Eremophilane Sesquiterpenes from a Deep Marine-Derived Fungus, Aspergillus sp. SCSIOW2, Cultivated in the Presence of Epigenetic Modifying Agents

Chemical epigenetic manipulation was applied to a deep marine-derived fungus, Aspergillus sp. SCSIOW2, resulting in significant changes of the secondary metabolites. Three new eremophilane-type sesquiterpenes, dihydrobipolaroxin B (2), dihydrobipolaroxin C (3), and dihydrobipolaroxin D (4), along with one known analogue, dihydrobipolaroxin (1), were isolated from the culture treated with a combination of histone deacetylase inhibitor (suberohydroxamic acid) and DNA methyltransferase inhibitor (5-azacytidine). 1-4 were not produced in the untreated cultures. 2 and 3 might be artificial because 1 could form 2 and 3 spontaneously in water by intracellular acetalization reaction. The absolute configurations of 1 and 2 were assigned based on ECD spectroscopy combined with time-dependent density functional theory calculations. All four compounds exhibited moderate nitric oxide inhibitory activities without cytotoxic effects.