NO‐donor melatonin derivatives: synthesis and in vitro pharmacological characterization
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| Názov: | NO‐donor melatonin derivatives: synthesis and in vitro pharmacological characterization |
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| Autori: | CHEGAEV, Konstantin, LAZZARATO, Loretta, ROLANDO, Barbara, MARINI, Elisabetta, TOSCO, Paolo, CENA, Clara, FRUTTERO, Roberta, F. BERTOLINI, M. REIST, P. A. CARRUPT, V. LUCINI, F. FRASCHINI, GASCO, Alberto |
| Zdroj: | Journal of Pineal Research, Vol. 42, No 4 (2007) pp. 371-85 |
| Informácie o vydavateľovi: | Wiley, 2007. |
| Rok vydania: | 2007 |
| Predmety: | Male, 0301 basic medicine, Receptor, Melatonin, MT1/metabolism, Nitric Oxide Donors/chemical synthesis/chemistry/pharmacology, Thiobarbituric Acid Reactive Substances/metabolism, In Vitro Techniques, ABTS, alkaline phosphatase, antioxidants, melatonin, multitarget drugs, nitric oxide-donors, thiobarbituric acid reactive substances assay, Thiobarbituric Acid Reactive Substances, Antioxidants, 03 medical and health sciences, Animals, Humans, Nitric Oxide Donors, Rats, Wistar, Melatonin, Recombinant Proteins/metabolism, ddc:615, 0303 health sciences, Molecular Structure, Receptor, Melatonin, MT2, Receptor, Melatonin, MT1, Vasodilation/drug effects, Lipid Peroxidation/drug effects, Alkaline Phosphatase, Recombinant Proteins, Rats, 3. Good health, Receptor, Melatonin, MT2/metabolism, Vasodilation, Antioxidants/chemical synthesis/chemistry/pharmacology, Melatonin/analogs & derivatives/chemical synthesis/pharmacology, Alkaline Phosphatase/metabolism, Microsomes, Liver/drug effects/metabolism, Microsomes, Liver, Lipid Peroxidation |
| Popis: | Numerous studies document that melatonin possesses a broad‐spectrum antioxidant activity. It traps a number of reactive oxygen species (ROS) such as hydroxyl and peroxyl radicals, singlet oxygen and hypochlorous acid. It also inhibits peroxynitrite‐induced reactions. It is known that atherosclerosis progression involves ROS‐induced oxidation of low‐density lipoproteins in sub‐endothelial space and the depletion of nitric oxide (NO) in blood vessels, as well as a decreased sensitivity of the vessels to the actions of NO. Considering this, a series of new NO‐donor antioxidants were designed and synthesized by joining melatonin with NO‐donor nitrooxy and furoxan moieties as polyvalent agents potentially useful for the treatment of cardiovascular diseases involving atherosclerotic vascular changes. The in vitro antioxidant properties of the resulting products were assessed in the thiobarbituric acid reactive substances assay (TBARS), the ABTS+• as well as in the alkaline phosphatase (ALP) assay. The antioxidant capacities of NO‐donor melatonins to inhibit lipoperoxidation (TBARS‐IC50) was predominantly dependent on their lipophilicity, and therefore on their partitioning process into membranes. On the other hand, their comparable capacity to inhibit protein oxidation (ALP‐IC50) was independent of their lipophilicity and was consistent with their similar ability to participate in electron transfer reactions. All the NO‐donor melatonins were also evaluated for their ability to relax rat aorta strips precontracted with 1 μm phenylephrine. Finally, binding affinities and intrinsic activity studies, carried out at MT1 and MT2 receptor subtypes, showed a rather complex picture in need of further investigation. |
| Druh dokumentu: | Article |
| Popis súboru: | application/pdf |
| Jazyk: | English |
| ISSN: | 1600-079X 0742-3098 |
| DOI: | 10.1111/j.1600-079x.2007.00429.x |
| Prístupová URL adresa: | https://pubmed.ncbi.nlm.nih.gov/17439554 https://www.ncbi.nlm.nih.gov/pubmed/17439554 https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-079X.2007.00429.x https://iris.unito.it/handle/2318/41596 https://archive-ouverte.unige.ch/unige:3982 https://archive-ouverte.unige.ch/unige:3982 https://doi.org/10.1111/j.1600-079x.2007.00429.x https://archive-ouverte.unige.ch/unige:3982 http://www.blackwellpublishing.com/journal.asp?ref=0742-3098 https://hdl.handle.net/2318/41596 https://doi.org/10.1111/j.1600-079X.2007.00429.x |
| Rights: | Wiley Online Library User Agreement |
| Prístupové číslo: | edsair.doi.dedup.....d89627ba1c03fea64d2f7a4263f95626 |
| Databáza: | OpenAIRE |
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Nájsť tento článok vo Web of Science | Abstrakt: | Numerous studies document that melatonin possesses a broad‐spectrum antioxidant activity. It traps a number of reactive oxygen species (ROS) such as hydroxyl and peroxyl radicals, singlet oxygen and hypochlorous acid. It also inhibits peroxynitrite‐induced reactions. It is known that atherosclerosis progression involves ROS‐induced oxidation of low‐density lipoproteins in sub‐endothelial space and the depletion of nitric oxide (NO) in blood vessels, as well as a decreased sensitivity of the vessels to the actions of NO. Considering this, a series of new NO‐donor antioxidants were designed and synthesized by joining melatonin with NO‐donor nitrooxy and furoxan moieties as polyvalent agents potentially useful for the treatment of cardiovascular diseases involving atherosclerotic vascular changes. The in vitro antioxidant properties of the resulting products were assessed in the thiobarbituric acid reactive substances assay (TBARS), the ABTS+• as well as in the alkaline phosphatase (ALP) assay. The antioxidant capacities of NO‐donor melatonins to inhibit lipoperoxidation (TBARS‐IC50) was predominantly dependent on their lipophilicity, and therefore on their partitioning process into membranes. On the other hand, their comparable capacity to inhibit protein oxidation (ALP‐IC50) was independent of their lipophilicity and was consistent with their similar ability to participate in electron transfer reactions. All the NO‐donor melatonins were also evaluated for their ability to relax rat aorta strips precontracted with 1 μm phenylephrine. Finally, binding affinities and intrinsic activity studies, carried out at MT1 and MT2 receptor subtypes, showed a rather complex picture in need of further investigation. |
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| ISSN: | 1600079X 07423098 |
| DOI: | 10.1111/j.1600-079x.2007.00429.x |