Cubebin and derivatives as inhibitors of mitochondrial complex I. Proposed interaction with subunit B8

The effects on mitochondrial respiration and complex I NADH oxidase activity of cubebin and derivatives were evaluated. The compounds inhibited the state 3 glutamate/malate-supported respiration of hamster liver mitochondria with IC50 values ranging from 12.16 to 83.96 μM. NADH oxidase reaction was...

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Veröffentlicht in:	Journal of enzyme inhibition and medicinal chemistry 2009-04, Vol.24 (2), p.599-606
Hauptverfasser:	Saraiva, Juliana, Siqueira, Claudia Meirelles, de Paula da Silva, Carlos Henrique Tomich, Barreto da Silva, Vinicius, Tudella, Valeria Gomes, Silva, Rosângela, Andrade e Silva, Marcio Luis, Dorta, Daniel Junqueira, Bastos, Jairo Kenupp, Uyemura, Sérgio Akira, de Albuquerque, Sergio, Curti, Carlos
Format:	Artikel
Sprache:	eng
Schlagworte:	Animals Cell Respiration - drug effects CI-B8 Cricetinae Cubebin Dose-Response Relationship, Drug Electron Transport Complex I - antagonists & inhibitors Electron Transport Complex I - chemistry Electron Transport Complex I - metabolism inhibition Inhibitory Concentration 50 Kinetics Lignans - chemistry Lignans - pharmacology mitochondria Mitochondria, Liver - drug effects Mitochondria, Liver - metabolism mitochondrial complex I Models, Molecular Multienzyme Complexes - antagonists & inhibitors Multienzyme Complexes - metabolism NADH oxidase NADH, NADPH Oxidoreductases - antagonists & inhibitors NADH, NADPH Oxidoreductases - metabolism Protein Conformation Protein Subunits - chemistry Protein Subunits - metabolism
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Zusammenfassung:	The effects on mitochondrial respiration and complex I NADH oxidase activity of cubebin and derivatives were evaluated. The compounds inhibited the state 3 glutamate/malate-supported respiration of hamster liver mitochondria with IC50 values ranging from 12.16 to 83.96 μM. NADH oxidase reaction was evaluated in submitochondrial particles. The compounds also inhibited this activity, showing the same order of potency observed for effects on state 3 respiration, as well as a tendency towards a non-competitive type of inhibition (KI values ranging from 0.62 to 16.1 μM). A potential binding mode of these compounds with complex I subunit B8, assessed by docking calculations, is proposed.
ISSN:	1475-6366 1475-6374
DOI:	10.1080/14756360802318845