Two new cyclopiane diterpenes and a new cladosporin precursor, together with four known related compounds, were isolated from the marine sediment-derived fungus Penicillium antarcticum KMM 4670, which was re-identified based on phylogenetic inference from ITS, BenA, CaM, and RPB2 gene regions. The absolute stereostructures of the isolated cyclopianes were determined using modified Mosher’s method and quantum chemical calculations of the ECD spectra. The isolation from the natural source of two biosynthetic precursors of cladosporin from a natural source has been reported for the first time. The antimicrobial activities of the isolated compounds against Staphylococcus aureus, Escherichia coli, and Candida albicans as well as the inhibition of staphylococcal sortase A activity were investigated. Moreover, the cytotoxicity of the compounds to mammalian cardiomyocytes H9c2 was studied. As a result, new cyclopiane diterpene 13-epi-conidiogenone F was found to be a sortase A inhibitor and a promising anti-staphylococcal agent.

Marine fungal metabolites often exhibit antioxidant activity, but their effects on the Keap1/Nrf2 cellular system are rarely studied, possibly due to insufficient isolated amounts. In this work, we used a bioinformatics approach to evaluate the ability of some promising cytoprotective compounds to bind Kelch domain of Keap1 protein, and thus inhibit its interaction with Nrf2. The molecular docking data suggested that gliorosein, niveoglaucin A, 6-hydroxy-N-acetyl-β-oxotryptamine, 4-hydroxyscytalone and 4-hydroxy-6-dehydroxyscytalone can form the hydrogen building with Arg415 or Arg483 amino acid residues of P1-P2 sub-pockets in the Nrf2 binding site of Keap1′s Kelch domain. These positions of the small molecules in the Kelch domain of Keap1 can inhibit the interaction of Keap1 with Nrf2 and enhance the nuclear translocation of Nrf2 from cytosol that can result in overexpression of relative genes. This assumption, based on virtual screening of a number of low molecular weight metabolites of marine fungi, makes them promising for further studies.

The aim of this study was to investigate the metabolites in Aspergillus subramanianii 1901NT-1.40.2 extract using UPLC-MS, isolate and elucidate the structure of individual compounds, and study the antimicrobial and cytotoxic activities of the isolated compounds. The structures of two previously unreported ergostane triterpenoid aspersubrin A (1) and pyrazine alkaloid ochramide E (2) were established using NMR and HR ESI-MS. The absolute configuration of 1 was determined using quantum chemical calculations. Moreover, the known polyketides sclerolide (3) and sclerin (4); the indolediterpene alkaloid 10,23-dihydro-24,25-dehydroaflavinine (5); the bis-indolyl benzenoid alkaloids kumbicin D (6), asterriquinol D dimethyl ether (7), petromurin C (8); and the cyclopentenedione asterredione (9) were isolated. The effects of compounds 3-9 on the growth and biofilm formation of the yeast-like fungus Candida albicans and the bacteria Staphylococcus aureus and Escherichia coli were investigated. Compounds 5 and 6 inhibited C. albicans growth and biofilm formation at an IC₅₀ of 7–10 µM. Moreover, the effects of compounds 3-9 on non-cancerous H9c2 cardiomyocytes, HaCaT keratinocytes, MCF-10A breast epithelial cells, and breast cancer MCF-7 and MDA-MB-231 cells were also investigated. Compound 8 (10 µM) significantly decreased the viability of MCF-7 cells, inhibited colony formation, and arrested cell cycle progression and proliferation in monolayer culture. Moreover, 8 significantly decreased the area of MCF-7 3D spheroids by approximately 30%. A competitive test with 4-hydroxytamoxyfen and molecular docking showed that estrogen receptors (ERβ more than ERα) were involved in the anticancer effect of petromurin C (8).

Background: Mycophenolic acid (MPA) is an IMPDH inhibitor used clinically as an immunosuppressant, but its antiproliferative potency is offset by immune toxicity. We previously identified marine-derived MPA analogues as candidate estrogen receptor α (ERα) ligands. Here, we tested whether penicacid G (PG), a C-4′-oxidized MPA derivative from the marine fungus Penicillium sp. 1901NT-2.53.1, exerts ERα-dependent antiproliferative activity against ER-positive breast cancer cells. Methods: Molecular targets were predicted with TargetNet and OCHEM QSAR models; ERα binding was modeled by docking (PDB 3UUD) and 100 ns molecular dynamics. Cytotoxicities of PG, 4′-hydroxy-MPA, and MPA were determined in MCF-7, MDA-MB-231, H9c2, and MonoMac-1 cells. ERα dependence was interrogated by 4-hydroxytamoxifen (4-OHT) competition, clonogenic assay, ERα monomer/dimer analysis, qPCR of ER-regulated transcripts, cell-cycle flow cytometry, and LINCS L1000 analysis. Results: PG docked into the ERα ligand-binding pocket (−7.7 kcal/mol) and remained stably bound over 100 ns. PG reduced MCF-7 viability at 1 μM (−19.4%) without affecting MDA-MB-231, H9c2, or MonoMac-1 cells (IC50 > 100 μM) and inhibited MCF-7 colony formation (IC50 3.1 μM). Its effect was attenuated by 4-OHT and accompanied by altered ERα monomer/dimer ratios, rapid PHB2 upregulation, and IGFBP4 suppression, indicating ERα pathway engagement. In contrast, MPA inhibited both cancer cell lines, was not blocked by 4-OHT, and its LINCS L1000 profile suggests indirect antagonism of ER-dependent transcription secondary to nucleotide depletion. Conclusions: Penicacid G is an ERα-engaging MPA analogue that selectively impairs ER-positive breast cancer cell proliferation while sparing monocytic immune cells, representing a promising ERα-targeted lead scaffold.