Lignans and [11]-chaetoglobosins from Pseudeurotium bakeri and their immunosuppressive activity.

Two previously unreported lignans (1-2) and four undescribed [11]-chaetoglobosins (3-6) were obtained from the culture extract of an endophytic fungus Pseudeurotium bakeri P1-1-1. Their structures with absolute configurations were determined by spectroscopic data analysis, single-crystal X-ray diffraction, electronic circular dichroism (ECD) calculations, the modified Mosher's method, and Mo2(OAc)4-induced electronic circular dichroism (ICD) experiments. Compounds 5 and 6 showed moderate cytotoxic effects against seven human cancer cell lines. Compounds 2-4 exhibited immunosuppressive activities on concanavalin A-induced T cell proliferation with IC50 values of 3.7, 3.4, and 14.5 µM, and on lipopolysaccharide-induced B cell proliferation with IC50 values of 4.1, 3.9, and 14.2 µM, respectively. Further investigation revealed that 2 and 3 induced apoptosis in activated T cells in a dose-dependent manner.

Penicamins A-L, Polyoxygenated Diterpenes from Penicillium camemberti JSB-7212.

Penicamins A-L (1-12), 12 highly oxygenated novel diterpenes, were obtained from the fungus Penicillium camemberti JSB-7212. Compounds 1-12 share the same 7/6/5 tricyclic skeleton as valparane-type diterpenes but differ in the absolute configurations at C-7, C-11, and C-14, as well as in the oxidation levels at C-6 and C-8, which were determined through extensive spectroscopic data interpretation. Stereochemical assignments of compounds 1, 2, and 4-12 were established by single-crystal X-ray diffraction, and the absolute configuration of 3 was determined by analysis of the NOESY data and biogenetic consideration. Compounds 2 and 3 were immunosuppressive against lipopolysaccharide (LPS)-induced B cells, with IC50 values of 3.0 and 7.9 µM, respectively. They also moderately suppressed concanavalin A (ConA)-induced T cell proliferation, with IC50 values of 19 and 20 µM, respectively.

Diaporaustalides A-L, Austalide Meroterpenoids from a Plant Endophytic Diaporthe sp.

Twelve new austalide meroterpenoids (1-12) were isolated from the endophytic fungus Diaporthe sp. XC1211. Their structures were elucidated by extensive spectroscopic analysis. The absolute configurations of compounds 1, 3, 4, and 6 were established by single-crystal X-ray diffraction, whereas those for the others were established by experimental electronic circular dichroism (ECD) data analysis. Compounds 1-12 represent a rare class of austalides with a 24α-CH3. Compounds 2 and 5 demonstrated potent proliferation inhibitory effects against LPS-induced B cells with IC50 values of 6.7 (SI = 3.6) and 3.8 (SI > 13) µM, respectively. Compounds 2 and 5 decreased the secretion of IL-6 in LPS-induced B cells in a dose-dependent manner.

Asperustins A-J: Austocystins with Immunosuppressive and Cytotoxic Activities from Aspergillus ustus NRRL 5856.

Ten new (1-10) and nine known (11-19) austocystins, along with four known anthraquinones (20-23), were isolated from the culture of Aspergillus ustus NRRL 5856 by bioactivity-guided fractionation. The structures of the new compounds were elucidated by spectroscopic data analysis, X-ray crystallographic study, the modified Mosher's method, [Rh2(OCOCF3)4]-induced ECD spectral analysis, and comparison of the experimental ECD spectra with those of the similar analogues. Compounds 1-8 represent the first examples of austocystins with a C-4' oxygenated substitution. The absolute configuration of 1″-hydroxy austocystin D (11) was determined by single-crystal X-ray diffraction and consideration of its biosynthetic origin. Compounds 5, 9, and 11 exhibited significant inhibitory effects against the proliferation of ConA-induced T cells with IC50 values of 1.1, 1.0, and 0.93 µM, respectively. Furthermore, these compounds suppressed the expression of IL-6 in a dose-dependent manner. Compounds 10-12 and 14 showed pronounced cytotoxicities against MCF-7 with IC50 values of 3.9, 1.3, 0.46, and 2.3 µM, respectively.

Peniandranoids A-E: Meroterpenoids with Antiviral and Immunosuppressive Activity from a Penicillium sp.

Peniandranoids A-E (1-5), five new meroterpenoids, together with three known analogues (6-8), were isolated from the fermentation of a soil-derived fungus, Penicillium sp.sb62. Their structures including absolute configurations were determined by extensive spectroscopic analysis, and the absolute configurations of compounds 1 and 5 were further elucidated by single-crystal X-ray diffraction. Peniandranoids A-E belong to a rare class of andrastin-type meroterpenoids incorporating an extra polyketide unit (a C10 polyketide unit for 1 and 2, a C9 polyketide unit for 3 and 4, and a furancarboxylic acid unit for 5). Compounds 1 and 6 exhibited favorable inhibitory activities against influenza virus A (H1N1) with EC50 values of 19 and 14 µg/mL, respectively. Compounds 3-8 exhibited potent immunosuppressive activities against concanavalin A-induced T cell proliferation with EC50 values ranging from 4.3 to 27 µM and lipopolysaccharide-induced B cell proliferation with EC50 values ranging from 7.5 to 23 µM, respectively.

Peniandrastins A-H: Andrastin-type meroterpenoids with immunosuppressive activity from a Penicillium sp.

Eight unreported andrastin-type meroterpenoids, namely peniandrastins A-H (1-8), along with six known analogues (9-14), were isolated from the fermentation of a soil-derived fungus Penicillium sp.sb62. Their structures with absolute configurations were elucidated by detailed analyses of the spectroscopic data and single-crystal X-ray diffraction. Compounds 1-4 belong to a rare class of 21-nor-andrastin meroterpenoids, of which 1 bears a 10-hydroperoxyl group, and 2 and 3 feature a 6/6/6/5/5 and a 6/6/6/5/6 pentacyclic systems, respectively. Compounds 5-8 are C25 andrastin-type meroterpenoids, wherein 5 features an unprecedented cyclopentan-1-keton-3-hemiacetal moiety. Additionally, the absolute configuration of compound 9 was corroborated by single-crystal X-ray crystallography for the first time. All isolates were evaluated for their immunosuppressive activities. As a result, compounds 1, 3, 4, 7-9 and 12-14 inhibited concanavalin A-induced T cell proliferation with IC50 values ranging from 7.49 to 36.52 µM, and 1-4, 6-9 and 12-14 inhibited lipopolysaccharide-induced B cell proliferation with IC50 values ranging from 6.73 to 26.27 µM. The preliminary structure-activity relationships (SARs) of those isolates were also discussed.

(±)-Usphenethylones A-C, three pairs of heterodimeric polyketide enantiomers from Aspergillus ustus 3.3904.

Three pairs of new heterodimeric polyketide enantiomers, (±)-usphenethylones A-C (1-3), were isolated from the culture extract of Aspergillus ustus 3.3904. Compounds 1-3 present two heterodimerization patterns by a phenylethyl unit connected to an α-pyrone moiety, of which usphenethylones A-B (1-2) feature a 2,6,18-trioxa-tetracyclo-[8.8.0.03,8.011,16]octadecane core and usphenethylone C (3) possesses a 2-phenyl-3,4-dihydro-pyrano[4,3-b]pyran-5-one scaffold. The structures of (±)-1-3 were elucidated based on spectroscopic data analyses, and their absolute configurations were determined by single-crystal X-ray diffraction analysis and ECD calculation. Plausible biosynthetic pathways for 1-3 were proposed. Compounds (+)-3 and (-)-3 exhibited moderate inhibitory effects against ConA-induced T cell and LPS-induced B cell proliferation.

Ilyomycins A - K, radicicol-type resorcylic acid lactones as potential immunosuppressants from a soil-derived Ilyonectria sp.

Eleven previously undescribed radicicol-type resorcylic acid lactones (RALs), namely ilyomycins A - K (1-9, 10a and 10b), were isolated and identified from the fermented rice culture of a soil-derived fungus, Ilyonectria sp. (strain sb65). Their gross structures were determined by extensive spectroscopic data, and the absolute configurations were elucidated by single-crystal X-ray diffraction, the modified Mosher's method, and Rh2(OCOCF3)4-induced electronic circular dichroism (ICD) experiment. Among them, 10a and 10b were a pair of inseparable regioisomers via intramolecular transacetylation. Compounds 3, 7, 8 and 10a/10b displayed immunosuppressive activities against T cell proliferation with IC50 values ranging from 1.2 to 21.7 µM, and against B cell proliferation with IC50 values ranging from 1.1 to 20.1 µM, which suggested that the α, ß-unsaturated ketone from C-8 to C-10 was an important pharmacophore. Further study revealed that ilyomycin C (3) exerted anti-proliferative effect on T lymphocytes through Hsp90 inhibition.

Resorcylic acid lactones from a Podospora sp. that induce apoptosis in activated T cells through MAPKs/AKT pathway.

Podomycins A-L (1-12), 12 undescribed hypothemycin-type resorcylic acid lactones (RALs), were characterized from Podospora sp. G214, an endophyte harbored in the roots of Sanguisorba officinalis L. Their structures were addressed by spectroscopic data, X-ray crystallography, the modified Mosher's method, together with Mo2(OAc)4- and Rh2(OCOCF3)4-induced electronic circular dichroism (ICD) experiments. Podomycins A-C (1-3) represent the first class of natural RALs with a 13-membered macrolactone ring, while 4-12 are rearranged methoxycarbonyl substituted RALs. Biologically, compounds 2, 6, 8, 10, and 12 displayed immunosuppressive activities against T cell proliferation with IC50 values of 14.5-21.9 µM, and B cell proliferation with IC50 values of 22.3-36.5 µM, respectively. Further mechanism of action research demonstrated that podomycin F (6) distinctly induced apoptosis in activated T cells via MAPKs/AKT pathway.

[11]-chaetoglobosins with cytotoxic activities from Pseudeurotium bakeri.

Fourteen new [11]-chaetoglobosins (1-14), along with two known congeners, cytochalasins X and Y (15 and 16), were isolated from the cultures of an endophytic fungus Pseudeurotium bakeri P1-1-1. Their structures incorporating absolute configurations were elucidated based on the comprehensive analyses of one- and two-dimensional NMR data, HRESIMS spectrometry, chemical methods, and single-crystal X-ray diffraction analysis (Cu Kα). All isolates were evaluated for their cytotoxic activities and chaetopseudeurin M (1) displayed significant cytotoxic effects against seven human cancer cell lines, with IC50 values ranging from 5.1 ± 0.9 to 10.8 ± 0.1 µM. Western blot experiments exhibited that compound 1 exerted its cytotoxic effect in MCF-7 cells by inducing G2/M cell cycle arrest and apoptosis via downregulating the expression of cyclin B1 and Cdk1, and activating Bcl-2/caspase-3/PARP pathway, respectively.

TRAIL-sensitizing Cytochalasins from the Endophytic Fungus Phoma multirostrata.

Seven undescribed cytochalasins, multirostratins K - Q (2: -8: ), together with one known analogue, cytochalasin Z3 (1: ), were isolated from the culture of Phoma multirostrata XJ-2-1, an endophytic fungus obtained from the root of Parasenecio albus. Their structures with absolute configurations were determined by 1D and 2D NMR, high-resolution electrospray ionization mass spectrometry (HRESIMS), electronic circular dichroism (ECD), single-crystal X-ray crystallography, and chemical methods. The structure of ascochalasin was revised from Δ 13 to Δ 21 by detailed analysis of the NMR data and by comparison with the data for 7: . In a TRAIL (tumor necrosis factor related apoptosis inducing ligand)-resistance-overcoming experiment, co-treatment of 2: or 6: with TRAIL reduced the cell viability of A549 cells by 30.3% and 27.5% at 10 µM, respectively.

Cytochalasan Alkaloids as TRAIL Sensitizers from an Endophytic Fungus Chaetomium sp.

Two new cytochalasans with a rare 6/6/5/5/7 pentacyclic ring system, named chaetoconvosins C-D (1: -2: ), together with two known congeners (3: -4: ), were isolated from the fermentation of an endophytic fungus, Chaetomium sp. SG-01, harbored in the fibrous roots of Schisandra glaucescens Diels. Their structures including the absolute configuration were elucidated by extensive spectroscopic (HRESIMS, NMR, and ECD) and X-ray crystallographic analyses. The TRAIL-resistance-overcoming activity of 1: -4: in a TRAIL-resistant HT29 colorectal cancer cell line was evaluated, which revealed that co-treatment of 1: -4: at 50 µM with TRAIL (150 ng/mL) reduced the HT29 cell viability by 19.0%, 24.1%, 17.9%, and 15.5%, respectively, compared to treatment with 1: -4: alone.

[11]-Chaetoglobosins from Pseudeurotium bakeri Induce G2/M Cell Cycle Arrest and Apoptosis in Human Cancer Cells.

Twelve new [11]-chaetoglobosins, chaetopseudeurins A-L (1-12), were identified from the fermentation of the endophytic fungus Pseudeurotium bakeri P1-1-1. Their structures with absolute configurations were elucidated by detailed interpretation of NMR spectroscopy, mass spectrometry, and single-crystal X-ray diffraction. Compounds 2 and 5-7 exhibited significant cytotoxicities against seven human cancer cell lines, with IC50 values ranging from 4.7 ± 1.0 to 12.2 ± 0.7 µM, and induced G2/M cell cycle arrest and apoptosis in MCF-7 and A427 cells dose dependently. Western blot analysis showed that compound 2 induced apoptosis of MCF-7 cells via the Bcl-2/caspase-3/PARP pathway.

Hypothemycin-Type Resorcylic Acid Lactones with Immunosuppressive Activities from a Podospora sp.

Twelve new hypothemycin-type resorcylic acid lactones, three 10-membered (1-3) and nine 14-membered (4-12), together with seven known analogues (13-19), were obtained from the solid rice-based culture of Podospora sp. G214. Their structures were elucidated utilizing spectroscopic analysis, and the absolute configurations were determined by modified Mosher's method, Mo2(OAc)4-induced electronic circular dichroism experiments, and single-crystal X-ray diffraction. Compounds 1, 5, 10, and 12-19 exhibited potent immunosuppressive activities against concanavalin A-induced T cell proliferation with IC50 values ranging from 6.0 to 25.1 µM and lipopolysaccharide-induced B cell proliferation with IC50 values ranging from 6.2 to 29.1 µM. Further studies revealed that 1 induced apoptosis in activated T cells through the JNK-mediated mitochondrial pathway.

Eremophilane sesquiterpenoids from the whole plant of Parasenecio albus with immunosuppressive activity.

Fifteen new highly oxygenated eremophilane sesquiterpenoids, parasubolides A-O (1-15), were obtained from the whole plant of Parasenecio albus. The structures of 1-15 were elucidated based on the interpretation of NMR and HRESIMS data, along with experimental electronic circular dichroism (ECD) and single-crystal X-ray diffraction analysis. Compounds 1-6, and 9-14 represent the first class of 1,2,10-trioxygenated eremophilane lactones. Selected isolates were evaluated for their immunosuppressive activities. Compounds 4, 5, and 12 exhibited moderate inhibition against LPS-induced B-cell proliferation with IC50 values of 23.1, 33.8, and 26.6 µM, respectively.

Ergocytochalasin A, a polycyclic merocytochalasan from an endophytic fungus Phoma multirostrata XJ-2-1.

Ergocytochalasin A (1), an unprecedented merocytochalasan formed via Diels-Alder cycloaddition of a cytochalasin with an ergosterol, was isolated from an endophytic fungus Phoma multirostrata XJ-2-1. Compound 1 possessed a unique 5/6/14/6/5/6/6/6 fused octacyclic ring system and its structure was established by detailed NMR and HRESIMS spectroscopic analyses. The absolute configuration of 1 was determined by single-crystal X-ray diffraction. A plausible biogenetic pathway of 1 was postulated. Compound 1 was evaluated for its cytotoxicity against six cancer cell lines and showed inhibitory effects with IC50 values ranging from 6.92 to 26.63 µM. The in vitro immunosuppressive activity of 1 against ConA-induced T cell and LPS-induced B cell proliferation, as well as its antiviral activity against Human dengue virus type 3 (DV3), influenza A virus (H1N1) and respiratory syncytial virus (RSV), was also evaluated. Ergocytochalasin A is the first example of a merocytochalasan which consists of one cytochalasin moiety and one ergosterol moiety. Containing eighteen chiral centers, ergocytochalasin A owns a folded framework, which makes it extremely compact in space.

Antimicrobial Furancarboxylic Acids from a Penicillium sp.

Ten novel (1, 2, 3a, 3b, 4a, 4b, 5a, 5b, 6a, and 6b) furancarboxylic acids including four pairs of epimers (3a, 3b; 4a, 4b; 5a, 5b; 6a, 6b), together with seven known analogues (7a, 7b, 8a, 8b, 9a, 9b, and 10), were isolated from the fermentation of the soil-derived fungus Penicillium sp. sb62. Their structures were established on the basis of spectroscopic data analysis, and the absolute configurations were determined by time-dependent density functional theory electronic circular dichroism calculations, comparison of the specific optical rotation values, and modified Mosher's method. Compounds 1-4 represent the first class of natural furancarboxylic acids featuring a thiophene moiety. Compounds 1-7 showed antimicrobial inhibitory activities against Escherichia coli, Staphylococcus aureus, and Candida albicans with MIC values ranging from 0.9 to 7.0 µg/mL, from 1.7 to 3.5 µg/mL, and from 3.3 to 7.0 µg/mL, respectively.

Resorcylic Acid Lactones from an Ilyonectria sp.

Twelve new resorcylic acid lactones (RALs) including three new 16-membered RALs (1a, 1b and 2), eight new 14-membered RALs (3-10), and one new 12-membered RAL (11), along with five known 14-membered RALs (12-16), were identified from the fermentation of the soil-derived fungus Ilyonectria sp. sb65. Their structures were established by detailed analyses of 1D and 2D NMR, HRESIMS, and X-ray diffraction crystallography. All new compounds were evaluated for their cytotoxic effects against three human cancer cell lines, along with their potential as TRAIL sensitizers in TRAIL-resistant A549 human lung adenocarcinoma cells and their in vitro immunosuppressive effects against ConA-induced T-cell and LPS-induced B-cell proliferation.

Cytochalasins from an endophytic fungus Phoma multirostrata XJ-2-1 with cell cycle arrest and TRAIL-resistance-overcoming activities.

Nine new (1-9) and four known (10-13) [13]cytochalasins, along with three known 24-oxa[14]cytochalasins (14-16), were isolated from the culture of Phoma multirostrata XJ-2-1, an endophytic fungus obtained from the fibrous root of Parasenecio albus. Their structures were elucidated by interpretation of the nuclear magnetic resonance (NMR) and high-resolution electrospray ionization mass spectroscopy (HRESIMS). The absolute configurations were assigned by single-crystal X-ray crystallography, modified Mosher's method, and by analysis of their experimental electronic circular dichroism (ECD) spectra. Compound 6 could induce cell cycle arrest at G2-phase in CT26 and A549 cells, and displayed moderate cytotoxicity against CT26 and A549 cell lines with IC50 values of 6.03 and 5.04 µM, respectively. Co-treatment of 7-9, 13 and 16 with tumor necrosis factor related apoptosis inducing ligand (TRAIL) could significantly decrease the cell viability of A549, which revealed that cytochalasins could possibly be a new group of TRAIL sensitizers in lung cancer therapy.

Trichothecenes from an Endophytic Fungus Alternaria sp. sb23.

Three new (alterchothecenes A - C, 1:  -3: ) and 3 known (4:  -6: ) trichothecenes, along with 9 known compounds (7:  -15: ), were isolated from the culture of Alternaria sp. sb23, an endophytic fungus separated from the root of Schisandra sphenanthera Rehd. et Wils. Their structures were elucidated by spectroscopic analyses, and the absolute configurations of 1: -3: were determined through comparison of the experimental electronic circular dichroism (ECD) spectra and optical rotations with similar analogues. In vitro cytotoxicity tests of compounds 1: -6: against human HT-29 colon carcinoma and human MCF-7 breast cancer cell lines indicated that 4: -6: exhibited significant cytotoxic effects, with IC50 values ranging from 0.89 to 9.38 µM. And the potential of compounds 1: -6: as tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) sensitizers in HT-29 cells was evaluated. The results revealed that combination treatment of TRAIL with compounds 1: -6: synergistically decreased cell viability compared with the sole treatment with those compounds.