Streptomyces albogriseolus SY67903 Produces Eunicellin Diterpenoids Structurally Similar to Terpenes of the Gorgonian Muricella sibogae, the Bacterial Source.

Microeunicellols A (1) and B (2), two undescribed eunicellin diterpenoids, were isolated from the culture of a bacterial symbiont, Streptomyces albogriseolus SY67903. Their structures, including absolute configurations revealed by spectroscopic data and single-crystal X-ray diffraction analysis, are closely related with the diterpenoids from its host, a South China Sea gorgonian, Muricella sibogae. This is the first report of eunicellin diterpenoids, commonly coral-derived, from a bacterial symbiont of coral. The chemical metabolic relationship between the bacterium and its host is discussed. Biological evaluation revealed that compound 1 possessed cytotoxicities against several human cancer cell lines.

Biotransformation of Huperzine B by a Fungal Endophyte of Huperzia serrata.

The biotransformation of huperzine B (hupB), one of the characteristic bioactive constituents of the medicinal plant Huperzia serrata, by a fungal endophyte of the host plant was studied. One new compound, 8α,15α-epoxyhuperzine B (1), along with two known oxygenated hupB analogs, 16-hydroxyhuperzine B (2) and carinatumin B (3), was isolated and identified. The structures of all the isolates were deduced by spectroscopic methods including NMR, MS, IR, and UV spectra. The known compounds 2 and 3 were obtained from a microbial source for the first time. To the best of our knowledge, it is the first report on the microbial transformation of hupB and would facilitate further structural modification of hupB by chemo-enzymatic method. In the LPS-induced neuro-inflammation injury assay, 8α,15α-epoxyhuperzine B (1) exhibited moderate neuroprotective activity by increasing the viability of U251 cell lines with an EC50 of 40.1 nm.

Studies on the Chemical Diversities of Secondary Metabolites Produced by Neosartorya fischeri via the OSMAC Method.

The One Strain Many Compounds (OSMAC) method was applied to explore the chemical diversities of secondary metabolites produced by Neosartorya fischeri NRRL 181. Four pyripyropenes 1⁻4, eight steroids 5⁻11, and four prenylated indole alkaloids 12⁻15, were obtained from the fungus cultured in petri dishes containing potato dextrose agar (PDA). 1,7,11-trideacetylpyripyropene A (1) and 1,11-dideacetyl pyripyropene A (2) were obtained and spectroscopically characterized (1D, 2D NMR, and HR-ESI-MS) from a natural source for the first time. It offered a sustainable source of these two compounds, which were usually used as starting materials in preparing pyripyropene derivatives. In addition, as compared with all the other naturally occurring pyripyropenes, 1 and 2 possessed unique acetylation patterns that did not follow the established late-step biosynthetic rules of pyripyropenes. The natural occurrence of 1 and 2 in the fungus implied that the timing and order of hydroxylation and acetylation in the late-step biosynthetic pathway of pyripyropenes remained to be revealed. The isolation and identification of 1⁻15 indicated that the OSMAC method could remarkably alter the metabolic profile and enrich the chemical diversities of fungal metabolites. Compounds 1⁻4 exhibited no obvious cytotoxicity against the triple-negative breast cancer cell line MDA-MB-231 as compared with taxol.

Synthesis of 3- and 29-substituted celastrol derivatives and structure-activity relationship studies of their cytotoxic activities.

A series of 3-carbamate and 29-ester celastrol derivatives (compounds 1-26) were designed and synthesized. These analogues were evaluated for their cytotoxic activities against several cancer cell lines. Cytotoxicity data revealed that the properties of substituents and substitution position had important influence on cytotoxic activity. Modification of C-3 hydroxyl with size-limited groups did not reduce the activity obviously. The introduction of polarity group like piperazine could improve the solubility. Compound 23 was chosen to further evaluate anti-tumor efficacy in vivo. It showed higher inhibition rate and better safety than celastrol during in vivo experiment by intragastric administration. The preliminary antitumor studies of compound 23in vivo showed that it might be promising for the development of new antitumor agents.

Bergamotane Sesquiterpenes with Alpha-Glucosidase Inhibitory Activity from the Plant Pathogenic Fungus Penicillium expansum.

Two new bergamotane sesquiterpene lactones, named expansolides C and D (1 and 2), together with two known compounds expansolides A and B (3 and 4), were isolated from the plant pathogenic fungus Penicillium expansum ACCC37275. The structures of the new compounds were established by detailed analyses of the spectroscopic data, especially 1D-, 2D-NMR, and HR-ESI-MS. In an in vitro bioassay, the epimeric mixture of expansolides C and D (1 and 2) (in a ratio of 2:1 at the temprature of the bioassay) exhibited more potent α-glucosidase inhibitory activity (IC50 =0.50 ± 0.02 mm) as compared with the positive control acarbose (IC50 = 1.90 ± 0.05 mm). To the best of our knowledge, it was the first report on the α-glucosidase inhibitory activity of bergamotane sesquiterpenes.

α-Glucosidase Inhibitors from the Fungus Aspergillus terreus 3.05358.

One new diketopiperazine alkaloid amauromine B (1), along with three known meroterpenoids, austalide B (2), austalides N and O (3 and 4), and two known steroids (5 and 6), was isolated and identified from the culture broth of the fungus Aspergillus terreus 3.05358. Their structures were elucidated by extensive spectroscopic techniques, including 2D-NMR and MS analysis, the absolute configuration of 1 was unambiguously established by single crystal X-ray diffraction analysis. All the isolates were evaluated for their inhibitory effects on α-glucosidase. Amauromine B (1) and austalide N (3) exhibited more potent α-glucosidase inhibitory activities than the positive control acarbose.

Lupane- and Friedelane-Type Triterpenoids from Celastrus stylosus.

Two new triterpenoids, 30-hydroxylup-20(29)-ene 3ß-caffeate (1) and 24-nor-friedelan-6α,10-dihydroxy-1,2-dioxo-4,7-dien-29-oic acid (2), together with eight known compounds 3-10, were isolated from the roots of Celastrus stylosus. The structures of these compounds were elucidated on the basis of spectroscopic analyses. To the best of our knowledge, this represents the first study on the chemical constituents of C. stylosus. The antiproliferative activities of the triterpenoids against six human cancer cell lines (PANC-1, A549, PC-3, HepG2, SGC-7901, and HCCLM3) were evaluated. Compounds 3, 4, and 10 exhibited comparable activities against PC-3 and HCCLM3 cell lines as the positive control taxol.

Biotransformation of huperzine A by a fungal endophyte of Huperzia serrata furnished sesquiterpenoid-alkaloid hybrids.

Biotransformation of huperzine A (hupA) by a fungal endophyte, Ceriporia lacerate HS-ZJUT-C13A, afforded compounds 1-5 and three tremulane sesquiterpenoids, 6-8. Huptremules A-D (1-4) feature unusual sesquiterpenoid-alkaloid hybrid structures that integrate the characteristics of fungal metabolites (tremulane sesquiterpenoids) and the exogenous substrate (hupA). These results support the use of fungal endophytes as biocatalysts for the biotransformation of natural products, particularly those originating from the host plant.

Solid-state-cultured mycelium of Antrodia camphorata exerts potential neuroprotective activities against 6-hydroxydopamine-induced toxicity in PC12 cells.

Antrodia camphorata (A. camphorata) is an edible fungus containing various bioactive compounds generally used for health benefits. This study aimed to explore the potential neuroprotective activities of solid-state-cultured mycelium of A. camphorata (SCMAC) against Parkinson's disease (PD), as well as the underlying mechanism using an in vitro 6-hydroxydopamine (6-OHDA)-induced PC12 cell model. The results showed that SCMAC extracts alleviated cell toxicity induced by 6-OHDA and the loss of dopaminergic neurons, which was confirmed by the increase of cell viabilities, inhibition of cell apoptosis, the upregulation of tyrosine hydroxylase (TH) and dopamine transporter (DAT) levels and the downregulation of α-Synuclein level. After purification, 11 compounds were identified by the NMR technique, including a quinone, four phenolic acid derivatives, three ubiquinone derivatives, two alkaloids, and a triterpenoid. The present study suggests that SCMAC could be an attractive candidate for the prevention or treatment of PD. PRACTICAL APPLICATIONS: Parkinson's disease seriously affects the lifetime and quality of the elder population for a long history. Long-term consumption of L-DOPA will result in side effects, such as developing abnormal involuntary movements called dyskinesia. This study showed that natural SCMAC extracts could be a potential therapeutic agent for the treatment of neurodegenerative disorder.

Dibenzocyclooctadiene lignans from the stems of Schisandra sphaerandra.

Chemical investigation into the stems of the medicinal plant Schisandra sphaerandra led to the isolation and identification of a new dibenzocyclooctadiene lignan sphaerandrin A (1) and 11 known ones gomisin B (2), schirubrisin B (3), kadsuphilin B (4), schizandrin (5), benzoylgomisin Q (6), angeloylgomisin Q (7), gomisin G (8), schisanwilsonin O (9), isogomisin O (10), schisantherin D (11), and wuweizisu C (12). The structure of the new compound was elucidated by comprehensive spectroscopic methods including 1 D/2D NMR, HRESIMS, and CD spectrometry. To the best of our knowledge, compounds 2 - 11 were obtained from this species for the first time. All the compounds were evaluated for the cytotoxic activity against the triple-negative breast cancer cell lines MDA-MB-231 and HCC-1937.

Diverse diterpenoids with α-glucosidase and ß-glucuronidase inhibitory activities from Euphorbia milii.

Four undescribed regular rosane-type diterpenoids euphominoids M-P and three undescribed rearranged rosane-type diterpenoids euphomilones C-E were isolated from the whole plants of Euphorbia milii Des Moul., along with nine known compounds. Their structures were elucidated by detailed interpretation of the NMR and mass spectroscopy. The absolute configurations were established by single-crystal X-ray diffraction experiments, as well as comparative analyses of calculated and experimental ECD spectra. Euphominoid M featured a highly oxygenated ring A and a rare four-membered oxygen ring while euphomilones C-E possessed 7/5/6 or 5/7/6 fused ring systems, which were rarely occurring in rosane-type diterpenoids. In the in-vitro bioassays, 19-norrosa-1,3,5(10),15-tetraene-2,3-diol and antiquorin showed more potent α-glucosidase inhibitory activity than the positive control acarbose while euphominoid C exhibited significant inhibitory activity against both α-glucosidase and ß-glucuronidase. To the best of our knowledge, it was the first time that rosane-type diterpenoids were reported as ß-glucuronidase inhibitors.

Natural disesquiterpenoids.

This review covers the isolation, structural determination, biological activities and biomimetic synthesis of all natural dimeric sesquiterpenoids, along with a detailed discussion of the biogenesis of these metabolites. Syntheses leading to the revision of structures have also been included, and 368 references are cited.

Induced production of a new polyketide in Penicillium sp. HS-11 by chemical epigenetic manipulation.

Chemical investigation into the culture broth of the plant endophyte Penicillium sp. HS-11 in the modified Martin's medium supplemented with subemylanilide hydroxamic acid (SAHA), a well-known histone deacetylase (HDACs) inhibitor, led to the isolation and identification of two induced products 4-epipenicillone B (1) and (R)-(+)-chrysogine (2). 4-epipenicillone B (1) was obtained as a new compound whose structure was elucidated by comprehensive spectroscopic methods including 1 D/2D NMR, HRESMS, and quantum chemistry calculations including DFT GIAO 13C NMR and ECD calculation. Acquisition of 4-epipenicillone B (1) enriched the chemical diversities of fungal natural products possessing a tricyclo [5.3.1.03,8] undecane skeleton. The cytotoxic activity of 1 was also evaluated.

A Cell Factory of a Fungicolous Fungus Calcarisporiumarbuscula for Efficient Production of Natural Products.

Fungal natural products are rich sources of clinical drugs. Particularly, the fungicolous fungi have a large number of biosynthetic gene clusters (BGCs) to produce numerous bioactive natural products, but most BGCs are silent in the laboratory. We have shown that a fungicolous fungus Calcarisporiumarbuscula NRRL 3705 predominantly produces the highly reduced polyketide-type mycotoxins aurovertins. Here after evaluation of the aurovertin-null mutant ΔaurA as an efficient host, we further screened two strong promoters aurBp and A07068p based on RNA-Seq, and successfully activated an endogenous gene cluster from C. arbuscula as well as three additional exogenous BGCs from other fungi to produce polyketide-type natural products. Thus, we showed an efficient expression system from the fungicolous fungus C. arbuscula, which will be highly beneficial and complementary to the conventional Aspergillus and Penicillium fungal cell factories, and provides a useful toolkit for genome-wide mining of bioactive natural products from fungicolous fungi.

Spiroinonotsuoxotriols A and B, Two Highly Rearranged Triterpenoids from Inonotus obliquus.

Spiroinonotsuoxotriols A (1) and B (2), two highly rearranged pentacyclic triterpenoids featuring a novel 7(8 → 9)abeo-21,24-cyclo-lanostane skeleton, together with their proposed precursors 3-5, were isolated from the sclerotia of the white-rot fungus Inonotus obliquus. Their structures including the absolute configurations were elucidated by extensive spectroscopic analyses and single-crystal X-ray diffraction. The biogenetic pathway of 1 and 2 was proposed. Compounds 1 and 2 exhibited potent α-glucosidase inhibitory activity as compared with the positive control acarbose.

Effects of α-Mangostin Derivatives on the Alzheimer's Disease Model of Rats and Their Mechanism: A Combination of Experimental Study and Computational Systems Pharmacology Analysis.

α-Mangostin (α-M) is a natural xanthone from the pericarp of fruit Garcinia mangostana and possesses versatile biological activities. α-M has a therapeutic potential to treat Alzheimer's disease (AD) because of its anti-inflammatory, antioxidative, and neuroprotective activities. However, the use of α-M for AD treatment is limited due to its cytotoxic activities and relatively low potency. Modifications of its chemical structure were needed to reduce its cytotoxicity and improve its therapeutic potential against AD. For this purpose, 16 α-M carbamate derivatives were synthesized. An animal model of AD was established, and the effects of AMG-1 on the spatial learning ability and memory ability were evaluated using behavioral tests. The effect on neuropathology was tested by histopathological evaluation, Nissl staining, and silver staining. Computational systems pharmacology analysis using the chemogenomics knowledgebase was applied for network studies. Compound-target, target-pathway, and target-disease networks were constructed, integrating both in silico analysis and reported experimental data. The results show that AMG-1 can demonstrate its therapeutic effects in a one-molecule, multiple-targets manner to remarkably ameliorate neurological changes and reverse behavioral deficits in AD model rats. The improved cognitive function and alleviated neuronal injury can be observed. The ability of AMG-1 to scavenge ß-amyloid in the hippocampus was validated in AD model rats.

Biotransformation of Huperzine A by Irpex lacteus-A fungal endophyte of Huperzia serrata.

The biotransformation of huperzine A (hupA), one of the characteristic bioactive constituents of the medicinal plant Huperzia serrata, by a fungal endophyte of the host plant was studied. Two previously undescribed compounds 1-2, along with a known analog 8α,15α-epoxyhuperzine A (3), were isolated and identified. The structures of all the isolates were established by spectroscopic methods including NMR, MS, IR, and UV spectra. In particular, the absolute configurations of 1 and 2 were elucidated by CD spectra comparison and theoretic NOE strength calculation. In the LPS-induced neuro-inflammation injury assay, 1-3 exhibited moderate neuroprotective activity by increasing the viability of U251 cell lines with EC50 values of 35.3 ±â€¯0.9, 32.1 ±â€¯0.9, and 50.3 ±â€¯0.8 nM, respectively.

Marsdeniae tenacissima extract-induced growth inhibition and apoptosis in hepatoma carcinoma cells is mediated through the p53/nuclear factor-κB signaling pathway.

An extract from a traditional Chinese herb, Marsdeniae tenacissima (trade name, Xiao-Ai-Ping) has been approved for use on the Chinese market as a cancer chemotherapeutic agent for decades. Previous studies have demonstrated the cytostatic and pro-apoptotic effects of M. tenacissima extract (MTE) in multiple cancer cells. However, the contributions of MTE to the proliferation and apoptosis of hepatoma carcinoma cells and the underlying mechanisms remain unclear. In the present study, Bel-7402 cells were incubated with increasing concentrations of MTE ranging from 0-320 µl/ml to explore the effects and potential mechanisms of MTE on the proliferation and apoptosis of Bel-7402 cells. 3-(4,5-dimethylthiazol-2-yl)-5(3-carboxymethoxyphenyl)-2-(4-sulfopheny)-2H-tetrazolium, inner salt and propidium iodide (PI)-stained flow cytometry assays demonstrated that MTE significantly suppressed the proliferation of Bel-7402 cells in a dose-dependent manner by arresting the cell cycle at S phase (P<0.05). Annexin V-fluorescein isothiocyanate PI-stained flow cytometry confirmed the significantly pro-apoptotic effect of MTE at both 160 and 240 µl/ml (P<0.001). Reverse transcription-quantitative polymerase chain reaction and western blot analysis demonstrated that MTE (both 160 and 240 µl/ml) induced a significant downregulation of B-cell lymphoma (Bcl)-2 (P<0.01), upregulation of Bcl-2-associated X protein (P<0.01) and activation of caspase-3 (P<0.05). Furthermore, a significant downregulation of murine double minute-2 (MDM2) (P<0.001) and activation of p53 (P<0.001) in Bel-7402 cells following treatment with 160 or 240 µl/ml MTE was observed, accompanied by the inhibition of the nuclear factor (NF)-κB pathway (P<0.001). These results suggested that MTE inhibited growth and exhibited pro-apoptotic effects in Bel-7402 cells, which was mediated by downregulation of the MDM2-induced p53-dependent mitochondrial apoptosis pathway and blocking the NF-κB pathway. Overall, these data serve as preliminary identification of the significant roles of MTE in hepatic carcinoma cells, and suggest that MTE may be a promising candidate for hepatocellular carcinoma therapy.

Marsdeniae tenacissimae extract (MTE) suppresses cell proliferation by attenuating VEGF/VEGFR2 interactions and promotes apoptosis through regulating PKC pathway in human umbilical vein endothelial cells.

Marsdeniae tenacissimae extract (MTE), commonly known as Xiao-Ai-Ping in China, is a traditional Chinese herb medicine capable of inhibiting proliferation and metastasis and boosting apoptosis in various cancer cells. However, little is known about the contribution of MTE towards tumor angiogenesis and the underlying mechanism. The present study aimed to evaluate the effects of MTE on the proliferation and apoptosis of human umbilical vein endothelial cells (HUVECs) and the molecular mechanism. 3-(4,5-dimethylthiazol-2-yl)-5(3-carboxymethoxyphenyl)-2-(4-sulfopheny)-2H-tetrazolium, inner salt (MTS) and PI-stained flow cytometry assays revealed that MTE dose-dependently reduced the proliferation of HUVECs by arresting cell cycle at S phase (P < 0.05). Annexin V-FITC/PI-stained flow cytometry confirmed that MTE (160 µL·L-1) enhanced the apoptosis of HUVECs significantly (P < 0.001). Real-time quantitative RT-PCR and Western blot analyses showed an increase in Bax expression and a sharply decline in Bcl-2 expression; caspase-3 was activated simultaneously in a dose-dependent manner (P < 0.05). Further study observed the dose-dependent down-regulation of vascular endothelial growth factor (VEGF) receptor-2 (VEGFR-2), P2Y6 receptor (P2Y6R), and chemokine (C-C motif) ligand 2 (CCL-2), along with the activation of PKC Δ and up-regulation of p53 in a dose-dependent manner in MTE-treated selected cells (P < 0.05). Collectively, the results from the present study suggested that MTE suppressed the proliferation by attenuating CCL-2-mediated VEGF/VEGFR2 interactions and promoted the apoptosis through PKCΔ-induced p53-dependent mitochondrial pathway in HUVECs, supporting that MTE may be developed as a potent anti-cancer medicine.

Terpenoids with alpha-glucosidase inhibitory activity from the submerged culture of Inonotus obliquus.

Lanostane-type triterpenoids, inotolactones A and B, a drimane-type sesquiterpenoid, inotolactone C, and five known terpenoids 6ß-hydroxy-trans-dihydroconfertifolin, inotodiol, 3ß,22-dihydroxyanosta-7,9(11),24-triene, 3ß-hydroxycinnamolide, and 17-hydroxy-ent-atisan-19-oic acid, were isolated from the submerged culture of chaga mushroom, Inonotus obliquus. Their structures were characterized by spectroscopic methods, including MS and NMR (1D and 2D) spectroscopic techniques. Inotolactones A and B, examples of lanostane-type triterpenoids bearing α,ß-dimethyl, α,ß-unsaturated δ-lactone side chains, exhibited more potent alpha-glucosidase inhibitory activities than the positive control acarbose. This finding might be related to the anti-hyperglycemic properties of the fungus and to its popular role as a diabetes treatment. In addition, a drimane-type sesquiterpenoid and an atisane-type diterpenoid were isolated from I. obliquus.