title: Predictive Bioinformatic Assignment of Methyl-Bearing Stereocenters, Total Synthesis, and an Additional Molecular Target of Ajudazol B.
abstract: 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.
authors.affiliation: Institut für Organische Chemie, Ruprecht-Karls Universität Heidelberg , Im Neuenheimer Feld 270, 69120 Heidelberg, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Essig
authors.affiliation: Kekulé-Institut für Organische Chemie und Biochemie, Universität Bonn , Gerhard-Domagk-Strasse 1, 53121 Bonn, Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: Schmalzbauer
authors.affiliation: Institut für Organische Chemie, Ruprecht-Karls Universität Heidelberg , Im Neuenheimer Feld 270, 69120 Heidelberg, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Bretzke
authors.affiliation: Institute of Pharmacy, Friedrich Schiller Universität Jena , Philosophenweg 14, 07743 Jena, Germany.
authors.forename: Olga
authors.initials: O
authors.lastname: Scherer
authors.affiliation: Institute of Pharmacy, Friedrich Schiller Universität Jena , Philosophenweg 14, 07743 Jena, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Koeberle
authors.affiliation: Institute of Pharmacy, Friedrich Schiller Universität Jena , Philosophenweg 14, 07743 Jena, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Werz
authors.affiliation: Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) and Institut for Pharmaceutical Biotechnology, Universität des Saarlandes , C 2.3, 66123 Saarbrücken, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Müller
authors.affiliation: Kekulé-Institut für Organische Chemie und Biochemie, Universität Bonn , Gerhard-Domagk-Strasse 1, 53121 Bonn, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Menche
mesh_terms: D001094:Arachidonate 5-Lipoxygenase / Q000096:biosynthesis / Q000737:chemistry*; D001688:Biological Products / Q000138:chemical synthesis* / Q000737:chemistry; D019295:Computational Biology; D003374:Coumarins / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D006918:Hydroxyurea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism
chemical_list: D001688:Biological Products; D003374:Coumarins; C485091:ajudazol B; D001094:Arachidonate 5-Lipoxygenase; C063449:zileuton; D006918:Hydroxyurea