Antimicrobial tetrahydroanthraquinones from a strain of Alternaria solani

doi:10.1016/0031-9422(93)85401-C

Phytochemistry

Volume 33, Issue 1, 29 April 1993, Pages 87-91

https://doi.org/10.1016/0031-9422(93)85401-C Get rights and content

Abstract

Culture liquid and mycelia of a strain of Alternaria solani, which was isolated from a diseased Lycopersicon esculentum, afforded new tetrahydr

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Cited by (53)

Altersolanol B, a fungal tetrahydroanthraquinone, inhibits the proliferation of estrogen receptor-expressing (ER+) human breast adenocarcinoma by modulating PI3K/AKT, p38/ERK MAPK and associated signaling pathways
2022, Chemico-Biological Interactions
The present study focused on the apoptosis-inducing effects and cellular signal-modulating properties of altersolanol B (AB), a minor fungal tetrahydroanthraquinone (THAQ) metabolite, in the estrogen receptor positive (ER+) human breast adenocarcinoma cell line, MCF-7. AB demonstrated approximately 4-fold greater antiproliferative activity in ER+ MCF-7 cells (IC₅₀ 5.5 μM) compared to the ER-negative (triple-negative) MDA-MB-231 (IC₅₀ 21.3 μM). The viability of normal breast fibrocystic epithelial cells, MCF-10A, was unaffected. AB induced intrinsic apoptosis in MCF-7 cells; it triggered the activation of caspase 9 and poly (ADP-ribose) polymerase (PARP), upregulated the expression of pro-apoptotic Bax, and downregulated the expression of anti-apoptotic Bcl-2. AB induced cell cycle arrest at G0/G1, as indicated by the downregulation of key checkpoint proteins operating at the G0/G1 phase of the cell cycle (cyclin D1, CDK4 and CDK2). The observed increase in p21Waf1/Cip1 and p53 expression may facilitate cell cycle arrest, and the subsequent induction of apoptosis. AB lacked significant effects on intracellular ROS levels, while it down-regulated nuclear factor erythroid 2-related factor 2 (Nrf2), and the Nrf2-dependent antioxidant enzyme, heme oxygenase-1. The compound disrupted AKT signaling through the downregulation of phospho-AKT and phospho-FOXO1, and the upregulation of PTEN, a phosphatase and tumor suppressor that negatively regulates the PI3K/AKT pathway. AB also disrupted the phosphorylation of AKT-controlled eukaryotic translation initiation factor, 4E-BP1, and GSK-3β, both of which are aberrantly regulated in human cancer. The AB-dependent downregulation of NF-κB was corroborated by the inhibition of TNFα-induced NF-κB activity as monitored in a luciferase reporter. The NF-κB inhibitory activity of AB was 3-fold more potent than that of the standard inhibitor, N-p-Tosyl-l-phenylalanine chloromethyl ketone. In addition to reducing the pro-survival effects of NF-кB, the inhibition of AKT phosphorylation by AB may also lead to FOXO1-mediated growth arrest and apoptosis. AB upregulated the expression of phospho-MKK4 and phospho-p38, and downregulated the expression of phospho-MEK1/2 and phospho-ERK1/2 indicating opposing effects on the two important oncogenic signaling cascades that are aberrantly activated in many cancers. AB disrupted both the AKT and ERK1/2 signaling pathways leading to apoptosis in ER+ MCF-7 cells through mitochondria-associated mechanisms coupled with the potent inhibition of NF-кB activation. The clinical limitations of multi-agent combination therapy that targets multiple pathways in cancer may potentially be circumvented by using a single molecule, such as AB, that inhibits both AKT and ERK1/2 signaling. Our preliminary study suggested that the THAQ pharmacophore, with its disrupted conjugated ring system and relative redox inactivity, may possess greater mechanistic advantage against ER+ breast cancer when compared to the fully conjugated ring systems of the anthraquinone that possess intrinsic redox activity and DNA interacting ability. This study supports the continued investigation of THAQs as lead molecules in anticancer drug discovery and development.
Anthraquinone derivatives from a coral associated fungus Stemphylium lycopersici
2020, Natural Product Research
Two new anthraquinone derivatives, alterporriol Y (1) and macrosporin 2-O-α-D-glucopyranoside (2), together with five known analogues (3-7) were isolated from the fungus Stemphylium lycopersici associated with the gorgonian coral Dichotella gemmacea collected from the South China Sea. Their structures were determined on the basis of detailed spectroscopic analysis and comparison with reported data. The absolute configurations were determined by the ECD method. In an in vitro cytotoxic assay, compound 3 and 4 showed potent effects against HCT-116 and MCF-7 cell lines. Compound 4 also exhibited cytotoxicity toward Huh7 stem cell-like cells.
Novel anthraquinone derivatives as inhibitors of protein tyrosine phosphatases and indoleamine 2,3-dioxygenase 1 from the deep-sea derived fungus: Alternaria tenuissima DFFSCS013
2019, Organic Chemistry Frontiers
A novel hydroanthraquinone possessing an unprecedented hexacyclic spiro-fused ring system, anthrininone A (1), and two new anthraquinones with a 4,5-disubstituted butylaminolate unit, anthrininones B and C (2 and 3), together with six known analogues including 6-O-methylalaternin (4) and so on, were obtained from the deep-sea derived fungus Alternaria tenuissima DFFSCS013. Their structures were determined by spectroscopic methods, and the absolute configurations were further determined by single crystal X-ray diffraction analysis for 1 and quantum chemical calculations for 2 and 3, respectively. Compounds 1–4 had significant inhibition activity against indoleamine 2,3-dioxygenase 1 (IDO1), and 2–4 also exhibited selective inhibition activity against different protein tyrosine phosphatases. In addition, 1 could obviously stimulate intracellular calcium levels at a concentration of 10 μM. Their structure–bioactivity relationship was also discussed.
New cytotoxic compounds of endophytic fungus Alternaria sp. isolated from Broussonetia papyrifera (L.) Vent
2016, Fitoterapia
Citation Excerpt :
Based on the MS and NMR data and comparison with published data, compounds 2–10 was identified as known compounds: 3,4′,5′-trihydroxy-5-methoxy-6H-benzo [c]chromen-6-one (2) [29] and alternariol 4′-O-methyl ether (3) [30] and this is the first report of the new naturally occurring compounds 3 (Fig. 4). compound 4, altersolanol A [27]; compound 5, altertoxin I (dihydroalterperylenol), [31–32]; compound 6, ergosta-4, 6, 8 (14), 22-tetraen-3-one (ergone) [33]; compound 7, alternariol 5-O-methyl ether [34]; compound 8, alternariol [35]; compound 9, alternuene [36]; compound 10, altersolanol C [27]. Compound 4 and 10 are tetrahydroperylenone derivatives.
From the ethyl acetate extract of a culture of the endophytic fungus Alternaria species G7 in Broussonetia papyrifera, a new compound altertoxin IV (1) together with nine known compounds were isolated and identified by means of bioassay-guided fractionation. The structures of these compounds were established on the basis of spectroscopic methods, among which the absolute configuration of compound 1, a new tetrahydroperylenone derivative, was determined by means of X-Ray Crystallographic analysis. The isolated compounds were subjected to cytotoxic activity against three human cancer cell lines (A549, MG-63, and SMMC-7721). Compound 2 showed significant cytotoxic activities against tested cell lines, with IC₅₀ values of 1.47, 2.11 and 7.34 μg/mL, respectively. Additionally, compound 4 also exhibited significant cytotoxic activities against cell lines MG-63 and SMMC-7721, with IC₅₀ values of 0.53 and 2.92 μg/mL. Endophytic fungi Alternaria from B. papyrifera might be promising sources of natural bioactive and novel metabolites.
Tetrahydroanthraquinone derivatives from the mangrove-derived endophytic fungus Stemphylium globuliferum
2016, Tetrahedron Letters
Citation Excerpt :
Due to the 4–8′ biaryl linkage of the anthraquinone-tetrahydroanthraquione dimer, besides the central chirality elements, alterporriol X (3) had also axial chirality, which could be determined as (aR) on the basis of its similar ECD spectrum to that of the related biaryl natural product alterporriol W having (aR) axial chirality.16 By comparison of NMR and MS data with the literature, the 13 known compounds were identified as dihydroaltersolanol B (4) and C (5),17 altersolanol A (6),18 B (7),19 and N (8),10 1-hydroxy-3-methoxy-6-methylanthraquinone (9),20 macrosporin (10),21 altechromone A (11),22 alterporriol D (12),18 E (13),18 R (14),9 V (15),23 and W (16).23 Dihydroaltersolanol C (5),17 altersolanol A (6),17 B (7),17 N (8),10 and alterporriol E (13)17 have been reported to exhibit potent cytotoxicity against L5178Y mouse lymphoma cell line with IC50 values in the low micromolar range.
Two new tetrahydroanthraquinone derivatives, altersolanol Q (1) and 10-methylaltersolanol Q (2), and the new dimer alterporriol X (3), together with 13 known analogues were isolated from white bean solid culture media of the endophytic fungus, Stemphylium globuliferum, obtained from the Egyptian mangrove plant Avicennia marina. The present study resulted in the production of a large diversity of secondary metabolites including new derivatives. Their structures were elucidated using one- and two-dimensional NMR spectroscopy as well as HRESIMS. The absolute configurations of the new compounds 1–3 were determined by TDDFT-ECD calculations or by comparing ECD data with those of known analogues. Compounds 1–3 were tested against the L5178Y mouse lymphoma cell line but proved to be inactive in contrast to some of the known compounds such as altersolanol A (6) that were likewise isolated in this study.
Endophytic fungi - The treasure chest of antibacterial substances
2012, Phytomedicine
Citation Excerpt :
Altersolanol A featured a MIC value of 12.5 μg/ml against S. epidermidis and E. faecalis, and 25 μg/ml against S. aureus (Aly et al. 2008). An earlier report by Yagi et al. had already revealed that altersolanol A inhibits the growth of Gram-positive bacteria and Pseudomonas aeruginosa IFO 3080 when tested using the broth dilution method (Yagi et al. 1993). Aspergillus sp.
Over more than 20 years, the endophytic fungi have been explored as “biofactories” of novel bioactive substances, and they have not disappointed. Among the extracts and pure substances obtained from the culture broths or fungal biomass, some have exerted antibacterial activity ranging from moderate to powerful when tested on the bacterial strains resistant to the antibiotics currently in use. In this article we review the accumulated data on endophytic fungi isolated from plants that produce metabolites with antibacterial activity against human pathogenic bacteria.

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Antimicrobial tetrahydroanthraquinones from a strain of Alternaria solani

Abstract

Biosci. Biotech. Biochem.

Can. J. Chem.

J. Antibiot.

Can. J. Chem.