Isochromophilone IV

To discover the new medical entity from edible marine algae, our continuously natural product investigation focused on endophytes from marine macroalgae Grateloupia sp. Two new azaphilones, 8a-epi-hypocrellone A (1), 8a-epi-eupenicilazaphilone C (2), together with five known azaphilones, hypocrellone A (3), eupenicilazaphilone C (4), ((1E,3E)-3,5-dimethylhepta-1,3-dien-1-yl)-2,4-dihydroxy-3-methylbenzaldehyde (5), sclerotiorin (6), and isochromophilone IV (7) were isolated from the alga-derived fungus Penicillium sclerotiorum. The structures of isolated azaphilones (1-7) were elucidated by spectrometric identification, especially HRESIMS, CD, and NMR data analyses. Concerning bioactivity, cytotoxic, anti-inflammatory, and anti-fibrosis activities of those isolates were evaluated. As a result, compound 1 showed selective toxicity toward neuroblastoma cell line SH-SY5Y among seven cancer and one fibroblast cell lines. 20 μM of compounds 1, 3, and 7 inhibited the TNF-α-induced NFκB phosphorylation but did not change the NFκB activity. Compounds 2 and 6 respectively promoted and inhibited SMAD-mediated transcriptional activities stimulated by TGF-β.

New azaphilones named isochromophilones III-VI were isolated from the culture broth of Penicillium multicolor FO-3216 as inhibitors of acyl-CoA: cholesterol acyltransferase (ACAT). Their structures were elucidated by NMR and other spectroscopic analyses. The IC50 values of isochromophilones III, IV, V and VI for ACAT activity in an enzyme assay using rat liver microsomes were calculated to be 110, 50, 50 and 120 microM, respectively.

Mangrove is a unique marine ecosystem growing in the intertidal zone of tropical and subtropical coast, with the characteristics of hypoxia tolerance, high salinity, and high humidity. In order to discover novel leading compounds with potent phytotoxicity, seven pairs of azaphilones E/Z isomers, isochromophilone H (1a/1b), sclerotiorins A and B (2a/2b and 3a/3b), ochlephilone (4a/4b), isochromophilone IV (5a/5b), isochromophilone J (6a/6b), and isochromophilone I (7a/7b), were isolated from the culture broth of the mangrove-derived fungus, the Penicillium sclerotiorum HY5, by various chromatographic methods. Among them, 1a, 1b, 2a, 3a, 4a, 5a, 6a, and 6b were new compounds. Their chemical structures and absolute configurations were elucidated based on high resolution electrospray ionization mass spectroscopy (HRESIMS), 1D/2D nuclear magnetic resonance (NMR) spectroscopic analysis, and comparisons of electronic circular dichroism (ECD) data. Compounds 3, 4, and 7 exhibited potent phytotoxicity against the growth of radicle and plumule on Amaranthus retroflexus L., with EC50 values ranging from 234.87 to 320.84 μM, compared to the positive control glufosinate-ammonium, with EC50 values of 555.11 μM for radicle, and 656.04 μM for plumule. Compounds 4 and 7 also showed inhibitory effects on the growth of velvetleaf (Abutilon theophrasti Medikus), with EC50 values ranging from 768.97 to 1,201.52 μM. This study provides new leading compounds for the research and development of marine-derived bioherbicides.