Anton Nikolaevich Yurchenko

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.

Thirteen new decaline polyketides, namely, zosteropenillines T–W (1–4), 8-hydroxypallidopenilline A (5), 13-epi-zosteropenilline P (6), 11-epi-zosteropenilline N (7), 15-hydroxyzosteropenilline M (8), 8-hydroxyzosteropenilline M (9), 11-epi-zosteropenilline M (10), and zosteropenillines X–Z (11–13), along with 17 known related compounds (14–30) were isolated from the ethyl acetate extract of the marine-derived fungus Penicillium yezoense KMM 4679 cultivated on MgCl₂-containing nutrient medium. The structures of the isolated compounds were established based on spectroscopic methods. The absolute configurations of zosteropenillines T (1) and V (3) were determined using time-dependent density functional theory (TD-DFT) calculations of the ECD spectra. X-ray diffraction analysis data were obtained for the known zosteropenilline S (28). A biogenetic pathway for 1–13 was proposed. The effects of the compounds on Staphylococcus aureus and Candida albicans growth and biofilm formation were observed. Zosteropenillines U (2), Y (12) and Z (13) with higher activity against C. albicans biofilms were nontoxic for normal cardiomyocyte H9c2 cells, making them promising anti-candidal agents. Moreover, zosteropenillines U and Y demonstrated cardioprotective effects in acute ischemia/reperfusion and CoCl₂-mimicking hypoxia in vitro models.

Objectives: This study aimed to isolate secondary metabolites from sea cucumber-associated fungus Trichoderma koningii KMM 4751, obtain their bromine derivatives, and investigate their antimicrobial and cytotoxic activities. Results: 3-Ethyl-4-hydroxy-6-methyl-2H-pyran-2-one (EHMP) was isolated from fungal extract. It was brominated, and a previously unreported 6-(bromomethyl)-3-ethyl-4-hydroxy-2H-pyran-2-one (Br-EHMP) was obtained. EHMP inhibited the formation of Candida albicans biofilms with an IC₅₀ of 49.3 µM, but Br-EHMP was less active. Simultaneously, bromination of EHMP significantly enhanced the inhibitory effect of Br-EHMP on Staphylococcus aureus growth and biofilm formation without increasing cytotoxicity to H9c2 cells. Br-EHMP at 10 μM can inhibit sortase A activity by near 30% in a cell-free assay. In silico molecular docking predicted the interaction of Br-EHMP with Cys184 in the sortase A active site. Conclusions: Br-EHMP emerges as a promising antibiofilm agent, and its mechanism involves sortase A inhibition.

Aspergillus fungi are a source of low-molecular compounds of various structures possessing biological activities. We investigated the secondary metabolite profile of the soil fungus A. calidoustus VKM F-4916. The strain was found to synthesize new metabolites attributed to furoisocoumarins, which we named asperisocoumarin J and K, and a known siderophore desferritriacetylfusigen. The structure of asperisocoumarin J and K were determined by mass spectrometry and NMR spectroscopy. Asperisocoumarins J, K and desferritriacetylfusigen possessed a phytotoxicity, inhibiting the lettuce root growth. Sow thistle leaf and wheat leaf cuttings were sensitive to the action of asperisocoumarin J and K at a concentration of 5 mg/mL. Analysis of the structures of furoisocoumarins (asperisocoumarins J and K) using the online resource Pesti-DGI-Net showed that compounds had the physico-chemical properties favorable for pesticide development, in particular, fungicides and herbicides. An in-depth study of the phytotoxic properties of furoisocoumarins and their natural analogs is of interest in the context of the search for new herbicide compounds.

Background: Marine sponges and sponge-associated fungi are rich sources of bioactive compounds with pharmacological potential. However, the secondary metabolites of Vietnamese marine sponge-derived fungi have been poorly studied. Objective: The aim of this study was to investigate the low-molecular-weight compounds in the extract of Penicillium sp. 1901NT-2.53.1 fungus isolated from the Vietnamese marine sponge Cinachyrella sp., and the antiproliferative activity of the isolated compounds. Methods: The structures of isolated compounds were elucidated using spectroscopic methods. The cell viability effects of the compounds were evaluated using MTT assay. Molecular docking was performed using SwissDock. Results: UPLC-MS data suggested the presence of beauvericin, citreorosein, benzopyran and chlorotetracycline derivatives, 2-chloro-1,3,8-trihydroxy-6-(hydroxymethyl)anthracene-9,10- dione and ergosterol peroxide in the fungal extract. Chromatographic separation of the extract resulted in the isolation of three derivatives of mycophenolic acid (MPA), namely penicacids G and K and 4-hydroxy-MPA. Penicacid K was isolated from a natural source for the first time. Penicacid G inhibited the viability of human normal HaCaT keratinocytes with IC50 of 88.3 μM and 72.9 μM for 24 h and 48 h of treatment, respectively. Moreover, penicacid G arrested the proliferation of HaCaT keratinocytes. Both penicacids K and G can interact with the active site of IMPDH2, similar to other derivatives of MPA; however, the differences in their structures are important. Conclusion: Due to the selective action on cancer cells and good druggability, penicacid G may be interesting as an antiproliferative anticancer compound.

The present study aimed to isolate new specialized metabolites from the obligate marine fungus Asteromyces cruciatus KMM 4696. The strain KMM 4696 was identified based on the 28S rRNA, ITS, and TEF1 molecular genetic markers. Chromatographic separation of the fungal extract obtained from KI-containing nutrient media cultivation led to the isolation of undescribed pentanorlanostanes curvalarols C (1) and D (2), as well as an undescribed 6/6/5 anthraquinone acruciquinone D (3), along with eight known metabolites. The structures of the isolated compounds were established based on 1D and 2D NMR and MS data. The cytotoxic activity of curvalarol C (1) was assessed in MCF-10A and MCF-7 cells. Curvalarol C exhibited selective activity against cancer MCF-7 cells and inhibiting colony formation with an IC₅₀ of 4.7 µM.

The unreported peptide versicotide K (1), along with known averufin (2), 1′- hydroxyversicolorin B (3), averufanin (4), and sterigmatocystin (5), was isolated from the sponge-derived fungal strain Aspergillus versicolor 01NT- 1.5.1. Moreover, the new 6,8-dimethoxyaverythrin (6) and known averythrin (7) and sclerotiotide F (8) were isolated from another sponge-derived fungus Aspergillus flavus КMM 4695 (= VO49-48.3). The antimicrobial and cytotoxic activities of the isolated compounds were studied. The obtained data on the low cytotoxicity of averufanin (4) to normal HaCaT keratinocytes and H9c2 cardiomyocytes confirms its anticancer potential for future research. The significant activity of averythrin (7) against Staphylococcus aureus growth and biofilm formation (IC₅₀ of approximately 10 µM) is the first. The anti-inflammatory activity of versicotide K (1) was predicted using the PASS online server. Moreover, SwissTargetPrediction services predicted COX2 as a possible target for 1, and the interaction of 1 with COX2 was calculated using a molecular docking approach. In in vitro experiments, versicotide K (1) reduced S. aureus infection and ischemia/reperfusion damage of H9c2 cells and prevented TNF-α induced damage of H9c2 cardiomyocytes by 24%, confirming its anti-inflammatory properties.

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).

Marine alga-derived fungal strain КММ 4176 was identified as Aspergillus niveoglaucus based on ITS region BenA, CaM and RPB2 gene sequence analysis. The anthraquinone derivatives emodin anthrone (1) and 4-hydroxyemodin anthrone (2), chromone derivative aloesone (3), and indole diketopiperazine alkaloid neoechinulin B (4) were isolated from the ethyl acetate extract of this fungus. In addition, UPLC MS data analysis of the KMM 4176 extract showed the presence of 17 echinulin-family alkaloids, as well as their biogenetic precursor cyclo(l-alanyl-l-tryptophyl) and a number of polyketide compounds. Emodin anthrone and 4-hydroxyemodin anthrone were found as inhibitors of biofilm formation by Staphylococcus aureus with half-maximal inhibitory concentrations (IC₅₀) of 5.5 µM and 23.7 µM, respectively. Moreover, emodin anthrone (1) and 4-hydroxyemodin anthrone (2) inhibited staphylococcal sortase A activity with IC₅₀ of 9.2 µM and 37.6 µM, respectively. Aloesone (3) also inhibited S. aureus biofilm formation but was less active. The first data on neoechinulin B (4) antibiofilm activity and sortase A inhibition were obtained. The positive effects of the isolated compounds on the growth of HaCaT keratinocytes infected with S. aureus were also observed.

Background: During the cultivation of the marine fungus KMM 4668 on solid agar medium, the morphological instability of the strain was observed. As a result of the selection work, five intra-strain variants, named KMM 4711, KMM 4712, KMM 4713, KMM 4714, and KMM 4715, were obtained. Methods: The main objectives of this work were to compare the parent strain and its intra-strain variants using multi-locus phylogenetic analysis and to study the UPLC MS metabolite profiles and cytotoxic activities of their extracts. Results: A study of the original strain, KMM 4668, and its intra-strain variants using multi-locus phylogenetic analysis showed that they are sequence identical and belong to Penicillium antarcticum. UPLC MS metabolite profiling of fungal extracts revealed 20 compounds, including cladosporin-related polyketides, carotane sesquiterpenoids, andrastine meroterpenoids, and alkaloids. It was shown that the intra-strain variants KMM 4713 and KMM 4714 differed most strongly from the others in the increased production of cladosporin-related compounds, carotanoids, and the alkaloid chrysogin. In addition, the influence of fungal extracts on the viability of four mammalian cell lines was investigated. Conclusions: It has been shown that the intra-strain variants of P. antarcticum KMM 4668 may be promising sources of bioactive secondary metabolites.