New Zosteropenillines and Pallidopenillines from the Seagrass-Derived Fungus Penicillium yezoense KMM 4679.

Ten new decalin polyketides, zosteropenilline M ( 1 ), 11- epi -8-hydroxyzosteropenilline M ( 2 ), zosteropenilline N ( 3 ), 8-hydroxyzosteropenilline G ( 4 ), zosteropenilline O ( 5 ), zosteropenilline P ( 6 ), zosteropenilline Q ( 7 ), 13-dehydroxypallidopenilline A ( 8 ), zosteropenilline R ( 9 ) and zosteropenilline S ( 10 ), together with known zosteropenillines G ( 11 ) and J ( 12 ), pallidopenilline A ( 13 ) and 1-acetylpallidopenilline A ( 14 ), were isolated from the ethyl acetate extract of the fungus Penicillium yezoense KMM 4679 associated with the seagrass Zostera marina . The structures of isolated compounds were established based on spectroscopic methods. The absolute configurations of zosteropenilline Q ( 7 ) and zosteropenilline S ( 10 ) were determined using a combination of the modified Mosher's method and ROESY data. The absolute configurations of zosteropenilline M ( 1) and zosteropenilline N ( 3 ) were determined using time-dependent density functional theory (TD-DFT) calculations of the ECD spectra. A biogenetic pathway for compounds 1 - 14 is proposed. The antimicrobial, cytotoxic and cytoprotective activities of the isolated compounds were also studied. The significant cytoprotective effects of the new zosteropenilline M and zosteropenillines O and R were found in a cobalt chloride (II) mimic in in vitro hypoxia in HEK-293 cells. 1-Acetylpallidopenilline A ( 14 ) exhibited high inhibition of human breast cancer MCF-7 cell colony formation with IC 50 of 0.66 µM and its anticancer effect was reduced when MCF-7 cells were pretreated with 4-hydroxitamoxifen. Thus, we propose 1-acetylpallidopenilline A as a new xenoestrogen with significant activity against breast cancer.