Bioactive Chaetoglobosins from the Mangrove Endophytic Fungus Penicillium chrysogenum

A novel chaetoglobosin named penochalasin I (1) with a unprecedented six-cyclic 6/5/6/5/6/13 fused ring system, and another new chaetoglobosin named penochalasin J (2), along with chaetoglobosins G, F, C, A, E, armochaetoglobosin I, and cytoglobosin C (3–9) were isolated from the culture of Penicillium chrysogenum V11. Their structures were elucidated by 1D, 2D NMR spectroscopic analysis and high resolution mass spectroscopic data. The absolute configuration of compounds 1 and 2 were determined by comparing the theoretical electronic circular dichroism (ECD) calculation with the experimental CD. Compound 1 was the first example, with a six-cyclic fused ring system formed by the connection of C-5 and C-2′ of the chaetoglobosin class. Compounds 5–8 remarkably inhibited the plant pathogenic fungus R. solani (minimum inhibitory concentrations (MICs) = 11.79–23.66 μM), and compounds 2, 6, and 7 greatly inhibited C. gloeosporioides (MICs = 23.58–47.35 μM), showing an antifungal activity higher than that of carbendazim. Compound 1 exhibited marked cytotoxicity against MDA-MB-435 and SGC-7901 cells (IC₅₀ < 10 μM), and compounds 6 and 9 showed potent cytotoxicity against SGC-7901 and A549 cells (IC₅₀ < 10 μM).     

Identification and Bioactivity of Compounds from the Mangrove Endophytic Fungus Alternaria sp.

Racemic new cyclohexenone and cyclopentenone derivatives, (±)-(4R*,5S*,6S*)-3-amino-4,5,6-trihydroxy-2-methoxy-5-methyl-2-cyclohexen-1-one (1) and (±)-(4S*,5S*)-2,4,5-trihydroxy-3-methoxy-4-methoxycarbonyl-5-methyl-2-cyclopenten-1-one (2), and two new xanthone derivatives 4-chloro-1,5-dihydroxy-3-hydroxymethyl-6-methoxycarbonyl-xanthen-9-one (3) and 2,8-dimethoxy-1,6-dimethoxycarbonyl-xanthen-9-one (4), along with one known compound, fischexanthone (5), were isolated from the culture of the mangrove endophytic fungus Alternaria sp. R6. The structures of these compounds were elucidated by analysis of their MS (Mass), one and two dimensional NMR (nuclear magnetic resonance) spectroscopic data. Compounds 1 and 2 exhibited potent ABTS [2,2′-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid)] scavenging activities with EC₅₀ values of 8.19 ± 0.15 and 16.09 ± 0.01 μM, respectively. In comparison to Triadimefon, compounds 2 and 3 exhibited inhibitory activities against Fusarium graminearum with minimal inhibitory concentration (MIC) values of 215.52 and 107.14 μM, respectively, and compound 3 exhibited antifungal activity against Calletotrichum musae with MIC value of 214.29 μM.     

Verrucisidinol and verrucosidinol acetate, two pyrone-type polyketides isolated from a marine derived fungus, Penicillium aurantiogriseum

The new secondary metabolites verrucosidinol (1) and its derivative verrucosidinol acetate (2), together with a potent neurotoxin verrucosidin (3), a congener norverrucosidin (4) and a mixture of two known phytotoxic metabolites terrestric acids (5 and 6), were isolated from the marine derived fungus Penicillium aurantiogriseum. Verrucosidinol has a ring-opened ethylene oxide moiety in the polyene α-pyrone skeleton, and verrucosidinol acetate is its acetate derivative. The chemical structures were determined by comparing with literature data and a combination of spectroscopic techniques, including high resolution mass spectrum and two-dimentional nuclear magnetic resonance spectroscopic analysis.     

Secondary Metabolites of a Mangrove Endophytic Fungus Aspergillus terreus (No. GX7-3B) from the South China Sea

The mangrove endophytic fungus Aspergillus terreus (No. GX7-3B) was cultivated in potato dextrose liquid medium, and one rare thiophene compound (1), together with anhydrojavanicin (2), 8-O-methylbostrycoidin (3), 8-O-methyljavanicin (4), botryosphaerone D (5), 6-ethyl-5-hydroxy-3,7-dimethoxynaphthoquinone (6), 3β,5α-dihydroxy-(22E,24R)-ergosta-7,22-dien-6-one (7), 3β,5α,14α-trihydroxy-(22E,24R)-ergosta-7,22-dien-6-one (8), NGA0187 (9) and beauvericin (10), were isolated. Their structures were elucidated by analysis of spectroscopic data. This is the first report of a natural origin for compound 6. Moreover, compounds 3, 4, 5, 7, 8 and 10 were obtained from marine microorganism for the first time. In the bioactive assays in vitro, compounds 2, 3, 9 and 10 displayed remarkable inhibiting actions against α-acetylcholinesterase (AChE) with IC₅₀ values 2.01, 6.71, 1.89, and 3.09 μM, respectively. Furthermore, in the cytotoxicity assays, compounds 7 and 10 exhibited strong or moderate cytotoxic activities against MCF-7, A549, Hela and KB cell lines with IC₅₀ values 4.98 and 2.02 (MCF-7), 1.95 and 0.82 (A549), 0.68 and 1.14 (Hela), and 1.50 and 1.10 μM (KB), respectively; compound 8 had weak inhibitory activities against these tumor cell lines; compounds 1, 2, 3, 4, 5, 6 and 9 exhibited no inhibitory activities against them.     

Quinazolin-4-one coupled with pyrrolidin-2-iminium alkaloids from marine-derived fungus Penicillium aurantiogriseum

Three new alkaloids, including auranomides A and B (1 and 2), a new scaffold containing quinazolin-4-one substituted with a pyrrolidin-2-iminium moiety, and auranomide C (3), as well as two known metabolites auranthine (4) and aurantiomides C (5) were isolated from the marine-derived fungus Penicillium aurantiogriseum. The chemical structures of compounds 1-3 were elucidated by extensive spectroscopic methods, including IR, HRESIMS and 2D NMR spectroscopic analysis. The absolute configurations of compounds 1-3 were suggested from the perspective of a plausible biosynthesis pathway. Compounds 1-3 were subjected to antitumor and antimicrobial screening models. Auranomides A-C exhibited moderate cytotoxic activity against human tumor cells. Auranomides B was the most potent among them with an IC(50) value of 0.097 μmol/mL against HEPG2 cells.     

Three New Resveratrol Derivatives from the Mangrove Endophytic Fungus Alternaria sp.

Three new resveratrol derivatives, namely, resveratrodehydes A–C (1–3), were isolated from the mangrove endophytic fungus Alternaria sp. R6. The structures of these compounds were elucidated by analysis of their MS, 1D and 2D NMR spectroscopic data. All compounds showed broad-spectrum inhibitory activities against three human cancer cell lines including human breast MDA-MB-435, human liver HepG2, and human colon HCT-116 by MTT assay (IC₅₀ < 50 μM). Among them, compounds 1 and 2 both exhibited marked cytotoxic activities against MDA-MB-435 and HCT-116 cell lines (IC₅₀ < 10 μM). Additionally, compounds 1 and 3 showed moderate antioxidant activity by DPPH radical scavenging assay.     

New Meroterpenoids from the Endophytic Fungus Aspergillus flavipes AIL8 Derived from the Mangrove Plant Acanthus ilicifolius

Four new meroterpenoids (2–5), along with three known analogues (1, 6, and 7) were isolated from mangrove plant Acanthus ilicifolius derived endophytic fungus Aspergillus flavipes. The structures of these compounds were elucidated by NMR and MS analysis, the configurations were assigned by CD data, and the stereochemistry of 1 was confirmed by X-ray crystallography analysis. A possible biogenetic pathway of compounds 1–7 was also proposed. All compounds were evaluated for antibacterial and cytotoxic activities.     

Dihydroisocoumarins from the Mangrove-Derived Fungus Penicillium citrinum

Three new dihydroisocoumarin penicimarins G–I (1–3), together with one known dihydroisocoumarin (4) and three known meroterpenoids (5–7), were obtained from a fungus Penicillium citrinum isolated from the mangrove Bruguiera sexangula var. rhynchopetala collected in the South China Sea. Their structures were elucidated by the detailed analysis of spectroscopic data. The absolute configuration of 1 was determined by the X-ray diffraction analysis using Cu Kα radiation. The absolute configurations of 2 and 3 were determined by comparison of their circular dichroism (CD) spectra with the literature. All compounds were evaluated for their antibacterial activities and cytotoxic activities.     

Alkaloids with Cardiovascular Effects from the Marine-Derived Fungus Penicillium expansum Y32

Three new alkaloids (1, 4 and 8), together with nine known analogues (2, 3, 5–7, and 9–12), were isolated from the marine-derived fungus Penicillium expansum Y32. Their structures including the absolute configurations were elucidated by spectroscopic and Mosher’s and Marfey’s methods, along with quantum electronic circular dichroism (ECD) calculations. Each of the compounds was evaluated for cardiovascular effects in a live zebrafish model. All of the compounds showed a significant mitigative effect on bradycardia caused by astemizole (ASM) in the heart rate experiments. Compounds 4–6 and 8–12 exhibited potent vasculogenetic activity in vasculogenesis experiments. This is the first study to report that these types of compounds show cardiovascular effects in zebrafish. The results suggest that these compounds could be promising candidates for cardiovascular disease lead compounds.     

Four New Chromones from the Endophytic Fungus Phomopsis asparagi DHS-48 Isolated from the Chinese Mangrove Plant Rhizophora mangle

Four new chromones, phomochromenones D–G (1–4), along with four known analogues, diaporchromone A (5), diaporchromanone C (6), diaporchromanone D (7), and phomochromenone C (8), were isolated from the culture of Phomopsis asparagi DHS-48 from Chinese mangrove Rhizophora mangle. Their structures were elucidated on the basis of comprehensive spectroscopic analysis. The absolute configurations of 1 and 4 were assigned on the basis of experimental and calculated electronic circular dichroism (ECD) data, and those of enantiomers 2 and 3 were determined by a modified Mosher’s method and basic hydrolysis. To the best of our knowledge, phomochromenones D–F (1–4) possessing a 3-substituted-chroman-4-one skeleton are rarely found in natural sources. Diaporchromone A (5) showed moderate to weak immunosuppressive activity against T and/or B lymphocyte cells with IC₅₀ of 34 μM and 117 μM.     

Peniciadametizine A,a Dithiodiketopiperazine with a Unique Spiro[furan-2,7'-pyrazino[1,2-b][1,2]oxazine] Skeleton,and a Related Analogue,Peniciadametizine B,from the Marine Sponge-Derived Fungus Penicillium adametzioides

Peniciadametizine A (1); a new dithiodiketopiperazine derivative possessing a unique spiro[furan-2,7''-pyrazino[1,2-b][1,2]oxazine] skeleton, together with a highly oxygenated new analogue, peniciadametizine B (2); as well as two known compounds, brasiliamide A (3); and viridicatumtoxin (4), were isolated and identified from Penicillium adametzioides AS-53, a fungus obtained from an unidentified marine sponge. The unambiguous assignment of the relative and absolute configuration for the spiro center C-2 of compound 1 was solved by the combination of NMR and ECD measurements with Density-Functional Theory (DFT) conformational analysis and Time-Dependent Density-Functional Theory-Electronic Circular Dichroism (TDDFT-ECD) calculations. The spiro[furan-2,7''-pyrazino[1,2-b][1,2]oxazine] skeleton of 1 has not been reported yet among natural products and the biosynthetic pathway for 1 and 2 was discussed. Compounds 1 and 2 showed inhibitory activity against the pathogenic fungus Alternaria brassicae.     

Meroterpenes from Endophytic Fungus A1 of Mangrove Plant Scyphiphora hydrophyllacea

Four new meroterpenes, guignardones F–I (1–4), together with two known compounds guignardones A (5) and B (6) were isolated from the endophytic fungus A1 of the mangrove plant Scyphiphora hydrophyllacea. Their structures and relative configurations were elucidated by spectroscopic data and single-crystal X-ray crystallography. A possible biogenetic pathway of compounds 1–6 was also proposed. All compounds were evaluated for inhibitory activity against methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus aureus.     

Secondary Metabolites from Penicillium pinophilum SD-272, a Marine Sediment-Derived Fungus

Two new secondary metabolites, namely, pinodiketopiperazine A (1) and 6,7-dihydroxy-3-methoxy-3-methylphthalide (2), along with alternariol 2,4-dimethyl ether (3) and l-5-oxoproline methyl ester (4), which were isolated from a natural source for the first time but have been previously synthesized, were characterized from the marine sediment-derived fungus Penicillium pinophilum SD-272. In addition, six known metabolites (5–10) were also identified. Their structures were elucidated by analysis of the NMR and mass spectroscopic data. The absolute configuration of compound 1 was determined by experimental and calculated ECD spectra. Compound 2 displayed potent brine shrimp (Artemia salina) lethality with LD₅₀ 11.2 μM.     

Polyketide Derivatives,Guhypoxylonols A–D from a Mangrove Endophytic Fungus Aspergillus sp. GXNU-Y45 That Inhibit Nitric Oxide Production

Four undescribed compounds, guhypoxylonols A (1), B (2), C (3), and D (4), were isolated from the mangrove endophytic fungus Aspergillus sp. GXNU-Y45, together with seven previously reported metabolites. The structures of 1–4 were elucidated based on analysis of HRESIMS and NMR spectroscopic data. The absolute configurations of the stereogenic carbons in 1–3 were established through a combination of spectroscopic data and electronic circular dichroism (ECD). Compounds 1–11 were evaluated for their anti-inflammatory activity. Compounds 1, 3, 4, and 6 showed an inhibitory activity against the production of nitric oxide (NO), with the IC₅₀ values of 14.42 ± 0.11, 18.03 ± 0.14, 16.66 ± 0.21, and 21.05 ± 0.13 μM, respectively.     

Drimane Sesquiterpene-Conjugated Amino Acids from a Marine Isolate of the Fungus Talaromyces minioluteus (Penicillium Minioluteum)

Four new sesquiterpene lactones (3, 4, 6 and 7) and three known compounds, purpuride (1), berkedrimane B (2) and purpuride B (5), were isolated from the marine fungus, Talaromyces minioluteus (Penicillium minioluteum). New compounds were drimane sesquiterpenes conjugated with N-acetyl-l-valine, and their structures were elucidated by analysis of spectroscopic data, as well as by single crystal X-ray analysis. The isolated compounds could not inhibit the apoptosis-regulating enzyme, caspase-3, while three of the compounds (2, 3 and 7) exhibited weak cytotoxic activity.     

New Polyketides from Mangrove Endophytic Fungus Penicillium sp. BJR-P2 and Their Anti-Inflammatory Activity

Four new polyketide compounds, including two new unique isocoumarins penicillol A (1) and penicillol B (2) featuring with spiroketal rings, two new citreoviridin derivatives citreoviridin H (3) and citreoviridin I (4), along with four known analogues were isolated from the mangrove endophytic fungus Penicillium sp. BJR-P2. Their structures were elucidated by extensive spectroscopic methods. The absolute configurations of compounds 1–4 based on electronic circular dichroism (ECD) calculations, DP4+ analysis, and single-crystal X-ray diffraction are presented. All the new compounds were evaluated for anti-inflammatory activity. An anti-inflammatory assay indicated that compound 2 inhibited lipopolysaccharide (LPS)-induced NO production in RAW 264.7 cells, with half-maximal inhibitory concentration (IC₅₀) values of 12 μM, being more potent than the positive control, indomethacin (IC₅₀ = 35.8 ± 5.7 μM). Docking study showed that compound 2 was perfectly docking into the active site of murine inducible nitric oxide oxygenase (iNOS) via forming multiple typical hydrogen bonds.     

Bioactive Metabolites from Mangrove Endophytic Fungus Aspergillus sp. 16-5B

Chemical investigation of the endophytic fungus Aspergillus sp. 16-5B cultured on Czapek’s medium led to the isolation of four new metabolites, aspergifuranone (1), isocoumarin derivatives (±) 2 and (±) 3, and (R)-3-demethylpurpurester A (4), together with the known purpurester B (5) and pestaphthalides A (6). Their structures were determined by analysis of 1D and 2D NMR spectroscopic data. The absolute configuration of Compound 1 was determined by comparison of the experimental and calculated electronic circular dichroism (ECD) spectra, and that of Compound 4 was revealed by comparing its optical rotation data and CD with those of the literature. The structure of Compound 6 was further confirmed by single-crystal X-ray diffraction experiment using CuKα radiation. All isolated compounds were evaluated for their α-glucosidase inhibitory activities, and Compound 1 showed significant inhibitory activity with IC₅₀ value of 9.05 ± 0.60 μM. Kinetic analysis showed that Compound 1 was a noncompetitive inhibitor of α-glucosidase. Compounds 2 and 6 exhibited moderate inhibitory activities.     

Alterporriol-Type Dimers from the Mangrove Endophytic Fungus,Alternaria sp. (SK11), and Their MptpB Inhibitions

A new alterporriol-type anthranoid dimer, alterporriol S (1), along with seven known anthraquinone derivatives, (+)-aS-alterporriol C (2), hydroxybostrycin (3), halorosellinia A (4), tetrahydrobostrycin (5), 9α-hydroxydihydrodesoxybostrycin (6), austrocortinin (7) and 6-methylquinizarin (8), were isolated from the culture broth of the mangrove fungus, Alternaria sp. (SK11), from the South China Sea. Their structures and the relative configurations were elucidated using comprehensive spectroscopic methods, including 1D and 2D NMR spectra. The absolute configurations of 1 and the axial configuration of 2 were defined by experimental and theoretical ECD spectroscopy. 1 was identified as the first member of alterporriols consisting of a unique C-10−C-2′ linkage. Atropisomer 2 exhibited strong inhibitory activity against Mycobacterium tuberculosis protein tyrosine phosphatase B (MptpB) with an IC₅₀ value 8.70 μM.     

Asperlones A and B,Dinaphthalenone Derivatives from a Mangrove Endophytic Fungus Aspergillus sp. 16-5C

Racemic dinaphthalenone derivatives, (±)-asperlone A (1) and (±)-asperlone B (2), and two new azaphilones, 6″-hydroxy-(R)-mitorubrinic acid (3) and purpurquinone D (4), along with four known compounds, (−)-mitorubrinic acid (5), (−)-mitorubrin (6), purpurquinone A (7) and orsellinic acid (8), were isolated from the cultures of Aspergillus sp. 16-5C. The structures were elucidated using comprehensive spectroscopic methods, including 1D and 2D NMR spectra and the structures of 1 further confirmed by single-crystal X-ray diffraction analysis, while the absolute configuration of 3 and 4 were determined by comparing their optical rotation and CD with those of the literature, respectively. Compounds 1, 2 and 6 exhibited potent inhibitory effects against Mycobacterium tuberculosis protein tyrosine phosphatase B (MptpB) with IC₅₀ values of 4.24 ± 0.41, 4.32 ± 0.60 and 3.99 ± 0.34 μM, respectively.     

New Deoxyisoaustamide Derivatives from the Coral-Derived Fungus Penicillium dimorphosporum KMM 4689

Seven new deoxyisoaustamide derivatives (1–7) together with known compounds (8–10) were isolated from the coral-derived fungus Penicillium dimorphosporum KMM 4689. Their structures were established using spectroscopic methods, X-ray diffraction analysis and by comparison with related known compounds. The absolute configurations of some alkaloids were determined based on CD and NOESY data as well as biogenetic considerations. The cytotoxic and neuroprotective activities of some of the isolated compounds were examined and structure-activity relationships were pointed out. New deoxyisoaustamides 4–6 at concentration of 1 µM revealed a statistical increase of PQ(paraquat)-treated Neuro-2a cell viability by 30–39%.