Curvularin

NF-kappaB inhibitory, antimicrobial and antiproliferative potentials of compounds from Hawaiian fungus Aspergillus polyporicola FS910.[Pubmed:34458061]

3 Biotech. 2021 Aug;11(8):391.

Bioassay-guided experimental design and chromatographic analysis led to the isolation and identification of ten compounds (1-10) including two unusual sulfur-containing Curvularin macrolides (1 and 2) from a Hawaiian fungal strain Aspergillus polyporicola FS910. Compounds 1 and 2 are rare Curvularin macrolides each with a five-membered cyclic sulfur-containing moiety. The structures of the compounds were identified by HRESIMS, NMR spectroscopy, X-ray crystallography, ECD and DFT energy calculation, as well as comparing with previous literatures. Compounds 4, 6 and 8 were active against TNF-alpha-induced NF-kappaB inhibitory activity with IC50 values of 26.45, 5.41 and 15.8 microM, respectively. Compounds 3 and 5-8 exhibited anti-proliferative activity against HT1080, T46D, and A2780S cell lines, with IC50 values ranging from 2.48 to 29.17 muM. Additionally, Compound 3 showed promising antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA), Bacillus subtilis, Escherichia coli and Candida albicans. Moreover, when tested in combination with antibiotic adjuvant disulfiram [4 microg/mL], compounds 4, 5 and 10 also displayed significant antibacterial activity against S. aureus. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-021-02877-7.

10,11-dehydrocurvularin exerts antitumor effect against human breast cancer by suppressing STAT3 activation.[Pubmed:32868906]

Acta Pharmacol Sin. 2021 May;42(5):791-800.

Aberrant activation of signal transducer and activator of transcription 3 (STAT3) plays a critical role in many types of cancers. As a result, STAT3 has been identified as a potential target for cancer therapy. In this study we identified 10,11-dehydroCurvularin (DCV), a natural-product macrolide derived from marine fungus, as a selective STAT3 inhibitor. We showed that DCV (2-8 muM) dose-dependently inhibited the proliferation, migration and invasion of human breast cancer cell lines MDA-MB-231 and MDA-MB-468, and induced cell apoptosis. In the two breast cancer cell lines, DCV selectively inhibited the phosphorylation of STAT3 Tyr-705, but did not affect the upstream components JAK1 and JAK2, as well as dephosphorylation of STAT3. Furthermore, DCV treatment strongly inhibited IFN-gamma-induced STAT3 phosphorylation but had no significant effect on IFN-gamma-induced STAT1 and STAT5 phosphorylation in the two breast cancer cell lines. We demonstrated that the alpha, beta-unsaturated carbonyl moiety of DCV was essential for STAT3 inactivation. Cellular thermal shift assay (CETSA) further revealed the direct engagement of DCV with STAT3. In nude mice bearing breast cancer cell line MDA-MB-231 xenografts, treatment with DCV (30 mg.kg(-1).d(-1), ip, for 14 days) markedly suppressed the tumor growth via inhibition of STAT3 activation without observed toxicity. Our results demonstrate that DCV acts as a selective STAT3 inhibitor for breast cancer intervention.

Alterchromanone A, one new chromanone derivative from the mangrove endophytic fungus Alternaria longipes.[Pubmed:32843724]

J Antibiot (Tokyo). 2021 Feb;74(2):152-155.

One new chromanone derivative, alterchromanone A (1), and four known Curvularin-type macrolides (2-5) were isolated from the crude extract of the mangrove-derived endophytic fungus Alternaria longipes. Their structures were elucidated by MS and NMR spectroscopic analyses and by a comparison with data from the literature. The absolute configuration of 1 was assigned by combination of experimental and calculated electronic circular dichroism (ECD) spectra. Compound 1 exhibited 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity with an IC50 value of 56.3 mug ml(-1). According to the structural features of these compounds, the plausible biosynthetic pathways of 1-5 were also proposed.

The Anti-Inflammatory and Cytoprotective Efficiency of Curvularin, a Fungal Macrolactone against Lipopolysaccharide-Induced Inflammatory Response in Nucleus Pulposus Cells: An In Vitro Study.[Pubmed:32252191]

Asian Spine J. 2021 Apr;15(2):143-154.

STUDY DESIGN: Developing an in vitro model for assessing the anti-inflammatory properties of Curvularin. PURPOSE: To evaluate the efficacy of natural fungal macrolactone as a therapeutic drug against lipopolysaccharide (LPS)-induced inflammation in primary human nucleus pulposus cells (NPCs) in vitro. OVERVIEW OF LITERATURE: Lumbar disk disease is a common cause of lower back pain (LBP) and sciatica. It is an established fact that inflammation, rather than mechanical compression on the nerve root, plays a role in the cause of LBP and sciatica. Current treatment options for reducing inflammation are either nonsteroidal anti-inflammatory drugs or steroids, prolonged use of which can potentially lead to adverse effects such as gastrointestinal disturbances and renal and cardiac issues. Hence, there is a need for better antiinflammatory drugs with no or minimal complications for treating inflammation-induced LBP and sciatica. Curvularin (Cur), a fungal macrolactone, is known for its anti-inflammatory activity, but nothing is known about its impact on inflammation due to disk pathologies. METHODS: Primary NPCs were cultured and characterized by flow cytometry and immunocytochemistry using the CD24 antibody and treated with 10 mug/mL LPS for 36 hours and then treated with Cur, betamethasone, and dexamethasone (10 mug/mL) for 48 hours, after which cell cycle analysis, cell viability assay, and gene expression studies (quantitative polymerase chain reaction [PCR] and quantitative real-time-PCR) were conducted. The NPCs treated with Cur downregulated the expression of pro-inflammatory cytokines (tumor necrosis factor-alpha, interleukin [IL]-1beta, and IL-6); matrix metalloproteinases (MMPs; MMP-2 and MMP-3), ADAMTS; and apoptotic marker (cytochrome c). RESULTS: In our study, Cur-treated cells showed enhanced expression of collagen 9A1 and insulin-like growth factor receptor 1, indicating the recovery of NPCs from inflammatory assault. CONCLUSIONS: Based on observations, the anti-inflammatory properties of Cur render it an excellent drug molecule for treating disk degeneration nonsurgically, by direct injection into spinal disks when treating LBP and sciatica.

Alternaria host-specific (HSTs) toxins: An overview of chemical characterization, target sites, regulation and their toxic effects.[Pubmed:31406682]

Toxicol Rep. 2019 Jul 17;6:745-758.

Alternaria causes pathogenic disease on various economically important crops having saprophytic to endophytic lifecycle. Pathogenic fungi of Alternaria species produce many primary and secondary metabolites (SMs). Alternaria species produce more than 70 mycotoxins. Several species of Alternaria produce various phytotoxins that are host-specific (HSTs) and non-host-specific (nHSTs). These toxins have various negative impacts on cell organelles including chloroplast, mitochondria, plasma membrane, nucleus, Golgi bodies, etc. Non-host-specific toxins such as tentoxin (TEN), Alternaric acid, alternariol (AOH), alternariol 9-monomethyl ether (AME), brefeldin A (dehydro-), Alternuene (ALT), Altertoxin-I, Altertoxin-II, Altertoxin-III, zinniol, tenuazonic acid (TeA), Curvularin and alterotoxin (ATX) I, II, III are known toxins produced by Alternaria species. In other hand, Alternaria species produce numerous HSTs such as AK-, AF-, ACT-, AM-, AAL- and ACR-toxin, maculosin, destruxin A, B, etc. are host-specific and classified into different family groups. These mycotoxins are low molecular weight secondary metabolites with various chemical structures. All the HSTs have different mode of actions, biochemical reactions, and signaling mechanisms to causes diseases in the host plants. These HSTs have devastating effects on host plant tissues by affecting biochemical and genetic modifications. Host-specific mycotoxins such as AK-toxin, AF-toxin, and AC-toxin have the devastating effect on plants which causes DNA breakage, cytotoxic, apoptotic cell death, interrupting plant physiology by mitochondrial oxidative phosphorylation and affect membrane permeability. This article will elucidate an understanding of the disease mechanism caused by several Alternaria HSTs on host plants and also the pathways of the toxins and how they caused disease in plants.

Mycotoxin and cyanogenic glycoside assessment of the traditional leafy vegetables mutete and omboga from Namibia.[Pubmed:31109256]

Food Addit Contam Part B Surveill. 2019 Dec;12(4):245-251.

Sixty traditional leafy vegetables, comprising of mutete (Hibiscus sabdariffa) (n = 20) and omboga (Cleome gynandra) (n = 40) were analysed for fungal, plant and bacterial metabolites using liquid-chromatography-tandem mass spectrometry. No European Union legislated mycotoxins were quantified and no vegetables contained levels above the FAO/WHO limit of 10 mg/kg for cyanogenic potential, suggesting comparative safety regarding regulated mycotoxins and cyanogenic glycosides. Quantified fungal metabolites included averufin and 3-Nitropropionic acid from Aspergillus flavus, beauvericin and equisetin from Fusarium, citrinin and Curvularin from Penicillium and altertoxin -1 and tentoxin from Alternaria. Of the plant cyanogenic glycosides, linamarin was quantifiable in 65% of mutete at a maximum of 398 microg/kg but not in omboga, while lotaustralin was quantifiable in both omboga and mutete. The bacterial metabolite nonactin was detected in 27.5% of omboga samples (range: 0.2-7.3 mug/kg). Minimal variation in metabolite patterns was recorded for omboga samples from Oshana and Oshikoto regions.

A Unified Synthetic Approach to Optically Pure Curvularin-Type Metabolites.[Pubmed:31083915]

J Org Chem. 2019 Jun 7;84(11):7227-7237.

A unified and concise approach to the synthesis of nine Curvularin-type metabolites and two analogues has been developed with few steps and high yields. Among them, sumalactones A-D were synthesized for the first time. The key steps in this approach included esterification, Friedel-Crafts acylation, and ring-closing metathesis (or cross metathesis).

Classic fungal natural products in the genomic age: the molecular legacy of Harold Raistrick.[Pubmed:29537034]

Nat Prod Rep. 2018 Mar 1;35(3):230-256.

Covering: 1893 to 2017Harold Raistrick was involved in the discovery of many of the most important classes of fungal metabolites during the 20th century. This review focusses on how these discoveries led to developments in isotopic labelling, biomimetic chemistry and the discovery, analysis and exploitation of biosynthetic gene clusters for major classes of fungal metabolites including: alternariol; geodin and metabolites of the emodin pathway; maleidrides; citrinin and the azaphilones; dehydroCurvularin; mycophenolic acid; and the tropolones. Key recent advances in the molecular understanding of these important pathways, including the discovery of biosynthetic gene clusters, the investigation of the molecular and chemical aspects of key biosynthetic steps, and the reengineering of key components of the pathways are reviewed and compared. Finally, discussion of key relationships between metabolites and pathways and the most important recent advances and opportunities for future research directions are given.

Anti-Inflammatory Effects of Curvularin-Type Metabolites from a Marine-Derived Fungal Strain Penicillium sp. SF-5859 in Lipopolysaccharide-Induced RAW264.7 Macrophages.[Pubmed:28869509]

Mar Drugs. 2017 Sep 2;15(9). pii: md15090282.

Chemical study on the extract of a marine-derived fungal strain Penicillium sp. SF-5859 yielded a new Curvularin derivative (1), along with eight known Curvularin-type polyketides (2-9). The structures of these metabolites (1-9) were established by comprehensive spectroscopic analyses, including 1D and 2D nuclear magnetic resonance (NMR) spectroscopy, and mass spectrometry (MS). In vitro anti-inflammatory effects of these metabolites were evaluated in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Among these metabolites, 3-9 were shown to strongly inhibit LPS-induced overproduction of nitric oxide (NO) and prostaglandin E(2) (PGE(2)) with IC50 values ranging from 1.9 muM to 18.1 muM, and from 2.8 muM to 18.7 muM, respectively. In the further evaluation of signal pathways involved in these effects, the most active compound, (10E,15S)-10,11-dehydroCurvularin (8) attenuated the expression of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) in LPS-stimulated RAW264.7 macrophages. Furthermore, compound 8 was shown to suppress the upregulation of pro-inflammatory mediators and cytokines via the inhibition of the nuclear factor-kappaB (NF-kappaB) signaling pathway, but not through the mitogen-activated protein kinase (MAPK) pathway. Based on the comparisons of the different magnitude of the anti-inflammatory effects of these structurally-related metabolites, it was suggested that the opening of the 12-membered lactone ring in Curvularin-type metabolites and blocking the phenol functionality led to the significant decrease in their anti-inflammatory activity.

Metabolites from the Endophytic Fungus Curvularia sp. M12 Act as Motility Inhibitors against Phytophthora capsici Zoospores.[Pubmed:28195475]

J Nat Prod. 2017 Feb 24;80(2):347-355.

The endophytic fungus Curvularia sp., strain M12, was isolated from a leaf of the medicinal plant Murraya koenigii and cultured on rice medium followed by chemical screening of the culture extract. Chromatographic analysis led to the isolation of four new compounds, murranofuran A (1), murranolide A (2), murranopyrone (3a), and murranoic acid A (4a), along with six known metabolites, N-(2-hydroxy-6-methoxyphenyl)acetamide (5), Curvularin (6), (S)-dehydroCurvularin (7), pyrenolide A (8), modiolide A (9), and 8-hydroxy-6-methoxy-3-methylisocoumarin (10). The structures of the known compounds were confirmed by comparing ESI HR mass spectra, (1)H and (13)C NMR, and optical rotation data with values reported in the literature. The planar structures of the new compounds were elucidated by extensive analysis of 1D and 2D NMR and mass data. The absolute configurations of the new compounds were established by coupling constant analysis, modified Mosher's method, and CD data. Compound 8 showed a strong motility impairing activity against Phytophthora capsici zoospores at a low concentration (100% at 0.5 mug/mL) in a short time (30 min). Compounds 2, 3a, 6, 7, 9, and 10 exhibited zoospore motility impairment activity at higher concentrations (IC50: 50-100 mug/mL).

Condensation of Macrocyclic Polyketides Produced by Penicillium sp. DRF2 with Mercaptopyruvate Represents a New Fungal Detoxification Pathway.[Pubmed:27227682]

J Nat Prod. 2016 Jun 24;79(6):1668-78.

Application of a refined procedure of experimental design and chemometric analysis to improve the production of Curvularin-related polyketides by a marine-derived Penicillium sp. DRF2 resulted in the isolation and identification of cyclothioCurvularins 6-8 and cyclosulfoxiCurvularins 10 and 11, novel Curvularins condensed with a mercaptolactate residue. Two additional new Curvularins, 3 and 4, are also reported. The structures of the sulfur-bearing Curvularins were unambiguously established by analysis of spectroscopic data and by X-ray diffraction analysis. Analysis of stable isotope feeding experiments with [U-(13)C3(15)N]-l-cysteine confirmed the presence of the 2-hydroxy-3-mercaptopropanoic acid residue in 6-8 and the oxidized sulfoxide in 10 and 11. CyclothioCurvularins A (6) and B (7) are formed by spontaneous reaction between 10,11-dehydroCurvularin (2) and mercaptopyruvate (12) obtained by transamination of cysteine. High ratios of [U-(13)C3(15)N]-l-cysteine incorporation into cyclothioCurvularin B (7), the isolation of two diastereomers of cyclothioCurvularins, the lack of cytotoxicity of cyclothioCurvularin B (7) and its methyl ester (8), and the spontaneous formation of cyclothioCurvularins from 10,11-dehydroCurvularin and mercaptopyruvate provide evidence that the formation of cyclothioCurvularins may well correspond to a 10,11-dehydroCurvularin detoxification process by Penicillium sp. DRF2.

A surprising switch in absolute configuration of anti-inflammatory macrolactones.[Pubmed:27035902]

Org Biomol Chem. 2016 Apr 12;14(15):3695-8.

Oxacyclododecindione-type macrolactones exhibit highly potent anti-inflammatory activities even at nanomolar concentration. After the determination of the relative configuration of the stereocenters at C14 and C15 by total synthesis of 4-dechloro-14-deoxyoxacyclododecindione and 14-deoxyoxacyclododecindione, the absolute configuration has now been assigned by X-ray crystallography. Surprisingly, the absolute configuration is (14S,15R) which differs for C15 from that of the well-known derivatives of (S)-Curvularin. The biological activities of both enantiomers of 14-deoxyoxacyclododecindione, obtained by racemic synthesis and optical resolution, were investigated and the ring conformation of the natural product was compared to that of (S)-Curvularin and (R)-dehydroCurvularin.

Biotransformation of (-)-(10E,15S)-10,11-Dehydrocurvularin.[Pubmed:26411029]

Nat Prod Commun. 2015 Jul;10(7):1277-8.

(-)-(10E,15S)-10,11-DehydroCurvularin (1), produced from an associated-fungus of Scolopendra subspinipes mutilans on a gram scale, was microbiologically converted to Curvularin (2) and 5-methoxyCurvularin (3) by Antrodiella semisupina in 61% totally isolated yield. The structures of these compounds were elucidated on the basis of spectroscopic and mass spectrometric analysis. The undescribed assignments of 1H and 13C NMR spectral data for 5-methoxyCurvularin (2) has now been explicitly provided. The cytotoxic activities of compounds 1-3 against four human cancer cell lines were evaluated. DehydroCurvularin (1) showed moderate cytotoxicity against Caski and Hep-G2, and Curvularin (2) was selectively cytotoxic against MDA-MB-231.

A new curvularin glycoside and its cytotoxic and antibacterial analogues from marine actinomycete Pseudonocardia sp. HS7.[Pubmed:26119337]

Nat Prod Res. 2016;30(10):1156-61.

Five Curvularin macrolides (1-5) were isolated from the cultured broth of marine actinomycete Pseudonocardia sp. HS7 that was obtained from the cloacal aperture of sea cucumber Holothuria moebii. The structures of these isolates were characterized as (11S,15R)-11-hydroxyCurvularin (1), (11R,15R)-11-hydroxyCurvularin (2), Curvularin-7-O-alpha-D-glucopyranoside (3), trans-dehydroCurvularin (4) and Curvularin (5) based on their NMR and HRESIMS data as well as chemical degradation. Compound 3 is a new macrolide with a rare alpha-D-glucopyranose substituent. Compounds 1-4, 5a and 5c (the acyl products of 5), suppressed the proliferation of all six tested cancer cell lines and 4 is the most active compound with IC50 values ranging from 0.59 to 3.39 muM. The 11-hydroxyCurvularins 1 and 2 also showed antibacterial activity inhibiting the growth of Escherichia coli.