Four new compounds, including three new benzo[j]fluoranthene derivatives, namely, daldinones H – J [1], and an unusual ten-membered macrocyclic lactone, together with six known metabolites were isolated from the endophytic fungus Annulohypoxylon sp. that was obtained from the Mangrove plant Rhizophora racemosa, collected in Cameroon. The structures and absolute configurations of the new compounds were elucidated on the basis of comprehensive NMR, MS, and ECD spectroscopic data analyses. Several attempts were undertaken to influence the pattern of fungal metabolites through co-cultivation of the fungus with a panel of Gram-positive bacteria. Accordingly, co-cultivation of Annulohypoxylon sp. either with Streptomyces lividans or with Streptomyces coelicolor resulted in an up to 38-fold increase in the accumulation of the constitutively present metabolite 1-hydroxy-8-methoxynaphthalene. On the other hand, no significant effect on metabolite accumulation was observed when the fungus was co-cultivated either with Bacillus subtilis or with Bacillus cereus. In a second set of experiments, feeding of the fungal culture with 1,8-dihydroxynaphthalene (DHN) resulted in a marked dose-dependent induction of the main metabolite daldinone B, which shows excellent agreement with its proposed biosynthesis involving oxidative coupling of two DHN units [1]. Among the isolated compounds, the new metabolite daldinone I exhibited the strongest activity against Ramos and Jurkat J16 cells with IC50 values of 6.6 and 14.1 μM, respectively. The distinct cytotoxicity of daldinone I against human lymphoma and leukemia cell lines was determined to be caused by induction of intrinsic apoptosis. Further mechanistic studies showed that daldinone I potently blocks autophagy, a potential pro-survival pathway for cancer cells, thus highlighting its potential as a promising lead for anticancer drug development.
References:
[1] Liu Y, Stuhldreier F, Kurtán T, Mándi A, Arumugam S, Lin W, Stork B, Wesselborg S, Weber H, Henrich B, Daletos G, Proksch P. RSC Adv 2017; 7: 5381–5393