Azaphilone Derivatives Research Articles

Chaephilones A and B, Two New Azaphilone Derivatives Isolated from Chaetomium globosum.

Two new azaphilone derivatives, chaephilones A (1) and B (2), were isolated from the fungus Chaetomium globosum, together with four structurally related analogs 3 - 6. The structures of 1 and 2 were elucidated by comprehensive spectroscopic analyses including HR-ESI-MS and NMR. The known compounds were identified as chaetomugilin Q (3), chaetomugilin D (4), 11-epichaetomugilin A (5), and chaetomugilin S (6) by comparing their NMR data and optical rotation values with those reported. Compound 2 represents the first example of azaphilone with an open furan ring. Compounds 1 and 2 were evaluated for cytotoxic activities against five human cancer cell lines (HL-60, SMMC-7721, A-549, MCF-7, and SW480) by the MTS method.

A New Azaphilone Metabolite from the Fungus Monascus ruber

Phytochemical investigation of the 95% EtOH extract of red yeast rice fermented with the fungus Monascus ruber led to the isolation and structural elucidation of one new azaphilone derivative, monascuspurone (1). The structure was defined on the basis of UV, IR, 1D and 2D NMR (1H–1H COSY, DEPT, HSQC, HMBC), as well as HR-ESI-MS analyses, and comparison of the spectroscopic data with those reported for structurally related compounds.

New Metabolite from the Fungus Monascus kaoliang

Investigation of the 95% alcohol extract of red yeast rice fermented with the fungus Monascus kaoliang has led to the isolation and structural elucidation of one new azaphilone derivative, monascuskaodione (1). The structure was elucidated by 1D and 2D NMR spectroscopy together with HR-ESI-MS analysis and comparison of the spectroscopic data with those reported for structurally related compounds.

Two phytotoxic azaphilone derivatives from Chaetomium globosum, a fungal endophyte isolated from Amaranthus viridis leaves

A fungal endophyte isolated from the leaves of the allelopathic plant Amaranthus viridis of the family Amaranthaceae was identified as Chaetomium globosum through molecular means using internal transcribed spacer (ITS) region of rDNA gene. This is the first report of the isolation of C. globosum from Amaranthaceae. Chromatographic separation of the EtOAc extract of the fungal fermentation in potato dextrose broth yielded two known chlorine-containing azaphilone derivatives, chaetomugilin D (1) and chaetomugilin J (2). Compounds 1 and 2 were found to show phytotoxic activity in the lettuce (Lactuca sativa) seed germination bioassay. The IC50 values of 1 and 2 for root growth inhibition were 24.2 and 22.6 ppm, respectively, while IC50 values for shoot growth inhibition were 27.8 and 21.9 ppm, respectively. Phytotoxic activities of the chaetomugilin group of compounds have been reported for the first time, although their antifungal, antimicrobial and cytotoxic activities are known.

Azaphilone and Diphenyl Ether Derivatives from a Gorgonian-Derived Strain of the Fungus Penicillium pinophilum.

Three new azaphilone derivatives, pinophilins D-F (1-3), and one new diphenyl ether derivative, hydroxypenicillide (10), together with nine known compounds (4-9, 11-13), were isolated from the gorgonian-derived fungus Penicillium pinophilum XS-20090E18. Their structures including absolute configurations were determined by spectroscopic data, chemical conversions, the ECD exciton chirality method, and ECD calculations. Compounds 10-13 exhibited inhibitory activity against the larval settlement of the barnacle Balanus amphitrite at nontoxic concentrations. Compounds 10 and 11 showed cytotoxicity against Hep-2, RD, and HeLa cell lines.

Chemical Constituents of the Endophytic Fungus Hypoxylon sp. 12F0687 Isolated from Taiwanese Ilex formosana

AbstractBioassay‐guided fractionation of an AcOEt‐soluble fraction of the liquid fermentation of an endophytic fungus Hypoxylon sp. BCRC 12F0687 associated with the root of Taiwanese Ilex formosana (Aquifoliaceae) resulted in the isolation of two new compounds, i.e., one benzenoid, hypoxyphenone (1), and one azaphilone derivative, hypoillexidiol (2), two metabolites isolated for the first time from natural source, (−)‐(3S)‐3‐hydroxy‐3‐methyloxindole (3) and (+)‐vermelone (4), along with twelve previously identified compounds, 5–16. Their structures were determined through in‐depth spectroscopic and mass‐spectrometric analyses. The effects of some isolates on the inhibition of NO and IL‐6 production in lipopolysaccharide‐activated RAW 264.7 murine macrophages were evaluated. Of the isolates, 2 and 3 exhibited potent anti‐NO production activity, with IC50 values of 17.5±1.8 and 24.7±1.6 μM, respectively, compared to that of quercetin, an iNOS inhibitor with an IC50 value of 35.9±1.7 μM. Compounds 2, 4, 5, and 12 also showed moderate inhibition of IL‐6 production, with IC50 values ranging from 27.2±1.8 to 35.3±5.8 μM. This is the first report on an oxindole metabolite from the genus Hypoxylon.

Cytotoxic Metabolites Produced by the Endophytic Fungus Aspergillus clavatus

Abstract A new spiro azaphilone derivative, aspergillusone C (1), and a new cadinane-type sesquiterpenoid, aspergillusone D (2), together with a known azaphilone, felinone A (3), were isolated from the endophytic fungus Aspergillus clavatus. The structures of the new compounds were elucidated by NMR spectroscopy and electron circular dichroism data. Compound 2 exhibited detectable cytotoxic activity against two cell lines (MCF-7 and A549), with IC50 values of 5.9 and 0.2 µM, respectively, in the MTT assay.

Xylariphilone: a new azaphilone derivative from the seagrass-derived fungus Xylariales sp. PSU-ES163

One new azaphilone derivative, named xylariphilone (1), along with 10 known compounds was isolated from the seagrass-derived fungus Xylariales sp. PSU-ES163. Their structures were elucidated on the basis of extensive spectroscopic analysis. The absolute and relative configurations of 1 were determined by circular dichroism spectroscopy and NOEDIFF data. The antimicrobial and cytotoxic activities of the isolated compounds were evaluated.

Azaphilones inhibit tau aggregation and dissolve tau aggregates in vitro.

The aggregation of the microtubule-associated protein tau is a seminal event in many neurodegenerative diseases, including Alzheimer's disease. The inhibition or reversal of tau aggregation is therefore a potential therapeutic strategy for these diseases. Fungal natural products have proven to be a rich source of useful compounds having wide varieties of biological activities. We have previously screened Aspergillus nidulans secondary metabolites for their ability to inhibit tau aggregation in vitro using an arachidonic acid polymerization protocol. One aggregation inhibitor identified was asperbenzaldehyde, an intermediate in azaphilone biosynthesis. We therefore tested 11 azaphilone derivatives to determine their tau assembly inhibition properties in vitro. All compounds tested inhibited tau filament assembly to some extent, and four of the 11 compounds had the advantageous property of disassembling preformed tau aggregates in a dose-dependent fashion. The addition of these compounds to the tau aggregates reduced both the total length and number of tau polymers. The most potent compounds were tested in in vitro reactions to determine whether they interfere with tau's normal function of stabilizing microtubules (MTs). We found that they did not completely inhibit MT assembly in the presence of tau. These derivatives are very promising lead compounds for tau aggregation inhibitors and, more excitingly, for compounds that can disassemble pre-existing tau filaments. They also represent a new class of anti-tau aggregation compounds with a novel structural scaffold.

Penidioxolanes A and B, 1,3-Dioxolane Containing Azaphilone Derivatives from Marine-derivedPenicilliumsp. KCB12C078

Two new azaphilone derivatives containing 1,3-dioxolane moiety, penidioxolanes A (1) and B (2), were isolated from marine-derived fungus Penicillium sp. KCB12C078, together with four known compounds (36) by chemical investigation. Compounds 1 6 were isolated by combination of silica gel, ODS column chromatography and preparative HPLC. Their structures were determined by analysis of spectroscopic data including 1D-, 2D-NMR, and MS techniques. The isolates were evaluated against cancer cell growth inhibition effects and antimicrobial activity.

Chemical constituents of red yeast rice fermented with the fungus Monascus pilosus

A chemical study on the n-BuOH-soluble fraction of the 95% EtOH extract of red yeast rice fermented with the fungus Monascus pilosus (Eurotiaceae) has resulted in the isolation of one new azaphilone derivative, designated as monapilosusazaphilone (1), together with nine known compounds, (+)-5,5′-dimethoxylariciresinol (2), (+)-lariciresinol (3), (+)-5-methoxylariciresinol (4), a mixture of 3β-hydroxylstigmast-5-en-7-one (5) and 3β-hydroxystigmasta-5,22-dien-7-one (6), 6β-hydroxystigmast-4-en-3-one (7), 6β-hydroxystigmasta-4,22-dien-3-one (8), N-cis-feruloylmethoxytyramine (9), and scopoletin (10). Their structures were elucidated by 1D and 2D-NMR spectroscopy together with HR-ESI-MS analysis, and comparison of the spectroscopic data with those reported for structurally related compounds.

Monascusazaphilones A–C, three new azaphilone analogues isolated from the fungus Monascus purpureus BCRC 38108

Investigation of the 95% EtOH extract of red yeast rice fermented with the pink mutant of the fungus Monascus purpureus BCRC 38108 led to the isolation of three new azaphilone derivatives, namely monascusazaphilones A–C (1–3), together with two known compounds. Compounds 1–3 were isolated from this species for the first time. Their structures were elucidated by 1-D and 2-D nuclear magnetic resonance spectroscopy together with HR–ESI–MS analysis and comparison of the spectroscopic data with those reported in the literatures. All isolates were evaluated for their inhibitory effects on nitric oxide (NO) production by macrophages. Among the isolates, compound 1 demonstrated stronger inhibition on NO production.

Absolute Configuration of Fusarone, a New Azaphilone from the Endophytic Fungus Fusarium sp. Isolated from Melia azedarach, and of Related Azaphilones

A new azaphilone derivative, named fusarone (1), has been isolated from the ethyl acetate soluble extract of the fermentation broth of an endophytic fungus, Fusarium sp. LN-12, isolated from the leaves of Melia azedarach Linn. The structure of the new compound was established on the basis of extensive spectroscopic analysis, including 1D-NMR and 2D-NMR ((1) H-(1)H COSY, TOCSY, HSQC, HMBC, and NOESY) experiments. The absolute configurations of fusarone (1) and of a second related azaphilone were determined by means of electronic circular dichroism spectroscopy and optical rotation calculations.

Secondary metabolites produced by the fungus Monascus pilosus and their anti-inflammatory activity

A detailed phytochemical study of the n-BuOH-soluble fraction of the 95% EtOH extract of red yeast rice fermented with the fungus Monascus pilosus BCRC 38072 (Eurotiaceae) revealed a new azaphilone derivative, namely monascusazaphilol (1) (rel-(3S,3aR,9aR)-3-(1-hydroxydecyl)-9a-methyl-6-((E)-propenyl)-3a,4,8,9a-tetrahydro-3H-furo[3,2-g]isochromene-2,9-dione), along with ten known compounds (2–11). Their structures were established by direct interpretation of their spectral data, mainly high resolution electrospray ionization mass spectrometry (HR-ESI-MS), 1D and 2D NMR (COSY, ROESY, HSQC and HMBC), and comparison of the spectroscopic data with those reported for structurally related compounds. We also evaluated the inhibitory effects of some isolates on the production of tumor necrosis factor (TNF-α) induced by lipopolysaccharide (LPS). Among the isolates, compounds 1–3 inhibited TNF-α production in U937 cells in vitro, and the IC50 values were 1.24, 2.35 and 3.75μg/ml, respectively.

Secondary metabolites from the endophytic fungus Biscogniauxia formosana and their antimycobacterial activity

Two new azaphilone derivatives, namely, biscogniazaphilones A (1) and B (2), along with ten known compounds (3–12), were isolated from the n-BuOH-soluble fraction of the 95% EtOH extract of long-grain rice fermented with the endophytic fungus Biscogniauxia formosana BCRC 33718, derived from the bark of medicinal plant Cinnamomum species. Their structures were elucidated on the basis of spectroscopic analysis, including 1D and 2D NMR as well as HRESIMS, ESIMS, UV, and IR, and comparison with literature data. In addition, the isolated compounds (1–12) were evaluated for their antimycobacterial activity. Two new constituents, biscogniazaphilones A (1) and B (2), exhibited the strongest antimycobacterial activities against Mycobacterium tuberculosis strain H37Rv, with MIC values of 5.12 and 2.52μg/mL, respectively.

Induction of Apoptosis in Human Breast Adenocarcinoma Cells MCF-7 by Monapurpyridine A, a New Azaphilone Derivative from Monascus purpureus NTU 568

A new azaphilonidal derivative, monapurpyridine A (MPA), has recently been isolated from the fermented products of Monascus purpureus NTU 568. The structure of MPA was elucidated by nuclear magnetic resonance (1H-NMR, 13C-NMR, COSY, HMQC, and HMBC) and other spectroscopic analyses. Biological evaluation revealed that MPA could induce cell death in human breast adenocarcinoma cells MCF-7, and it has no significant toxicity to normal mammary epithelial cells M10. The MTT assay and flow cytometric analysis were employed to investigate cell viability and cell cycle influenced by MPA. Moreover, we used Western blot and caspase activity assay to demonstrate the activation of caspase-3, -8 and -9 resulted from MPA. All evidence supported that MPA was suitable for developing into a chemotherapeutic or chemopreventive agent against breast cancer.

A novel tricyclic polyketide and its biosynthetic precursor azaphilone derivatives from the endophytic fungus Dothideomycete sp

Azaphilone derivatives 1 and 2 and a novel tricyclic polyketide 3, together with a known azaphilone, austdiol (4), were isolated from the endophytic fungus Dothideomycete sp., which was isolated from a Thai medicinal plant, Tiliacora triandra. Compound 3 is the first polyketide having a tricyclic 6,6,6 ring system, which is similar to that of a terpenoid skeleton. The absolute configurations of stereogenic centers in 1-3 were addressed by Mosher's method and biosynthetic analogy with a known azaphilone isolated from the same fungus. Cytotoxic and antimicrobial activities of the isolated compounds were evaluated.

Secondary metabolites from the endophytic fungus Annulohypoxylon boveri var. microspora BCRC 34012

A chemical study on the n-BuOH-soluble fraction of the 95% EtOH extract of long-grain rice (Oryza sativa) fermented with the endophytic fungus Annulohypoxylon boveri var. microspora (BCRC 34012) has resulted in the isolation of one new natural azaphilone derivative, designated as annulohypoxyboverin (1) together with 12 known compounds, (3R,6R,7E)-3-hydroxy-4,7-megstigma-dien-9-one (2), α-tocopheryl quinone (3), isofraxidin (4), coumarin (5), cinnamic acid (6), a mixture of palmitic acid (7) and stearic acid (8), N-cis-feruloyltyramine (9), luteolin (10), kaempferol (11), kaempferitrin (12), and 4,5,4′,5′-tetrahydroxy-1,1′-binaphthyl (13). Annulohypoxyboverin (1) contains a dihydrobenzofuran-2,4-dione backbone, 1-hydroxyhexyl side chain, and one γ-lactone ring. Their structures were elucidated by spectroscopic analyses including 1D and 2D NMR experiments, and by HR-ESI-MS. The relative configuration of 1 was confirmed by NOESY experiment. Other known compounds were identified by comparing their spectral data with those of literature data.

Comazaphilones A−F, Azaphilone Derivatives from the Marine Sediment-Derived Fungus Penicillium commune QSD-17

Chemical investigation of Penicillium commune QSD-17, a fungus isolated from a marine sediment sample collected in the southern China Sea, yielded six new azaphilone derivatives, namely, comazaphilones A-F (1-6). The structures of these compounds were established on the basis of spectroscopic analysis. Attempts to define the absolute configuration of these azaphilones through investigation of Mosher's esters failed, possibly due to steric crowding at C-6 and C-7 and due to the degradation of these azaphilone derivatives under the reaction conditions. The inhibitory activities of the six azaphilones against four bacteria, one pathogenic fungus, and seven tumor cell lines were evaluated. Compounds 3-5 displayed potent inhibitory activity against several of these bacteria, while compounds 4-6 showed cytotoxic activity against human pancreatic tumor cell line SW1990. The preliminary SAR results indicated that the double bond at C-10 and the location of the orsellinic acid unit at C-6 in these azaphilones are important for the antibacterial activity and cytotoxicity, respectively. This is the first report of the isolation of azaphilone derivatives from a marine sediment-derived fungus.

Monaphilones A−C, Three New Antiproliferative Azaphilone Derivatives from Monascus purpureus NTU 568

Monascus purpureus NTU 568 was a mutant strain from M. purpureus HM105. The methanol extract of red mold rice fermented by this strain exhibited four major yellow pigment signals on HPLC profile. By repeated chemical chromatography methods, three new azaphilone derivatives, namely, monaphilone A (1), B (2) and C (3), along with the known pigments ankaflavin (4) and monascin (5), were isolated and characterized. Based on spectroscopic analyses, mainly 1D and 2D NMR data, the structures of compounds 1-3 were completely elucidated; in addition, 1-3 were determined to be new azaphilone structures, due to the decrease of carbon monoxide for producing a gamma-lactone ring, compared with other azaphilone derivatives. Biological evaluations showed that monaphilone A (1) and B (2) exhibited an antiproliferative effect against HEp-2 (human laryngeal carcinoma cell line) and WiDr (human colon adenocarcinoma cell line), and none of the five compounds had toxicity to normal human lung cell lines (WI-38 and MRC-5) at 70 muM.