Abstract
Fermentation of the endophytic fungus Aplosporella javeedii on solid rice medium in presence of either 3.5% NaNO3 or 3.5% monosodium glutamate caused a significant change of the fungal metabolite pattern compared to fungal controls grown only on rice. Chemical investigation of the former fungal extracts yielded 11 new lactam derivatives, aplosporellins A–K (2–12), in addition to the known compound, pramanicin A (1). All of these compounds were not detected when the fungus was grown on rice medium without these activators thereby indicating the power of this OSMAC approach. The structures of the new compounds were elucidated by one- and two- dimensional NMR spectroscopy, DFT-NMR calculations and by mass spectrometry as well as by comparison with the literature whereas the absolute configuration of the lactam core was determined by TDDFT-ECD and OR calculations. Pramanicin A (1) showed strong cytotoxicity against human lymphoma (Ramos) and leukemia (Jurkat J16) cells with IC50 values of 4.7 and 4.4 μM, respectively. Mechanistic studies indicated that 1 activates caspase-3 and induces apoptotic cell death.
Highlights
Endophytic fungi have been proven to be important sources for bioprospecting for new pharmaceutical lead compounds (Frank et al, 2015; Ancheeva et al, 2018; Bohler et al, 2018; Rehberg et al, 2018)
As a part of our ongoing studies on fungal endophytes, we investigated the endophytic fungus Aplosporella javeedii derived from Orychophragmus violaceus (L.) O
Due to the pronounced chemical diversity of natural products obtained from this fungus, we have conducted an OSMAC study which involved the addition of different salts including 3.5% NaBr, 3.5% NaCl, 3.5% NaF, 3.5% KCl, 3.5% NH4Cl, 3.5% (NH4)2SO4, 3.5% C5H8NNaO4·H2O, 3.5% NaNO3, 3.5% Na2HPO4, 3.5% K2HPO4·3H2O, 3.5% KH2PO4, 3.5% FeSO4, 3.5% ZnSO4, or 3.5% MgSO4 to solid rice medium
Summary
Endophytic fungi have been proven to be important sources for bioprospecting for new pharmaceutical lead compounds (Frank et al, 2015; Ancheeva et al, 2018; Bohler et al, 2018; Rehberg et al, 2018). Due to the pronounced chemical diversity of natural products obtained from this fungus, we have conducted an OSMAC study which involved the addition of different salts including 3.5% NaBr, 3.5% NaCl, 3.5% NaF, 3.5% KCl, 3.5% NH4Cl, 3.5% (NH4)2SO4, 3.5% C5H8NNaO4·H2O (monosodium glutamate), 3.5% NaNO3, 3.5% Na2HPO4, 3.5% K2HPO4·3H2O, 3.5% KH2PO4, 3.5% FeSO4, 3.5% ZnSO4, or 3.5% MgSO4 to solid rice medium. Chemical investigation of fungal extracts obtained from fermentation of A. javeedii in presence of either 3.5% NaNO3 or of 3.5% monosodium glutamate led to the isolation of 11 new lactam derivatives, aplosporellins A–K (2–12), in addition to the known compound, pramanicin A (1) (Figure 2), all of which were not detected when the fungus was grown on rice medium without these activators. We report the structure elucidation of the new metabolites and the pro-apoptotic activity of pramanicin A (1)
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