Phytochemical Profiling and Biological Testing of the Constituents of the Australian Plant Haemodorum brevisepalum.

Phytochemical profiling was undertaken on the crude extracts of the bulbs, stems, and the fruits of Haemodorum brevisepalum, to determine the nature of the chemical constituents present. This represents the first study to investigate the fruits of a species of Haemodorum. In total, 13 new and 17 previously reported compounds were isolated and identified. The new compounds were of the phenylphenalenone-type class, with a representative of a novel structural form, named tentatively "oxabenzochromenone" (1), a compound akin to an intermediate in a recently proposed phenylphenalenone metabolic network (2), seven new phenylphenalenones (4-10), four new phenylbenzoisochromenones (11-14), and a new phenylbenzoisochromenone derivative (18). The previously reported compounds identified were of the following structure classes: oxabenzochrysenone (3, 23-26), flavonol (15, 16), phenylbenzoisochromenone (17, 21, 22, 27-30), and phenylphenalenone (19, 20). Compounds 2-4, 6-9, 15-18, 21, 22, and 26 were subjected to antimicrobial evaluation with moderate activity observed against Staphylococcus aureus MRSA and slight activity against Pseudomonas aeruginosa and Candida albicans. Compounds 4, 6-9, 17, and 21 were also evaluated for anthelminthic activity against larvae of the blood-feeding parasitic nematode Haemonchus contortus.

Separation and configurational assignment of stereoisomeric phenalenones from the marine mangrove-derived fungus Penicillium herquei MA-370.

Eight phenalenone derivatives, including four new compounds, aceneoherqueinones A and B (1 and 2), (+)-aceatrovenetinone A (3a), and (+)-aceatrovenetinone B (3d), along with four known congeners, (-)-aceatrovenetinone A (3b), (-)-aceatrovenetinone B (3c), (-)-scleroderolide (4a), and (+)-scleroderolide (4b), were characterized from the marine mangrove-derived fungus Penicillium herquei MA-370. Among them, compounds 1 and 2 are rare phenalenone derivatives featuring cyclic ether unit between C-5 and C-2'. All of these compounds were subjected to chiral HPLC analysis, and the unstable stereoisomers 3a-3d, containing configurationally labile chirality centers, were characterized by online HPLC-ECD measurements supported with TDDFT-ECD calculations. The structures of these compounds were elucidated by detailed analysis of their NMR and mass spectroscopic data, and the absolute configuration of compound 1 was confirmed by X-ray diffraction analysis, while those of compounds 2 and 3a-3d were determined by TDDFT-ECD calculations of their ECD spectra. All of the isolated compounds were tested for the inhibitory activity against angiotensin-I-converting enzyme (ACE), and compounds 1 and 2 displayed activity with IC50 values 3.10 and 11.28 µM, respectively. The intermolecular interaction and potential binding sites of 1 and 2 with ACE were elaborated by molecular docking, showing that compound 1 bound well with ACE via hydrogen interactions with residues Ala261, Gln618, Trp621, and Asn624, while compound 2 interacted with residues Asp358 and Tyr360.

Herqueilenone A, a unique rearranged benzoquinone-chromanone from the Hawaiian volcanic soil-associated fungal strain Penicillium herquei FT729.

The study of a Hawaiian volcanic soil-associated fungal strain Penicillium herquei FT729 led to the isolation of one unprecedented benzoquinone-chromanone, herqueilenone A (1) and two phenalenone derivatives (2 and 3). Their structures were determined through extensive analysis of NMR spectroscopic data and gauge-including atomic orbital (GIAO) NMR chemical shifts and ECD calculations. Herqueilenone A (1) contains a chroman-4-one core flanked by a tetrahydrofuran and a benzoquinone with an acetophenone moiety. Plausible pathways for the biosynthesis of 1-3 are proposed. Compounds 2 and 3 inhibited IDO1 activity with IC50 values of 14.38 and 13.69 µM, respectively. Compounds 2 and 3 also demonstrated a protective effect against acetaldehyde-induced damage in PC-12 cells.

Alpha-Glucosidase- and Lipase-Inhibitory Phenalenones from a New Species of Pseudolophiostoma Originating from Thailand.

The alpha-glucosidase- and lipase-inhibitory activities of three phenalenones (1-3) and one phenylpropanoid (4) from the ethyl acetate extracts of a Pseudolophiosptoma sp. are described. They represent the first secondary metabolites reported from the genus Pseudolophiostoma. Scleroderolide (1) and sclerodione (2) exhibited potent α-glucosidase- and porcine-lipase-inhibitory activity during primary screening, with better IC50 values compared to the positive controls, N-deoxynojirimycin and orlistat. In silico techniques were employed to validate the probable biological targets and elucidate the mechanism of actions of phenalenones 1 and 2. Both compounds exhibited strong binding affinities to both alpha-glucosidase and porcine lipase through H-bonding and π-π interactions. Interestingly, favorable in silico ADME (absorption, distribution, metabolism, and excretion) properties such as gastrointestinal absorption were also predicted using software.

Trypethelone and phenalenone derivatives isolated from the mycobiont culture of Trypethelium eluteriae Spreng. and their anti-mycobacterial properties.

The metabolites of the mycobiont culture of the lichen Trypethelium eluteriae were isolated by column chromatography and preparative TLC. Nine compounds (1-9) including two new trypethelones, 8-methoxytrypethelone (6) and 5'-hydroxy-8-ethoxytrypethelone (9), together with four known trypethelones (3-4, 7-8), and two known phenalenones (1-2) were characterized. It is the first report of 8-methoxytrypethelone methyl ether (5) purification as a racemic mixture in T. eluteriae. Earlier, 7-hydroxyl-8-methoxyltrypethelone (10) was reported as new compound with erroneous spectroscopic data. This compound was identified later as 8-hydroxytrypethelone methyl ether (4). X-ray crystallographic structures of compounds 5-7 were elucidated for the first time. Phenalenones (1-2) and trypethelones (5-6 and 9) were the additional compounds discovered in the cultured mycobiont of T. eluteriae. Six compounds (1-2, 5-8) were screened against Mycobacterium tuberculosis H37Rv and two compounds (7-8) against non-tuberculosis mycobacteria and other human pathogenic bacteria. Compound (7) inhibited M. tuberculosis H37Rv strain with an MIC of 12.5 µg/mL.

Impact of the Cultivation Technique on the Production of Secondary Metabolites by Chrysosporium lobatum TM-237-S5, Isolated from the Sponge Acanthella cavernosa.

The fungi Chrysosporium lobatum TM-237-S5 was isolated from the sponge Acanthella cavernosa, collected from the mesophotic coral ecosystem of the Red Sea. The strain was cultivated on a potato dextrose agar (PDA) medium, coupling solid-state fermentation and solid-state extraction (SSF/SSE) with a neutral macroreticular polymeric adsorbent XAD Amberlite resin (AMBERLITE XAD1600N). The SSF/SSE lead to high chemodiversity and productivity compared to classical submerged cultivation. Ten phenalenone related compounds were isolated and fully characterized by one-dimensional and two-dimensional NMR and HRMS. Among them, four were found to be new compounds corresponding to isoconiolactone, (-)-peniciphenalenin F, (+)-8-hydroxyscleroderodin, and (+)-8-hydroxysclerodin. It is concluded that SSF/SSE is a powerful strategy, opening a new era for the exploitation of microbial secondary metabolites.

Phenalenones from a Marine-Derived Fungus Penicillium Sp.

Six new phenalenone derivatives (1⁻6), along with five known compounds (7⁻11) of the herqueinone class, were isolated from a marine-derived fungus Penicillium sp. The absolute configurations of these compounds were assigned based on chemical modifications and their specific rotations. 4-Hydroxysclerodin (6) and an acetone adduct of a triketone (7) exhibited moderate anti-angiogenetic and anti-inflammatory activities, respectively, while ent-peniciherqueinone (1) and isoherqueinone (9) exhibited moderate abilities to induce adipogenesis without cytotoxicity.

Metabolites from the Plant Endophytic Fungus Aspergillus sp. CPCC 400735 and Their Anti-HIV Activities.

Thirty-three metabolites including five phenalenone derivatives (1-5), seven cytochalasins (6-12), thirteen butenolides (13-25), and eight phenyl derivatives (26-33) were isolated from Aspergillus sp. CPCC 400735 cultured on rice. The structures of all compounds were elucidated by NMR, MS, and CD experiments, of which 1-5 (asperphenalenones A-E), 6 (aspochalasin R), and 13 (aspulvinone R) were identified as new compounds. Specifically, asperphenalenones A-E (1-5) represent an unusual structure composed of a linear diterpene derivative linked to a phenalenone derivative via a C-C bond. Compounds 1, 4, 10, and 26 exhibited anti-HIV activity with IC50 values of 4.5, 2.4, 9.2, and 6.6 µM, respectively (lamivudine 0.1 µM; efavirenz, 0.4 × 10-3 µM).

Anti-Cryptococcus Phenalenones and Cyclic Tetrapeptides from Auxarthron pseudauxarthron.

Auxarthrones A-E (1-5), five new phenalenones, and two new naturally occurring cyclic tetrapeptides, auxarthrides A (7) and B (8), were obtained from three different solvent extracts of cultures of the coprophilous fungus Auxarthron pseudauxarthron. Auxarthrones C (3) and E (5) possess an unusual 7a,8-dihydrocyclopenta[a]phenalene-7,9-dione ring system that has not been previously observed in natural products. Formation of 1-5 was found to be dependent on the solvent used for culture extraction. The structures of these new compounds were elucidated primarily by analysis of NMR and MS data. Auxarthrone A (1) was obtained as a mixture of chromatographically inseparable racemic diastereomers (1a and 1b) that cocrystallized, enabling confirmation of their structures by X-ray crystallography. The absolute configurations of 7 and 8 were assigned by analysis of their acid hydrolysates using Marfey's method. Compound 1 displayed moderate antifungal activity against Cryptococcus neoformans and Candida albicans, but did not affect human cancer cell lines.

New phenalenone derivatives from Pinellia ternata tubers derived Aspergillus sp.

Nine new phenalenone derivatives (1-9), along with two known analogues (10-11) have been isolated from the solid cultures of an endophytic fungus Aspergillus sp. which was obtained from Pinellia ternate. Their structures were established through interpretations of spectroscopic evidence, and some of their absolute configurations were determined by electronic circular dichroism (ECD) and Mo2(OCOCH3)4 induced ECD. All of the phenalenones are unusual acyclic diterpenoid adducts, which are diversely oxidized and partly epoxidized to form different heterocycles. In addition, compound 10 exhibited significant antimicrobial activity against Pseudomonas aeruginosa, Staphylococcus aureus, and Bacillus subtilis with MIC50 values of 1.87, 2.77, and 4.80µg/mL, respectively.

Application of the Crystalline Sponge Method to Revise the Structure of the Phenalenone Fuliginone.

The structure of fuliginone was revised from a phenyl substituted phenalenone to a hydroxyl substituted phenalenone as a result of its re-purification via HPLC with subsequent NMR analysis together with an independent synthesis and analysis of the crystal structure, which was secured via the crystalline sponge method. On-flow High Performance Liquid Chromatography coupled to Nuclear Magnetic Resonance spectroscopy (HPLC-NMR) was employed to confirm the presence of the natural product in the plant extract and to monitor for any possible degradation or conversion of the compound.

Antimicrobial Oligophenalenone Dimers from the Soil Fungus Talaromyces stipitatus.

New polyketide-derived oligophenalenone dimers, 9a-epi-bacillisporin E (1) and bacillisporins F-H (2-5), along with the known bacillisporin A (6), were isolated from the fungus Talaromyces stipitatus. Their structures and absolute configurations were determined on the basis of spectroscopic analyses, electronic circular dichroism, and GIAO NMR shift calculation followed by DP4 analysis. The antimicrobial activity of these compounds was evaluated against a panel of human pathogenic bacteria. Among them, bacillisporin H (5) exhibited antimicrobial activity together with modest cytotoxicity against HeLa cells.

Phenalenone derivatives and the unusual tricyclic sesterterpene acid from the marine fungus Lophiostoma bipolare BCC25910.

Ten compounds including nine phenalenone derivatives (five bipolarides and four bipolarols) and a sesterterpene acid (bipolarenic acid), were isolated from a marine isolated of the fungus Lophiostoma bipolare (BCC25910), along with the known compounds, (-)-scleroderolide, (-)-sclerodin, and oxasetin. Chemical structures were elucidated based on NMR spectroscopic data and HRESIMS analysis. In addition, the absolute configurations of the phenalenones were resolved using specific rotations and chemical means, while the relative configuration of bipolarenic acid was confirmed by X-ray crystallographic analysis. The compounds were evaluated for biological activity against the Plasmodium falciparum K-1 strain, Candida albicans, and Bacillus cereus, and for cytotoxicity against both cancerous and non-cancerous cells.

HPLC-NMR and HPLC-MS Profiling and Bioassay-Guided Identification of Secondary Metabolites from the Australian Plant Haemodorum spicatum.

Phytochemical dereplication was undertaken on the bioactive crude CH2Cl2 extract of the bulbs of the Australian plant Haemodorum spicatum employing HPLC-NMR and HPLC-MS methodologies. Subsequent bioassay-guided isolation resulted in the identification of two new phenylphenalenones [haemoxiphidone (8) and haemodoronol (17)] and two new chromenes [haemodordione (13) and haemodordiol (16)], together with seven previously described compounds. Antimicrobial testing showed that the compounds displayed selective antibacterial activity. Most noteworthy were the activities displayed by several of the compounds against multi-drug-resistant Pseudomonas aeruginosa.

High resolution mass spectrometry imaging reveals the occurrence of phenylphenalenone-type compounds in red paracytic stomata and red epidermis tissue of Musa acuminata ssp. zebrina cv. 'Rowe Red'.

The banana epidermis and in particular their stomata are conducive sites for the penetration of pathogenic fungi which can severely limit global banana production. The red pseudostem of the ornamental banana Musa acuminata ssp. zebrina cv. 'Rowe Red' was used to study the chemical constituents of the epidermal cell layer using matrix-free laser desorption/ionization Fourier transform ion cyclotron resonance mass spectrometric imaging (LDI-FT-ICR-MSI). The high resolution of this technique allowed phenylphenalenone-type compounds to be located in single plant cells. Some of these secondary metabolites were identified as constitutive compounds and found in specialized epidermal cells in banana pseudostem tissue. Especially the red paracytic stomata revealed higher signal intensities of certain phenylphenalenones than normal epidermis cells. The ease of detection of polycyclic aromatic compounds on the cellular level is discussed with regard to future investigations of plant-pathogen interactions.

γ-Butyrolactone, cytochalasin, cyclic carbonate, eutypinic acid, and phenalenone derivatives from the soil fungus Aspergillus sp. PSU-RSPG185.

Purification of an extract from the broth of the soil fungus Aspergillus sp. PSU-RSPG185 resulted in the isolation of two new cyclic carbonate derivatives, aspergillusols A (1) and B (2), and one new eutypinic acid derivative, aspergillusic acid (3), along with six known secondary metabolites. Compounds 1 and 2 contain an unusual cyclic-carbonate functionality. In addition, the mycelial extract afforded two new phenalenones, aspergillussanones A (4) and B (5), one new cytochalasin, aspergilluchalasin (6), and one new γ-butyrolactone, aspergillulactone (7). Their structures were established by interpretation of spectroscopic evidence. Compound 4 exhibited weak activity toward KB and Vero cells with IC50 values of 48.4 and 34.2 µM, respectively.

Three new compounds from the stem bark of Juglans mandshurica.

Three new compounds, 3,6-dihydroxy-4,5-dimethoxy-1,8-naphalic anhydride (1), 3,4,5,6-tetrahydroxy-1,8-naphalic anhydride (2), and methyl (7E,9E)-6,11-dioxononadeca-7,9-dienoate (3), were isolated from the stem bark of Juglans mandshurica. Their structures were elucidated on the basis of spectroscopic evidence, including 1D and 2D NMR, HR-TOF-MS, and by comparison with the literature data.

A new phenalenone derivative from the soil fungus Penicillium herquei PSU-RSPG93.

One new phenalenone derivative, peniciherqueinone (1), together with five known phenalenone derivatives (2-6), one known anthraquinone (7) and two known acetophenones (8 and 9) were isolated from the soil fungus Penicillium herquei PSU-RSPG93. Their structures were established by spectroscopic evidence. The absolute configuration of 1 was determined by anisotropic effect and electronic circular dichroism spectroscopy. Compound 2 exhibited mild antioxidant activity and is noncytotoxic to Vero (African green monkey kidney fibroblasts) cell lines.

Fungal phenalenones: chemistry, biology, biosynthesis and phylogeny.

Covering up to the end of August 2013. Phenalenones are members of a unique class of natural polyketides exhibiting diverse biological potential. This is a comprehensive review of 72 phenalenones with diverse structural features originating from fungal sources. Their bioactive potential and structure elucidation are discussed along with a review of their biosynthetic pathways and the taxonomical relationship between the fungi producing these natural products.

Phenylphenalenones and oxabenzochrysenones from the Australian plant Haemodorum simulans.

Chemical investigation of the Australian plant Haemodorum simulans (Haemodoraceae) resulted in the isolation of two new phenylphenalenones, haemoxiphidone and haemodordioxolane from the bulbs together with the first report of an oxabenzochrysenone glycoside, haemodoroxychrysenose from the aerial parts of the plant. Also isolated were two previously described phenylphenalenones 5,6-dimethoxy-7-phenyl-1H,3H-naphtho[1,8-cd]pyran-1,3-dione and haemodorone and two oxabenzochrysenones 5-hydroxyl-2-methoxy-1H-naphtho[2,1,8-mna]xanthen-1-one and 5-methoxy-1H-naphtho[2,1,8-mna]xanthen-1-one. The X-ray structure of the phenylphenalenone 5,6-dimethoxy-7-phenyl-1H,3H-naphtho[1,8-cd]pyran-1,3-dione was secured for the first time. All compounds were deduced by detailed spectroscopic analyses. HPLC-NMR chemical profiling of an enriched fraction containing a mixture of haemodordioxolane and 5,6-dimethoxy-7-phenyl-1H,3H-naphtho[1,8-cd]pyran-1,3-dione facilitated the partial identification of these secondary metabolites. The structure previously assigned as xiphidone in our initial studies of this plant was re-assigned as the new isomer haemoxiphidone.