Protein Kinase and HDAC Inhibitors from the Endophytic Fungus Epicoccum nigrum

Abstract

A chemical investigation of the endophytic fungus Epicoccum nigrum isolated from leaves of Mentha suaveolens collected in Morocco resulted in the isolation of five new polyketides, epicocconigrones A and B (1 and 2), 3-methoxyepicoccone B (3), 3-methoxyepicoccone (4), and 2,3,4-trihydroxy-6-(methoxymethyl)-5-methylbenzaldehyde (5), together with five known compounds (6-10). The structures of the new compounds were unambiguously determined by extensive analysis of the 1D and 2D NMR and mass spectroscopic data. Compounds 1 and 10 showed potent inhibition of at least 15 protein kinases with IC50 values ranging from 0.07 to 9.00 μM. Moreover, compounds 1 and 10 inhibited histone deacetylase (HDAC) activities with IC50 values of 9.8 and 14.2 μM, respectively. A preliminary structure-activity relationship is discussed. Interestingly, compounds 1 and 10 exert mainly cytostatic effects in human lymphoma RAJI and U-937 cell lines.

Pictet–Spengler reaction-based biosynthetic machinery in fungi

“…The characterization of 3-8 suggested that the aldehyde substrate of the PS reaction could be flavipin, which has been reported from some fungal cultures (28)(29)(30)(31)(32)(33). To confirm the postulation, C. globosum 1C51 was fed with sodium [1-13 C]-, [2-13 C]-, and [1,2-13 C 2 ]-acetates, respectively, to lead to the expected 13 C enrichment of the 4,5,6-trihydroxyisoindolin-1-one motif of chaetoglines E (5) and F (6), but not the aromatic methyl carbons (C-22 in 5 and C-21 in 6), whose intensity could only be enhanced by supplementing the fungal culture with L-[methyl-13 C]-methionine (SI Appendix, Tables S9 and S10).…”

“…The observation, along with their 1 Hand 13 C-NMR spectra, suggested that the latter was a methyl ester of the former. Scrutiny of the 1 H-1 H COSY, ROESY, HSQC, and HMBC spectra of 3 indicated the presence of a 4,5,6-trihydroxy-7-methylisoindolin-1-one motif (27,28), which was shown to share the nitrogen atom with the 1-MT moiety (SI Appendix, Fig. S9).…”

Endophytic Fungi as a Source of Novel Metabolites

“…A preliminary structure-activity relationship proposal suggested that a β-hydroxyl-α,β-unsaturated carbonyl moiety, present in 82, 84, and 86 but absent in inactive compounds (83 and 85), is necessary for the inhibition of protein kinases. Compound 82 showed also strong inhibition against histone deacetylase (HDAC), becoming a promising compound for the development of anticancer drugs [53].…”

Cytotoxic acyl amides from the soil fungus Gymnascella dankaliensis

“…One strategy to overcome these obstacles is to focus on new or less investigated habitats such as arctic glaciers or antarctic dry valleys, 10 deserts, 11 salt lakes 12 or endophytic and sponge-associated fungi. [13][14][15] Schulz et al hypothesized that ecological niches and a high metabolic interaction (e.g. with plants in the case of endophytic fungi) will yield higher proportions of fungi that are capable of producing new metabolites.…”

“…16 Other approaches for enhancing the chemical diversity of fungal products include the "one strain -many compounds" (OSMAC) strategy, 17-19 mixed fermentations (also called co-cultivation) of several microorganisms [20][21][22][23] or the use of epigenetic modifiers. 24,25 In our ongoing search for new bioactive compounds from fungi, 15,26,27 we investigated the fungus Gymnascella dankaliensis, which was isolated from a soil sample in the vicinity of the Giza pyramids, Egypt. Bioassay-guided fractionation of the extract following cultivation on solid rice medium yielded four new natural products (1 -4), as well as six known compounds (5 -10).…”