Concise synthesis of 1,4-benzoquinone based natural products as mitochondrial complex I substrates and substrate-based inhibitors

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 CH-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 with 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 (1i) an inhibitor with an IC-50 of 5 mM against MCI. The identified molecule showed high selectivity for MCI when tested against other quinone-converting enzymes including cytochrome bo3 oxidase, succinate dehydrogenase and the Na (+)-translocating NADH:quinone oxidoreductase. Moreover, the identified inhibitor was also active in cell-based proliferation assay. Therefore, 1i can be considered as a novel chemical probe for MCI.

Keywords: 1,4-benzoquinone; chemical probe; natural products; one-step synthesis; substrate-based inhibitors.