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1.
Antioxid Redox Signal ; 23(14): 1113-29, 2015 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-26415051

RESUMO

SIGNIFICANCE: Oxidative stress is suggested to be a disease mechanism common to a wide range of disorders affecting human health. However, so far, the pharmacotherapeutic exploitation of this, for example, based on chemical scavenging of pro-oxidant molecules, has been unsuccessful. RECENT ADVANCES: An alternative emerging approach is to target the enzymatic sources of disease-relevant oxidative stress. Several such enzymes and isoforms have been identified and linked to different pathologies. For some targets, the respective pharmacology is quite advanced, that is, up to late-stage clinical development or even on the market; for others, drugs are already in clinical use, although not for indications based on oxidative stress, and repurposing seems to be a viable option. CRITICAL ISSUES: For all other targets, reliable preclinical validation and drug ability are key factors for any translation into the clinic. In this study, specific pharmacological agents with optimal pharmacokinetic profiles are still lacking. Moreover, these enzymes also serve largely unknown physiological functions and their inhibition may lead to unwanted side effects. FUTURE DIRECTIONS: The current promising data based on new targets, drugs, and drug repurposing are mainly a result of academic efforts. With the availability of optimized compounds and coordinated efforts from academia and industry scientists, unambiguous validation and translation into proof-of-principle studies seem achievable in the very near future, possibly leading towards a new era of redox medicine.


Assuntos
Antioxidantes/farmacologia , Inibidores Enzimáticos/farmacologia , Animais , Antioxidantes/uso terapêutico , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/uso terapêutico , Humanos , Oxirredução , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo
2.
Free Radic Biol Med ; 86: 239-49, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26013584

RESUMO

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.


Assuntos
Inibidores Enzimáticos/farmacologia , NADPH Oxidases/antagonistas & inibidores , Fenotiazinas/farmacologia , Animais , Células CHO , Diferenciação Celular/efeitos dos fármacos , Cricetinae , Cricetulus , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/química , Células HEK293 , Humanos , Concentração Inibidora 50 , Miofibroblastos/efeitos dos fármacos , Miofibroblastos/fisiologia , NADPH Oxidases/química , NADPH Oxidases/metabolismo , Oxirredução , Estresse Oxidativo , Consumo de Oxigênio , Fenotiazinas/química , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade
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