Undescribed cytotoxic butenolides; asperterreunolides A-E, isolated from endophytic fungus Aspergillus terreus derived from Artemisia arborescens L. supported with in silico study.

Chemical investigation of the ethyl acetate extract of the endophytic fungus Aspergillus terreus AArEF2 found in the fresh leaves of Artemisia arborescens L. led to isolation of five previously undescribed butenolides, asperterreunolides A-E (1-5), along with the known metabolite butyrolactone IV (6). The structure elucidation of these metabolites was established by detailed spectroscopic analyses (1D, 2D NMR and HR-ESI-MS analyses). The absolute configuration of compounds 4 and 5 was determined using the modified Mosher's method. The isolated metabolites (1-6) were evaluated for their cytotoxic activity against A-431, C4-2B, and MDA PCa 2b cell lines by MTT assay using a 96-well microplate. The findings revealed that all the isolated compounds had notable cytotoxic properties with IC50 values ranging from 3.72 to 6.27 μmol/L. Moreover, molecular docking was applied to propose the mechanism of action for the potential antitumor activity of the five previously undescribed butenolides, asperterreunolides A-E (1-5), along with known metabolite butyrolactone IV (6) to be attributed to type IIA topoisomerase inhibition. Furthermore, molecular dynamic simulations were implemented for 200 ns to study the stability of the asperterreunolides A-E (1-5) and butyrolactone IV (6) inside the active site of the type IIA topoisomerase.