Inducing the Chemodiversity of Fucus vesiculosus-Derived Fungi by OSMAC Strategy for Discovery of New Anticancer Leads

Algae-derived (algicolous) fungi has been regarded as an important source for discovery of novel bioactive natural products. As one of the most-widespread brown algae that occur in the shallow coastal regions of Baltic Sea, Fucus vesiculosus provides habitat for many invertebrates and vertebrates. However, the fungal community associated with F. vesiculosus has not been investigated for their chemical constituents or bioactivity potential. This Ph.D. project aimed to pursue a culture-based approach to isolate fungi from F. vesiculosus for discovery of new anticancer lead compounds. In order to induce the chemical space of fungi associated with Fucus vesiculosus, an OSMAC approach that included variations in media composition and culture regimes (liquid/solid) was applied. The crude extracts of ten fungal isolates showed anticancer bioactivities against at least one cancer cell line under one culture condition. MS/MS-based molecular networking (MN) combined with bioactivity mapping was applied to those crude extracts, allowing the identification and prioritization of two endophytic fungal strain, Pyrenochaetopsis sp. FVE-001 and FVE-087 with anticancer activity. Both strains were selected for large-scale fermentation followed by massive metabolomics analysis and chemical work-up. For Pyrenochaetopsis sp. FVE-001, a modified Kupchan partition method was applied to crude extract to separate the crude extract into three subextracts. Bioactivity was tracked to the chloroform subextract, which was fractionated on a C18 solid-phase extraction (SPE) cartridge. The anticancer activity was mapped onto molecular networks (the so-called bioactivity-based MN), and with the aid of additional bioinformatics application, the anticancer activity of the compounds in the network was predicted. The compound isolation was carried out in a targeted manner from the bioactive fractions to yield three new decalinoylspirotetramic acid derivatives, pyrenosetins A-C, and a known decalin derivative, phomasetin. As expected, pyrenosetins A and B showed strong inhibitory potential against malignant melanoma cell A-375 with IC50 values of 2.8 and 6.3 μM, respectively. The bioactivity-guided isolation of the second Pyrenochaetopsis sp. FVE-087 strain yielded one new decalinoyltetramic acid derivative, pyrenosetin D, and two known compounds wakodecalines A and B. Pyrenosetin D possesses an unusual pentacyclic ring system, which is rare in nature. Bioassay results showed that pyrenosetins D exhibited moderate anticancer bioactivity against A-375 with IC50 value of 77.5 μM, while wakodecalines A and B were inactive. The current study represents a successful application of OSMAC in inducing new compounds with anticancer activity in algicolous fungi. Further combination of MN and additional information layers such as bioactivity data has successfully led to rapid purification of new compounds pyrenosetins A-D from two Fucus vesiculosus-derived Pyrenochaetopsis sp. strains. This is the first study focusing on secondary metabolites of algal-derived Pyrenochaetopsis sp.


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