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.

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.

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.

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.

[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.

(±)-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.

Chlorinated bisabolene sesquiterpenoids from the whole plant of Parasenecio rubescens.

Four new chlorinated bisabolene-type sesquiterpenoids (1-4) were isolated during the phytochemical investigation of an acetone extract of the whole plant of Parasenecio rubescens. The structures of 1-4 were determined by analysis of their HRESIMS and NMR spectroscopic data, and the absolute configuration of 1 was established through single-crystal X-ray diffraction. All isolates were evaluated for their cytotoxicity against three cancer cell lines (B16 mouse melanoma, HepG2 human hepatocellular carcinoma, and MCF7 human breast adenocarcinoma), as well as their antimicrobial effects against Staphylococcus aureus, Escherichia coli, and Monilia albicans. As a result, compounds 1-4 displayed a certain degree of antimicrobial activities.

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.

Aspersteroids A-C, Three Rearranged Ergostane-type Steroids from Aspergillus ustus NRRL 275.

Aspersteroid A (1), a highly rearranged 1(10 → 6)-abeo-18,22-cyclosterol, together with two new 18,22-cyclosterols (2 and 3), was isolated from the culture extract of Aspergillus ustus NRRL 275. Their structures were determined by spectroscopic analysis, X-ray diffraction, modified Mosher's method, and Rh2(OCOCF3)4-induced electronic circular dichroism experiments. Compound 1 represents a new carbon skeleton with an uncommon 6/6/6/5/5 ring system, which is presumably biosynthesized from A-ring scission, double 1,2-shifts, and C-18/C-22 cyclization. Compound 1 exhibited potent immunosuppressive and antimicrobial activities.

Pchaeglobolactone A, Spiropchaeglobosin A, and Pchaeglobosals A and B: Four Rearranged Cytochalasans from Chaetomium globosum P2-2-2.

Four novel rearranged cytochalasans (1-4) were isolated from an endophytic fungus Chaetomium globosum P2-2-2. Pchaeglobolactone A (1) possessed an unprecedented 13-aza-21-oxa-tetracyclo-[10.6.1.217,19.015,19]henicosane core. Spiropchaeglobosin A (2) was the first example of cytochalasans featuring a novel spiro[5.10]hexadecane unit. Pchaeglobosals A (3) and B (4) featured a unique 5/5/13 fused tricyclic ring system. Compounds 1-4 were tested for their antiproliferative, apoptosis, cell cycle arrest, and TRAIL-resistance-overcoming activities on cancer cell lines.

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.

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.

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.