A subset of N-substituted phenothiazines inhibits NADPH oxidases |
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| Institution: | 1. Department of Pathology and Immunology, Medical School, School of Pharmaceutical Sciences, University of Geneva, 1211 Geneva 4, Switzerland;2. Pharmaceutical Biochemistry Group, School of Pharmaceutical Sciences, University of Geneva, 1211 Geneva 4, Switzerland;3. Department of Genetic and Laboratory Medicine, Geneva University Hospitals, Geneva, Switzerland;1. Department of Anesthesiology, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany;2. Institute for Pathobiochemistry, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany;3. Department of Anesthesiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand;1. Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland;2. Department of Neurosciences, Faculty of Medicine, University of Geneva, Geneva, Switzerland;3. Department of Infectious Diseases and Hospital Epidemiology, University Hospital of Zurich, Zurich, Switzerland;4. Division of Hematology, University Hospital of Zurich, Zurich, Switzerland;5. Department of Otorhinolaryngology, Inselspital and University of Bern, Bern, Switzerland;6. Department of Head and Neck Surgery, University Hospital of Geneva, Geneva, Switzerland;1. Department of Cardiology, Royal Wolverhampton NHS Trust, UK;2. School of Biological Sciences, University of Reading, UK;3. Department of Cardiovascular Surgery, Nanjing Medical University, PR China;4. Faculty of Health and Medical Sciences, University of Surrey, UK;1. Department of Physiology, Semmelweis University, Faculty of Medicine, “Momentum” Peroxidase Enzyme Research Group of the Semmelweis University and the Hungarian Academy of Sciences, PO Box 259, H-1444 Budapest, Hungary |
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| Abstract: | NADPH oxidases (NOXs) constitute a family of enzymes generating reactive oxygen species (ROS) and are increasingly recognized as interesting drug targets. Here we investigated the effects of 10 phenothiazine compounds on NOX activity using an extensive panel of assays to measure production of ROS (Amplex red, WST-1, MCLA) and oxygen consumption. Striking differences between highly similar phenothiazines were observed. Two phenothiazines without N-substitution, including ML171, did not inhibit NOX enzymes, but showed assay interference. Introduction of an aliphatic amine chain on the N atom of the phenothiazine B ring (promazine) conferred inhibitory activity toward NOX2, NOX4, and NOX5 but not NOX1 and NOX3. Addition of an electron-attracting substituent in position 2 of the C ring extended the inhibitory activity to NOX1 and NOX3, with thioridazine being the most potent inhibitor. In contrast, the presence of a methylsulfoxide group at the same position (mesoridazine) entirely abolished NOX-inhibitory activity. A cell-free NOX2 assay suggested that inhibition by N-substituted phenothiazines was not due to competition with NADPH. A functional implication of NOX-inhibitory activity of thioridazine was demonstrated by its ability to block redox-dependent myofibroblast differentiation. Our results demonstrate that NOX-inhibitory activity is not a common feature of all antipsychotic phenothiazines and that substitution on the B-ring nitrogen is crucial for the activity, whereas that on the second position of the C ring modulates it. Our findings contribute to a better understanding of NOX pharmacology and might pave the path to discovery of more potent and selective NOX inhibitors. |
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| Keywords: | NADPH oxidase ROS NOX inhibitor SAR Phenothiazine Thioridazine Fibrosis Free radicals |
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