, despite its central role in the nitric oxide (NO) story as a NO-donating compound, establishing the precise mechanism of how GTN exerts its medicinal benefit has proven to be far more difficult. This review brings together the explosive and vasodilatory nature of this three-carbon molecule while providing an update on the likely in vivo pathways through which GTN, and the rest of the organic nitrate family, release NO, nitrite, or a combination of both, while also trying to explain nitrate tolerance. Over the last 20 years the alcohol detoxification enzyme, aldehyde dehydrogenase (ALDH), has undoubtedly emerged as the front runner to explaining GTN’s bioactivation. This is best illustrated by reduced GTN efficacy in subjects carrying the single point mutation (Glu504Lys) in ALDH, which is also responsible for alcohol intolerance, as characterized by flushing. While these findings are significant for anyone following the GTN story, they appear particularly relevant for healthcare professionals, and especially so, if administering GTN to patients as an emergency treatment. In short, although the GTN puzzle has not been fully solved, clinical study data continue to cement the importance of ALDH, as uncovered in 2002, as a key GTN activator. Full article
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27 pages, 8893 KiB  
Review
Recent Advances in the Synthesis and Biomedical Applications of Heterocyclic NO-Donors
by Leonid L. Fershtat and Egor S. Zhilin
Molecules 2021, 26(18), 5705; https://doi.org/10.3390/molecules26185705 - 21 Sep 2021
Cited by 21 | Viewed by 3187
Abstract
Nitric oxide (NO) is a key signaling molecule that acts in various physiological processes such as cellular metabolism, vasodilation and transmission of nerve impulses. A wide number of vascular diseases as well as various immune and neurodegenerative disorders were found to be directly [...] Read more.
Nitric oxide (NO) is a key signaling molecule that acts in various physiological processes such as cellular metabolism, vasodilation and transmission of nerve impulses. A wide number of vascular diseases as well as various immune and neurodegenerative disorders were found to be directly associated with a disruption of NO production in living organisms. These issues justify a constant search of novel NO-donors with improved pharmacokinetic profiles and prolonged action. In a series of known structural classes capable of NO release, heterocyclic NO-donors are of special importance due to their increased hydrolytic stability and low toxicity. It is no wonder that synthetic and biochemical investigations of heterocyclic NO-donors have emerged significantly in recent years. In this review, we summarized recent advances in the synthesis, reactivity and biomedical applications of promising heterocyclic NO-donors (furoxans, sydnone imines, pyridazine dioxides, azasydnones). The synthetic potential of each heterocyclic system along with biochemical mechanisms of action are emphasized. Full article
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