Protein kinase inhibitors from the endophytic fungus Stemphylium globuliferum

A Debbab; R Ebel; R Edrada; V Wray; MHG Kubbutat; P Proksch

doi:10.1055/s-0029-1234259

Planta Medica, Table of Contents

Protein kinase inhibitors from the endophytic fungus Stemphylium globuliferum

A Debbab ¹, R Ebel ², R Edrada ³, V Wray ⁴, MHG Kubbutat ⁵, P Proksch ¹

¹Institut fuer Pharmazeutische Biologie and Biotechnologie, Heinrich-Heine-Universitaet, Universitaetsstrasse 1, Geb. 26.23, D-40225 Duesseldorf, Germany
²Department of Chemistry, University of Aberdeen, Meston Building, Meston Walk, Aberdeen AB24 3UE, Scotland, U.K
³Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, The John Arbuthnott Building, 27 Taylor Street, Glasgow G4 0NR, Scotland, U.K
⁴Helmholtz Centre for Infection Research, Inhoffenstrasse 7, D-38124 Braunschweig, Germany
⁵ProQinase GmbH, Breisacher Strasse 117, 79106 Freiburg, Germany

Abstract

The endophytic fungus Stemphylium globuliferum was isolated from stem tissues of the Moroccan medicinal plant Mentha pulegium. Extracts of the fungus, which was grown on solid rice medium, exhibited considerable cytotoxicity when tested in vitro against L5178Y cells. Chemical investigation yielded eight new secondary metabolites, alterporriol F, alterporriol G and its atropisomer H, alterporriol I and its atropisomer J, altersolanol K, altersolanol L and stemphypyrone, beside eight known compounds. The structures were determined on the basis of one- and two-dimensional NMR spectroscopy and mass spectrometry. Among the alterporriol-type anthranoid dimers, the mixture of alterporriols G and H exhibited considerable cytotoxicity against L5178Y cells with an EC₅₀ value of 2.7 µg/mL, whereas the other congeners showed only modest activity. The compounds were also tested for protein kinase inhibitory activity in an assay involving 24 different kinases. Compounds methylalaternin, macrosporin, altersolanol A and the mixture of alterporriol G and H were the most potent and also selective inhibitors, displaying EC₅₀ values between 0.64 and 1.4 µg/mL toward individual kinases.