Azaphilone Derivatives Research Articles

Isochromophilones H-K, the new bioactive azaphilone derivatives isolated from fungal strain Diaporthe perseae associated with Pongamia pinnata plant

The phytochemical study of the Diaporthe species has revealed significant classes of mycotoxins and phomopsins. Dihydroanthracenone derivatives, chromanones and isochromophilones have also been isolated from Diaporthe sp. These findings led us to explore the Diaporthe perseae for phytochemical analysis that resulted in the isolation of four new compounds designated as isochromophilones H-K (1–4), alongside three previously identified metabolites. Using extensive spectroscopic investigations such as NMR, and Mass spectroscopy, their structures were elucidated. Furthermore, the antimicrobial and anti-diabetic potentials of all isolated compounds were assessed. Compounds 1–3 demonstrated significant antibacterial activity, while compounds 4–7 exhibited comparatively lower effectiveness than the reference antibiotics. Compounds 2–3 showed potent diabetic inhibition, displaying IC50 values of 16.3 ± 0.3 and 25.4 ± 0.3, respectively. Compounds 1, 5, and 6 displayed mild anti-diabetic effects, with IC50 values of 56.5 ± 0.8, 37.6 ± 0.4, and 48.2 ± 0.6. However, compounds 4 and 7 were found least active.

Isolation and Characterization of Antimicrobial Metabolites from the Sophora tonkinensis-Associated Fungus Penicillium sp. GDGJ-N37.

Chemical investigation of Penicillium sp. GDGJ-N37, a Sophora tonkinensis-associated fungus, yielded two new azaphilone derivatives, N-isoamylsclerotiorinamine (1) and 7-methoxyl-N-isoamylsclerotiorinamine (2), and four known azaphilones (3-6), together with two new chromone derivatives, penithochromones X and Y (7 and 8). Their structures were elucidated based on spectroscopic data, CD spectrum, and semi-synthesis. Sclerotioramine (3) showed significant antibacterial activities against B. subtilis and S. dysentery, and it also showed most potent anti-plant pathogenic fungi activities against P. theae, C. miyabeanus, and E. turcicum.

Molecular networking-based discovery of new polyketides from the deep-sea-derived fungus Talaromyces indigoticus FS688

Under the guidance of Molecular Networking (MN), four new azaphilone derivatives (1–3 and 5) and a new isoprenyl-substituted benzoate derivative (6) were isolated from the deep-sea-derived fungus Talaromyces indigoticus FS688 together with a known analogue (4). The structures of the new compounds were elucidated by comprehensive spectroscopic analysis as well as the quantum chemical ECD calculations. The bioactivities tests indicated that compound 4 exhibited significant NO prodcution and α-glucosidase inhibitory activities with the IC50 values of 31.1 and 22.7 μM, which were more potential than their corresponding positive control.

New Hybrid Phenalenone Dimer, Highly Conjugated Dihydroxylated C28 Steroid and Azaphilone from the Culture Extract of a Marine Sponge-Associated Fungus, Talaromyces pinophilus KUFA 1767

An undescribed hybrid phenalenone dimer, talaropinophilone (3), an unreported azaphilone, 7-epi-pinazaphilone B (4), an unreported phthalide dimer, talaropinophilide (6), and an undescribed 9R,15S-dihydroxy-ergosta-4,6,8 (14)-tetraen-3-one (7) were isolated together with the previously reported bacillisporins A (1) and B (2), an azaphilone derivative, Sch 1385568 (5), 1-deoxyrubralactone (8), acetylquestinol (9), piniterpenoid D (10) and 3,5-dihydroxy-4-methylphthalaldehydic acid (11) from the ethyl acetate extract of the culture of a marine sponge-derived fungus, Talaromyces pinophilus KUFA 1767. The structures of the undescribed compounds were elucidated by 1D and 2D NMR as well as high-resolution mass spectral analyses. The absolute configuration of C-9' of 1 and 2 was revised to be 9'S using the coupling constant value between C-8' and C-9' and was confirmed by ROESY correlations in the case of 2. The absolute configurations of the stereogenic carbons in 7 and 8 were established by X-ray crystallographic analysis. Compounds 1,2, 4-8, 10 and 11 were tested for antibacterial activity against four reference strains, viz. two Gram-positive (Staphylococcus aureus ATCC 29213, Enterococcus faecalis ATCC 29212) and two Gram-negative (Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853), as well as three multidrug-resistant strains, viz. an extended-spectrum β-lactamase (ESBL)-producing E. coli, a methicillin-resistant S. aureus (MRSA) and a vancomycin-resistant E. faecalis (VRE). However, only 1 and 2 exhibited significant antibacterial activity against both S. aureus ATCC 29213 and MRSA. Moreover, 1 and 2 also significantly inhibited biofilm formation in S. aureus ATCC 29213 at both MIC and 2xMIC concentrations.

Secondary Metabolites from Aspergillus sparsus NBERC_28952 and Their Herbicidal Activities

Fungi have been used in the production of a wide range of biologically active metabolites, including potent herbicides. In the search for pesticides of natural origin, Aspergillus sparsus NBERC_28952, a fungal strain with herbicidal activity, was obtained. Chemical study of secondary metabolites from NBERC_28952 resulted in the isolation of three new asperugin analogues, named Aspersparin A-C (2-4), and a new azaphilone derivative, named Aspersparin D (5), together with two known compounds, Asperugin B (1) and sydonic acid (6). The structures of these compounds were elucidated based on extensive spectroscopic data and single-crystal X-ray diffraction analysis. All of the isolated compounds were evaluated for their herbicidal activities on seedlings of Echinochloa crusgalli and Amaranthus retroflexus through Petri dish bioassays. Among them, compounds 5 and 6 exhibited moderate inhibitory activities against the growth of the roots and shoots of E. crusgalli seedlings in a dose-dependent manner, while 6 showed obvious inhibitory effect on seedlings of A. retroflexus, with an inhibitory rate of 78.34% at a concentration of 200 μg/mL. These herbicidal metabolites represent a new source of compounds to control weeds.

Additional Azaphilones from the Marine Algae-Derived Fungus Penicillium sclerotiorum with Anti-Angiogenic Activity

Abstract Sixteen azaphilone derivatives, including four new compounds, penicilazaphilones H and I (1 and 2), 11-epi-geumsanol F (3), and 11-epi-geumsanol B (4), together with twelve known analogues (5–16), were isolated from the algae-derived fungus Penicillium sclerotiorum purified from fresh marine macroalgae Grateloupia sp. The planar structures of 1–4 were identified by HRESIMS, IR, NMR, and UV spectroscopic analyses. Their absolute configurations were unambiguously determined by comparing the NMR and ECD spectra. These secondary metabolites were evaluated on the anti-angiogenic effect in human endothelial progenitor cells (EPCs). As a result, compounds 12, 14, and 16 exhibited anti-angiogenic activities by blocking cell growth, migration, and tube formation of EPCs. Additionally, the structure–activity relationships (SAR) for anti-angiogenic effects of isolated azaphilones were deduced.

Azaphilones from the Endophyte Diaporthe sp. and Their Toxicity.

Chemotherapy and targeted therapies are increasingly used as conventional means to control tumor growth and prolong survival. Patient treated with anti-neoplastic agents experience severe side effects, especially those cytotoxic chemotherapies. Exploring chemo agents with less side effects is the hot spot of anticancer research. In this study, three azaphilone derivatives (chaetoviridin A (1), chaetoviridin E (2) and chaetomugilin D (3)) were isolated from the endophyte of the plant Anoectochilus roxburghii (Wall.) Lindl, their structures were elucidated by NMR. The toxicity of these compounds was evaluated by zebrafish model. The results show that these compounds had no toxicity against zebrafish. These compounds may act as safe anticancer drug leads according to this result. These three azaphilone derivatives were first time reported isolated from Diaporthe species which mainly used to isolate from Chaetomium species.

Induction of Secondary Metabolite Biosynthesis by Deleting the Histone Deacetylase HdaA in the Marine-Derived Fungus Aspergillus terreus RA2905.

Aspergillus terreus is well-known for its ability to biosynthesize valuable pharmaceuticals as well as structurally unique secondary metabolites. However, numerous promising cryptic secondary metabolites in this strain regulated by silent gene clusters remain unidentified. In this study, to further explore the secondary metabolite potential of A. terreus, the essential histone deacetylase hdaA gene was deleted in the marine-derived A. terreus RA2905. The results showed that HdaA plays a vital and negative regulatory role in both conidiation and secondary metabolism. Loss of HdaA in A. terreus RA2905 not only resulted in the improvement in butyrolactone production, but also activated the biosynthesis of new azaphilone derivatives. After scaled fermentation, two new azaphilones, asperterilones A and B (1 and 2), were isolated from ΔhdaA mutant. The planar structures of compounds 1 and 2 were undoubtedly characterized by NMR spectroscopy and mass spectrometry analysis. Their absolute configurations were assigned by circular dichroism spectra analysis and proposed biosynthesis pathway. Compounds 1 and 2 displayed moderate anti-Candida activities with the MIC values ranging from 18.0 to 47.9 μM, and compound 1 exhibited significant cytotoxic activity against human breast cancer cell line MDA-MB-231. This study provides novel evidence that hdaA plays essential and global roles in repressing secondary metabolite gene expression in fungi, and its deletion represents an efficient strategy to mine new compounds from A. terreus and other available marine-derived fungi.

Azaphilone derivatives with anti-inflammatory activity from the mangrove endophytic fungus Penicillium sclerotiorum ZJHJJ-18

Nine undescribed azaphilone derivatives, sclerazaphilones A–H (1–9), and three known analogues (10–12), were obtained and identified from the fermented rice cultures of a mangrove endophytic fungus Penicillium sclerotiorum ZJHJJ-18. 1D and 2D NMR, HRESIMS and spectral data indicated the chemical structures of 1–9, and their absolute configurations were assigned by experimental and computational analyses of electronic circular dichroism (ECD) spectra, and application of the chemical transformations. Compounds 1–4 were the first reported N-containing azaphilone derivatives with 5/6 dicyclic core. The bioassay results showed that compounds 3–5 exhibited effective inhibitory effects on the nitric oxide (NO) production in lipopolysaccharide (LPS)-induced RAW264.7 macrophage cells with IC50 values in the range of 6.30–9.45 μM. Moreover, a molecular docking study was conducted to investigate the probable binding interaction of 3–5 with inducible nitric oxide synthase (iNOS).

Azaphilones as Activation-Free Primary-Amine-Specific Bioconjugation Reagents for Peptides, Proteins and Lipids.

Residue-selective bioconjugation methods for biomolecules are highly sought to expand the scope of their biological and medical applications. Inspired by the mechanism of the generation of natural vinylogous γ-pyridones (vPDNs), we have developed a novel unique azaphilone-based, activation-free primary-amine-selective bioconjugation method for biomolecules. Our strategy allows facile functionalization of primary amine groups in peptides and proteins, including the clinically used therapeutic antibody trastuzumab, by generating a highly stable vPDN linkage. Excellent chemoselectivity toward primary amines also enables the azaphilone derivatives to specifically modify the lipid components of Gram-positive bacteria while bypassing Gram-negative bacteria and mammalian cells. The new method shows significant advantages including chemoselectivity, efficiency, flexibility and biocompatibility, and therefore provides a valuable addition to the current toolbox for biomolecule conjugation.

Azaphilones as Activation‐Free Primary‐Amine‐Specific Bioconjugation Reagents for Peptides, Proteins and Lipids

AbstractResidue‐selective bioconjugation methods for biomolecules are highly sought to expand the scope of their biological and medical applications. Inspired by the mechanism of the generation of natural vinylogous γ‐pyridones (vPDNs), we have developed a novel unique azaphilone‐based, activation‐free primary‐amine‐selective bioconjugation method for biomolecules. Our strategy allows facile functionalization of primary amine groups in peptides and proteins, including the clinically used therapeutic antibody trastuzumab, by generating a highly stable vPDN linkage. Excellent chemoselectivity toward primary amines also enables the azaphilone derivatives to specifically modify the lipid components of Gram‐positive bacteria while bypassing Gram‐negative bacteria and mammalian cells. The new method shows significant advantages including chemoselectivity, efficiency, flexibility and biocompatibility, and therefore provides a valuable addition to the current toolbox for biomolecule conjugation.

Nigirpexin E, a new azaphilone derivative with anti-tobacco mosaic virus activity from soil-derived fungus Trichoderma afroharzianum LTR-2.

A new compound classified as one new azaphilone derivative, nigirpexin E (1), was obtained from the soil-derived fungus Trichoderma afroharzianum LTR-2, together with seven known compounds (2-8). The structures of 1-8 were determined by their HRESIMS, optical rotation, and NMR spectroscopic data. The absolute configuration of nigirpexin E (1) was determined on the basis of comparisons of experimental and theoretically calculated ECD spectra. Compound 3 was firstly isolated from Trichoderma. Bioactivities of the isolated compounds were assayed their anti-tobacco mosaic virus (anti-TMV) activities. The results showed that compound 1 exhibited significant inactivation effect against TMV with an inhibition rate of 67.25% (0.5 mg ml-1), which was higher than that of positive control ribavirin (56.74%). This is the first report of the anti-TMV activity of azaphilone derivatives.

Identification of azaphilone derivatives of Monascus colorants from Talaromyces amestolkiae and their halochromic properties

Currently, the ability to produce several kinds of water-soluble red natural colorants makes the genus Talaromyces particularly important to the dye industry, which can be an alternative to the use of harmful synthetic colorants. In this study, colored compounds produced by Talaromyces amestolkiae were extracted, characterized chemically and the color stability of the fermented broth without any extraction procedure was further evaluated over pH variation. Five azaphilones compounds were detected by Ultrahigh Performance Liquid Chromatography-Mass Spectrometry system, all being complexes of the fatty acid amino-hexanedioic acid and azaphilone Monascus colorants. The color of the fermented broth was stable at a wide range of pH (3–9). Furthermore, T. amestolkiae colorants precipitated through hydrolysis of key chemical groups at extremely acidic (pH 1) and lose red color in extremely basic (pH 13) medium, showing negative halochromism. Nevertheless, these findings enhance the industrial relevance of azaphilone colorants produced by biotechnological process.

A Novel Azaphilone Muyophilone A From the Endophytic Fungus Muyocopron laterale 0307-2.

Two known azaphilone derivatives, 4,6-dimethylcurvulinic acid (1) and austdiol (2), and their novel heterotrimer, muyophilone A (3), were isolated and identified from an endophytic fungus, Muyocopron laterale 0307-2. Their structures and stereochemistry were established by extensive spectroscopic analyses including HRMS, NMR spectroscopy, electronic circular dichroism (ECD) and vibrational circular dichroism (VCD) spectroscopic methods, as well as single crystal X-ray diffraction. In the structure of 3, two compound 2-derived azaphilone units were connected through an unprecedented five-membered carbon bridge which was proposed to be originated from compound 1. Compound 3 represents the first example of azaphilone heterotrimers.

Chaetolactam A, an Azaphilone Derivative from the Endophytic Fungus Chaetomium sp. g1.

Chaetolactam A (1), an unprecedented azaphilone derivative bearing a unique 9-oxa-7-azabicyclo[4.2.1]octan-8-onering system, together with two new compounds, 11-epi-chaetomugilide B (2) and chaetomugilide D (3) was isolated from an endophytic fungus, Chaetomium sp. g1. Notably, extensive NMR data analyses, NMR calculations with DP4 and DP4+ analyses, ECD calculations, and the RDC method were employed to establish the structure of 1. Furthermore, 2 exhibited potent apoptosis induction activity by mediating caspase-3 activation and PARP degradation at 3 μM in HL-60.

Tersaphilones A-E, cytotoxic chlorinated azaphilones from the deep-sea-derived fungus Phomopsis tersa FS441

Abstract Five new chlorinated azaphilone derivatives, tersaphilones A-E along with three known analogues were isolated from the deep-sea-derived fungus Phomopsis tersa FS441. Structures of the new compounds with absolute configurations were determined by comprehensive chemical analyses including spectroscopic techniques, ECD calculation, and single crystal X-ray diffraction. Among them, tersaphilone B possessed the unique 6/6-6 carbon skeleton with a cleaved tetrahydrofuranyl ring. Besides, tersaphilones D and E were a pair of diastereomers featuring a characteristic epoxide ring, which were rarely-occurring in azaphilones. Moreover, all compounds were evaluated for their anticancer activity using a panel of four tumor cell lines, wherein the novel tersaphilones D and E showed significant cytotoxicity against MCF-7, SF-268, and A549 cell lines with the IC50 values ranging from 5.4 to 8.3 μM.

Isolation and Characterization of New Anti-Inflammatory and Antioxidant Components from Deep Marine-Derived Fungus Myrothecium SP. Bzo-l062.

In the present study, four new compounds including a pair of 2-benzoyl tetrahydrofuran enantiomers, namely, (−)-1S-myrothecol (1a) and (+)-1R-myrothecol (1b), a methoxy-myrothecol racemate (2), and an azaphilone derivative, myrothin (3), were isolated along with four known compounds (4–7) from cultures of the deep-sea fungus Myrothecium sp. BZO-L062. Enantiomeric compounds 1a and 1b were separated through normal-phase chiral high-performance liquid chromatography. The absolute configurations of 1a, 1b, and 3 were assigned by ECD spectra. Among them, the new compound 1a and its enantiomer 1b exhibited anti-inflammatory activity, inhibited nitric oxide formation in lipopolysaccharide-treated RAW264.7 cells, and exhibited antioxidant activity in the 2,2-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) and oxygen radical absorbance capacity assays.

Identification of new pigments produced by the fermented rice of the fungus Monascus pilosus and their anti-inflammatory activity

Red yeast rice was used over than thousands of years, containing abundant secondary metabolites with different bioactivities. Nowadays, the investigation of Monascus spp. was changed from anti-cholesterol monacolin analogues to Monascus pigments. Monascus pilosus BCRC38072 is a citrinin-free red yeast rice from yellow mutant of mycelia, which was already sequenced and assembled. The EtOAc-soluble fraction of the 95 % EtOH extract of this strain has resulted in the isolation of three new azaphilone derivatives with reddish color, named monapilonitrile (1), monapilosine (2) and N-ethanolic monapilosine (3), along with seven known compounds. In addition, we provide complete data of monapilosine (2) and elucidated carefully to revise the structure of rubropunctamine into 2′, which was isolated from Monascus pilosus and elucidated only by UV, IR, and 1D NMR spectrum. The effects of the isolates on the inhibition of NO and production in lipopolysaccharide-activated RAW 264.7 murine macrophages were evaluated. Of the isolates, 1 and 2 exhibited potent anti-NO production activity, with IC50 values of 2.6 ± 0.8 and 12.5 ± 2.2 μM, respectively, compared to that of quercetin, an iNOS inhibitor with an IC50 value of 34.6 ± 1.4 μM. Compound 3 also showed moderate inhibition of NO production, with an IC50 value ranging from 27.5 ± 1.7 μM.

Azaphilones from the Red Sea Fungus Aspergillus falconensis.

The marine-derived fungus Aspergillus falconensis, isolated from sediment collected from the Canyon at Dahab, Red Sea, yielded two new chlorinated azaphilones, falconensins O and P (1 and 2) in addition to four known azaphilone derivatives (3−6) following fermentation of the fungus on solid rice medium containing 3.5% NaCl. Replacing NaCl with 3.5% NaBr induced accumulation of three additional new azaphilones, falconensins Q−S (7−9) including two brominated derivatives (7 and 8) together with three known analogues (10−12). The structures of the new compounds were elucidated by 1D and 2D NMR spectroscopy and HRESIMS data as well as by comparison with the literature. The absolute configuration of the azaphilone derivatives was established based on single-crystal X-ray diffraction analysis of 5, comparison of NMR data and optical rotations as well as on biogenetic considerations. Compounds 1, 3−9, and 11 showed NF-κB inhibitory activity against the triple negative breast cancer cell line MDA-MB-231 with IC50 values ranging from 11.9 to 72.0 µM.

Identification of a Unique Azaphilone Produced by Chaetomium globosum Isolated from Polygonatum sibiricum.

A new azaphilone, chaephilone E, eight azaphilone derivatives, and three chaetoglobosins were isolated from endophytic fungi Chaetomium globosum. The structures of the compounds were elucidated by 1D and 2D NMR as well as HR-ESI-MS data, and the absolute configuration of chaephilone E was established on the basis of electronic circular dichroism and NOESY spectrum. The activity of chaephilone E was evaluated via the cytotoxic assay (human hepatoma cell lines HepG-2) and brine shrimp (Artemia salina) bioassay.