Timm Anke

Strobilurins: Evolution of a New Class of Active Substances

A fungus that grows on pinecones yields a compound with antifungal activity that has become the natural model for a significant innovation in crop protection. Variation and optimization of the lead structure of strobilurin A (1) and selection of derivatives which fulfill all practical requirements, for example, kresoxim-methyl (2), led to an exciting and pan-industrial competition for the development of the strobilurines as a new, highly active, and broadly applicable class of fungicides-a fascinating success story.

Influence of apple polyphenols on inflammatory gene expression

Apples (Malus spp., Rosaceae) and products thereof contain high amounts of polyphenols which show diverse biological activities and may contribute to beneficial health effects, like protecting the intestine against inflammation initiated by chronic inflammatory bowel diseases (IBD). IBD are characterized by an excessive release of several proinflammatory cytokines and chemokines by different cell types which results consequently in an increased inflammatory response. In the present study we investigated the preventive effectiveness of polyphenolic juice extracts and single major constituents on inflammatory gene expression in immunorelevant human cell lines (DLD-1, T84, MonoMac6, Jurkat) induced with specific stimuli. Besides the influence on proinflammatory gene expression, the effect on NF-kappaB-, IP-10-, IL-8-promoter-, STAT1-dependent signal transduction, and the relative protein levels of multiple released cytokines and chemokines were studied. DNA microarray analysis of several genes known to be strongly regulated during gastrointestinal inflammation, combined with quantitative real-time PCR (qRT-PCR) revealed that the apple juice extract AE04 (100-200 microg/mL) significantly inhibited the expression of NF-kappaB regulated proinflammatory genes (TNF-alpha, IL-1beta, CXCL9, CXCL10), inflammatory relevant enzymes (COX-2, CYP3A4), and transcription factors (STAT1, IRF1) in LPS/IFN-gamma stimulated MonoMac6 cells without significant effects on the expression of house-keeping genes. A screening of some major compounds of AE04 revealed that the flavan-3-ol dimer procyanidin B(2 )is mainly responsible for the anti-inflammatory activity of AE04. Furthermore, the dihydrochalcone aglycone phloretin and the dimeric flavan-3-ol procyanidin B(1 )significantly inhibited proinflammatory gene expression and repressed NF-kappaB-, IP-10-, IL-8-promoter-, and STAT1-dependent signal transduction in a dose-dependent manner. The influence on proinflammatory gene expression by the applied polyphenols thereby strongly correlated with the increased protein levels investigated by human cytokine array studies. In summary, we evaluated selected compounds responsible for the anti-inflammatory activity of AE04. In particular, procyanidin B(1), procyanidin B(2), and phloretin revealed anti-inflammatory activities in vitro and therefore may serve as transcription-based inhibitors of proinflammatory gene expression.

Inhibition of interleukin-6 signaling by galiellalactone.

A search for inhibitors of the IL‐6‐mediated signal transduction in HepG2 cells using secreted alkaline phosphatase (SEAP) as reporter gene resulted in the isolation of galiellalactone (1) from fermentations of the ascomycete strain A111‐95. Galiellalactone inhibits the IL‐6‐induced SEAP expression with IC50 values of 250–500 nM by blocking the binding of the activated Stat3 dimers to their DNA binding sites without inhibiting the tyrosine and serine phosphorylation of the Stat3 transcription factor. Due to its selective activity, galiellalactone may serve as a lead compound for the development of new therapeutic agents for diseases originating from the inappropriate expression of IL‐6 and as molecular tool to dissect the JAK/STAT pathways.

The striatins--new antibiotics from the basidiomycete Cyathus striatus (Huds. ex Pers.) Willd.

Three crystalline antibiotics which we named striatins A, B, and C were isolated from the mycelium of the basidiomycete Cyathus striatus strain No. 12. The striatins are highly active against fungi imperfecti and a variety of Gram-positive bacteria, as well as against some Gram-negative bacteria. The molecular formulas as determined by mass spectrometry are C27H36O7 for striatin A, C27H36O8 for striatin B, and C25H34O7 for striatin C.

Zopfiellamides A and B, antimicrobial pyrrolidinone derivatives from the marine fungus Zopfiella latipes

Two new antimicrobial metabolites, zopfiellamides A (1) and B (2) were isolated from fermentations of the facultative marine fungus Zopfiella latipes CBS 611.97. Their structures were elucidated by spectroscopic techniques, and they are pyrrolidinone derivatives.

Hirsutane-Type Sesquiterpenes with Uncommon Modifications from Three Basidiomycetes

From three basidiomycetes, Xeromphalina sp., Stereum sp., and Pleurocybella porrigens, six triquinane sesquiterpenes with unprecendented modifications and a rearranged sesquiterpene related to coriolin C have been isolated. Their isolation, structure elucidation, and biological evaluation are described.

Strobilurine: Evolution einer neuen Wirkstoffklasse

Aus dem Kiefernzapfenrubling wurde eine Verbindung mit fungizider Wirkung isoliert, die das naturliche Vorbild fur eine bedeutende Produktinnovation im Pflanzenschutz war: Die Variation und Optimierung der Leitstruktur von Strobilurin A 1 und die Selektion praxisgerechter Derivate wie Kresoxim-methyl 2 fuhrten in einem spannenden und firmenubergreifenden Patentwettlauf zur Entwicklung der Strobilurine als neue, hochaktive und breit anwendbare Fungizidklasse – eine faszinierende Erfolgsstory.

Schizonellin A and B, new glycolipids from Schizonella melanogramma

Abstract Two new glycolipids, schizonellin A and B, were isolated from cultures of the smut fungus Schizonella melanogramma. Their structures were elucidated by chemical degradation and spectroscopic methods. The schizonellins are active against Gram-positive bacteria, as well as against some Gram-negative bacteria and some fungi. DNA-, RNA- and protein-syntheses in Ehrlich carcinoma ascitic cells are inhibited simultaneously after addition of the schizonellins. Strong haemolytic action on bovine erythrocytes was observed.

Striatin A, B, and C: novel diterpenoid antibiotics from Cyathus striatus; X-ray crystal structure of striatin A

Striatin A has been shown by X-ray structure analysis to contain a cyathin skeleton triple linked to a pentose unit; this result allows the assignment of structures to the closely related striatins B and C by n.m.r. spectroscopy.

Inhibitors of Inducible NO Synthase Expression: Total Synthesis of (S)-Curvularin and Its Ring Homologues

(S)‐Curvularin and its 13‐, 14‐, and 16‐membered lactone homologues were synthesized through a uniform strategy in which a Kochi oxidative decarboxylation and ring‐closing metathesis reactions constitute the key processes. In the evaluation of the anti‐inflammatory effects of the synthesized compounds in assays using cells stably transfected with a human iNOS promoter–luciferase reporter gene construct, the 14‐ and 16‐membered homologues showed a slightly higher inhibitory effect towards iNOS promoter activity than curvularin itself. However, the larger ring homologues also exhibited higher cytotoxicity, manifest in downregulated eNOS promoter activity. In contrast, the di‐O‐acetyl and 4‐chloro derivatives of (S)‐curvularin showed higher inhibitory efficiency towards induction of the iNOS promoter and less negative effect on eNOS promoter activity than curvularin.