Predictive Bioinformatic Assignment of Methyl-Bearing Stereocenters, Total Synthesis, and an Additional Molecular Target of Ajudazol B
| Autor: | Olga Scherer, Sebastian Essig, Dirk Menche, Björn Schmalzbauer, Oliver Werz, Andreas Koeberle, Rolf Müller, Sebastian Bretzke |
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| Rok vydání: | 2016 |
| Předmět: |
Biological Products
Arachidonate 5-Lipoxygenase 010405 organic chemistry Chemistry Stereochemistry Organic Chemistry Total synthesis Computational Biology Stereoisomerism 010402 general chemistry 01 natural sciences 0104 chemical sciences Stereocenter chemistry.chemical_compound Mitochondrial respiratory chain Ajudazol B Coumarins Amide Gene cluster Humans Hydroxyurea Oxazole |
| Zdroj: | The Journal of organic chemistry. 81(4) |
| ISSN: | 1520-6904 |
| Popis: | Full details on the evaluation and application of an easily feasible and generally useful method for configurational assignments of isolated methyl-bearing stereocenters are reported. The analytical tool relies on a bioinformatic gene cluster analysis and utilizes a predictive enoylreductase alignment, and its feasibility was demonstrated by the full stereochemical determination of the ajudazols, highly potent inhibitors of the mitochondrial respiratory chain. Furthermore, a full account of our strategies and tactics that culminated in the total synthesis of ajudazol B, the most potent and least abundant of these structurally unique class of myxobacterial natural products, is presented. Key features include an application of an asymmetric ortholithiation strategy for synthesis of the characteristic anti-configured hydroxyisochromanone core bearing three contiguous stereocenters, a modular oxazole formation, a flexible cross-metathesis approach for terminal allyl amide synthesis, and a late-stage Z,Z-selective Suzuki coupling. This total synthesis unambiguously proves the correct stereochemistry, which was further corroborated by comparison with reisolated natural material. Finally, 5-lipoxygenase was discovered as an additional molecular target of ajudazol B. Activities against this clinically validated key enzyme of the biosynthesis of proinflammatory leukotrienes were in the range of the approved drug zileuton, which further underlines the biological importance of this unique natural product. |
| Databáze: | OpenAIRE |
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