Concise Synthesis of 1,4-Benzoquinone-Based Natural Products as Mitochondrial Complex I Substrates and Substrate-Based Inhibitors
| Autor: | Hamid R. Nasiri, Karina Tuz, Iris Bischoff, Robert Fürst, Zhenyu Han, Oscar Juárez, Yihan Qin, Günter Fritz, Heike Angerer, Dana Lashley, Dennis P. Stegmann |
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| Rok vydání: | 2020 |
| Předmět: |
Antineoplastic Agents
Quinone oxidoreductase Biochemistry Substrate Specificity 1 4-Benzoquinone chemistry.chemical_compound Mice Structure-Activity Relationship Cell Line Tumor Drug Discovery Benzoquinones Molecule Animals Humans General Pharmacology Toxicology and Pharmaceutics Enzyme Inhibitors Cell Proliferation Pharmacology chemistry.chemical_classification Biological Products Natural product Electron Transport Complex I biology Molecular Structure Succinate dehydrogenase Organic Chemistry Substrate (chemistry) Combinatorial chemistry Quinone Enzyme chemistry Drug Design biology.protein Molecular Medicine Female Drug Screening Assays Antitumor |
| Zdroj: | ChemMedChem. 15(24) |
| ISSN: | 1860-7187 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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