Daldinone derivatives from the mangrove-derived endophytic fungus Annulohypoxylon sp.

Abstract

Two new benzo[j]fluoranthene metabolites, daldinones H, J (1 and 3), and the likewise undescribed artefact, daldinone I (2), along with six known compounds (4–9) were isolated from the endophytic fungus Annulohypoxylon sp. that was obtained from the Mangrove plant Rhizophora racemosa collected in Cameroon. The structures of the new compounds were elucidated by 1D and 2D NMR as well as by HRESIMS and ECD spectra analysis. Co-cultivation of this fungus with the actinomycetes Streptomyces lividans or with Streptomyces coelicolor resulted in an up to 38-fold increase of 1-hydroxy-8-methoxynaphthalene (9), while no significant induction was detected when the fungus was co-cultivated either with Bacillus subtilis or with Bacillus cereus. Compound 2 exhibited strong to moderate cytotoxicity against Ramos and Jurkat J16 cells with IC₅₀ values of 6.6 and 14.1 μM, respectively. Mechanistic studies indicated that compound 2 induces apoptotic cell death caused by induction of intrinsic apoptosis. Moreover, 2 potently blocks autophagy, a potential pro-survival pathway for cancer cells. Feeding experiments with 1,8-dihydroxynaphthalene (DHN) led to an enhanced accumulation of daldinone B (6), which supported the proposed biogenetic pathway.