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Concise Synthesis of 1,4-Benzoquinone-Based Natural Products as Mitochondrial Complex I Substrates and Substrate-Based Inhibitors.
Han, Zhenyu; Angerer, Heike; Bischoff, Iris; Qin, Yihan; Stegmann, Dennis; Tuz, Karina; Fritz, Günter; Juarez, Oscar; Fürst, Robert; Lashley, Dana; Nasiri, Hamid R.
Afiliación
  • Han Z; Department of Chemistry, William & Mary, Williamsburg, VA, 23185, USA.
  • Angerer H; Medical School, Institute of Biochemistry II Structural Bioenergetics Group, Goethe University, 60590, Frankfurt am Main, Germany.
  • Bischoff I; Centre for Biomolecular Magnetic Resonance Institute for Biophysical Chemistry, Goethe University, 60438, Frankfurt am Main, Germany.
  • Qin Y; Institute of Pharmaceutical Biology, Goethe University, 60438, Frankfurt am Main, Germany.
  • Stegmann D; Department of Chemistry, William & Mary, Williamsburg, VA, 23185, USA.
  • Tuz K; Department of Cellular Microbiology, University Hohenheim, 70599, Stuttgart, Germany.
  • Fritz G; Department of Biological Sciences, Illinois Institute of Technology, Chicago, IL, 60616, USA.
  • Juarez O; Department of Cellular Microbiology, University Hohenheim, 70599, Stuttgart, Germany.
  • Fürst R; Department of Biological Sciences, Illinois Institute of Technology, Chicago, IL, 60616, USA.
  • Lashley D; Institute of Pharmaceutical Biology, Goethe University, 60438, Frankfurt am Main, Germany.
  • Nasiri HR; Department of Chemistry, William & Mary, Williamsburg, VA, 23185, USA.
ChemMedChem ; 15(24): 2491-2499, 2020 12 15.
Article en En | MEDLINE | ID: mdl-32730688
A short, efficient one-step synthesis of 2-methyl-5-(3-methyl-2-butenyl)-1,4-benzoquinone, a natural product from Pyrola media is described. The synthesis is based on a direct late C-H functionalization of the quinone scaffold. The formation of the natural product was confirmed by means of 2D-NMR spectroscopy. Additional derivatives were synthesized and tested alongside the natural product as potential substrate and substrate-based inhibitors of mitochondrial complex I (MCI). The structure-activity relationship study led to the discovery of 3-methylbuteneoxide-1,4-anthraquinone (1 i), an inhibitor with an IC50 of 5 µM against MCI. The identified molecule showed high selectivity for MCI when tested against other quinone-converting enzymes, including succinate dehydrogenase, and the Na (+)-translocating NADH:quinone oxidoreductase. Moreover, the identified inhibitor was also active in cell-based proliferation assays. Therefore, 1 i can be considered as a novel chemical probe for MCI.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Productos Biológicos / Benzoquinonas / Complejo I de Transporte de Electrón / Inhibidores Enzimáticos Límite: Animals / Female / Humans Idioma: En Revista: ChemMedChem Asunto de la revista: FARMACOLOGIA / QUIMICA Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Alemania
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Productos Biológicos / Benzoquinonas / Complejo I de Transporte de Electrón / Inhibidores Enzimáticos Límite: Animals / Female / Humans Idioma: En Revista: ChemMedChem Asunto de la revista: FARMACOLOGIA / QUIMICA Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Alemania