| Affiliation: | 1. Department of Chemistry, William & Mary, Williamsburg, VA, 23185 USA;2. Medical School, Institute of Biochemistry II Structural Bioenergetics Group, Goethe University, 60590 Frankfurt am Main, Germany Centre for Biomolecular Magnetic Resonance Institute for Biophysical Chemistry, Goethe University, 60438 Frankfurt am Main, Germany;3. Institute of Pharmaceutical Biology, Goethe University, 60438 Frankfurt am Main, Germany;4. Department of Cellular Microbiology, University Hohenheim, 70599 Stuttgart, Germany;5. Department of Biological Sciences, Illinois Institute of Technology, Chicago, IL, 60616 USA |
| Abstract: | 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. |
