Protective effects of 4-geranyloxy-2,6-dihydroxybenzophenonel on DSS-induced ulcerative colitis in mice via regulation of cAMP/PKA/CREB and NF-κB signaling pathways.

Hypericum sampsonii Hance has traditionally been used to treat enteritis and diarrhea. As one of the main benzophenones isolated from H. sampsonii, 4-geranyloxy-2,6-dihydroxybenzophenonel (4-GDB) has been shown to possess anti-inflammatory effects. However, the therapeutic effect and potential mechanisms of 4-GDB in ulcerative colitis (UC) remain unclear. This study aimed to evaluate the role of 4-GDB in UC using a dextran sulfate sodium-induced colitis mouse model. Intragastric administration of 4-GDB (20 mg/kg/day) for 8 days significantly attenuated colonic injury, reduced the expression of inflammatory mediators, and improved colonic barrier function in mice with colitis. Furthermore, in vivo and in vitro experiments indicated that 4-GDB could activate cAMP/PKA/CREB and inhibit the NF-κB pathway. Collectively, 4-GDB may be a potential agent for treating UC by regulating the cAMP/PKA/CREB and NF-κB pathways.

Asymmetric Total Synthesis of the Highly Strained 4ß-Acetoxyprobotryane-9ß,15α-diol.

The first and asymmetric total synthesis of 4ß-acetoxyprobotryane-9ß,15α-diol, containing a rare and highly strained trans-fused bicyclo[3.3.0]octane ring system, has been achieved. The synthetically challenging [6-5-5] tricyclic ring system in the final product was efficiently and diastereoselectively synthesized via an asymmetric rhodium-catalyzed [4 + 2] cycloaddition reaction, followed by a unique benzilic acid type rearrangement under very mild conditions. The seven contiguous stereocenters were installed efficiently and diastereoselectively.

Polypropionate Derivatives with Mycobacterium tuberculosis Protein Tyrosine Phosphatase B Inhibitory Activities from the Deep-Sea-Derived Fungus Aspergillus fischeri FS452.

Fiscpropionates A-F (1-6), six new polypropionate derivatives featuring an unusual long hydrophobic chain, were isolated from the deep-sea-derived fungus Aspergillus fischeri FS452. Their structures were elucidated on the basis of spectroscopic analysis, and the absolute configurations were determined by J-HMBC analysis, electronic circular dichroism (ECD) calculations, and the modified Mosher's method. This is the first discovery of polypropionates from marine-derived fungi, and compounds 4 and 5 represent the first examples of polypropionate derivatives containing a 3-hydroxypiperidin-2-one as part of an imide linkage. In addition, compounds 1-4 exhibited significant inhibitory activities against Mycobacterium tuberculosis protein tyrosine phosphatase B (MptpB) with the IC50 values of 5.1, 12, 4.0, and 11 µM, respectively. Enzyme kinetic experiments suggested that they all acted through a noncompetitive mechanism. A preliminary structure-activity relationship is discussed.

Dechdigliotoxins A-C, Three Novel Disulfide-Bridged Gliotoxin Dimers from Deep-Sea Sediment Derived Fungus Dichotomomyces cejpii.

Dechdigliotoxins A-C (1-3), which represented the first examples of gliotoxin dimers with an unprecedented exocyclic disulfide linkage, were obtained from a deep-sea derived fungus Dichotomomyces cejpii FS110. The structures of these compounds were elucidated on the basis of spectroscopic analysis and the absolute configurations were unambiguously determined through quantum chemical calculations, as well as DP4+ probability simulations. The proposed biosynthetic pathway suggested 1-3 were generated from unusual L-Phe and D-Ser. All the isolates were evaluated for their cytotoxicity against four tumor cell lines.

Geospallins A⁻C: New Thiodiketopiperazines with Inhibitory Activity against Angiotensin-Converting Enzyme from a Deep-Sea-Derived Fungus Geosmithia pallida FS140.

Three new thiodiketopiperazines, geospallins A⁻C (1⁻3), together with nine known analogues (4⁻12), were isolated from the culture of the deep-sea sediment-derived fungus Geosmithia pallida FS140. Among them, geospallins A and B (1 and 2) represent rare examples of thiodiketopiperazines featuring an S-methyl group at C-10 and a tertiary hydroxyl group at C-11. Their structures were determined by high-resolution electrospray mass spectrometry (HRESIMS), spectroscopic analyses, and electronic circular dichroism (ECD) calculations. Their angiotensin-converting enzyme (ACE) inhibitory activity was reported, and geospallins A⁻C (1⁻3) showed inhibitory activity with IC50 values of 29⁻35 µM.

A new serratene triterpenoid from Lycopodium japonicum.

Phytochemical investigation on the herbs of Lycopodium japonicum led to the isolation of a new serratene triterpenoid, 3α,21α-dihydroxy-16-oxoserrat-14-en-24-yl p-coumarate (1), together with two known ones, lycernuic ketone C (2) and tohogenol (3). Their structures were elucidated by extensive spectroscopic methods, including 1D- and 2D-NMR and HR-ESI-MS. The 13C NMR data of tohogenol was first reported.

Monoterpenes and sesquiterpenes from the marine sediment-derived fungus Eutypella scoparia FS46.

Eutypellol A (1), the first norsesquiterpenoid of sequicarene family, as well as eutypellol B (2), a rare 7-methyl oxidized 2-carene derivative, and one new natural product 2-(2-hydroxy-4-methylcyclohex-3-enyl)propanoic acid (3), along with eight known terpenoids, were isolated from the marine sediment-derived fungus Eutypella scoparia FS46 collected from the South China Sea. Their structures were established on the basis of extensive spectroscopic analysis. Compounds 1-3 were evaluated for their antibacterial activities against Staphylococcus aureus and cytotoxic activities against MCF-7, NCI-H460, and SF-268 tumor cell lines.

Two New Metabolites from the Endophytic Fungus Alternaria sp. A744 Derived from Morinda officinalis.

Two new compounds isobenzofuranone A (1) and indandione B (2), together with eleven known compounds (3-13) were isolated from liquid cultures of an endophytic fungus Alternaria sp., which was obtained from the medicinal plant Morinda officinalis. Among them, the indandione (2) showed a rarely occurring indanone skeleton in natural products. Their structures were elucidated mainly on the basis of extensive spectroscopic data analysis. All of the compounds were evaluated with cytotoxic and α-glucosidase inhibitory activity assays. Compounds 11 and 12 showed significant inhibitory activities against four tumor cell lines; MCF-7, HepG-2, NCI-H460 and SF-268, with IC50 values in the range of 1.91-9.67 µM, and compounds 4, 5, 9, 10, 12 and 13 showed excellent inhibitory activities against α-glucosidase with IC50 values in the range of 12.05-166.13 µM.

[Sesquiterpenoids of endophytic fungus Cerrena sp. from Pogostemon cablin and their cytotoxic activities].

The secondary metabolites of endophytic fungus Cerrena sp.A593 from Pogostemon cablin and their cytotoxic activities were investigated. Eight sesquiterpenoids were isolated from the fermentation broth of the strain A593 by silica gel, reverse phase silica gel, Sephadex LH-20, HPLC and so on. Their structures were identified as chloriolin B(1), chloriolin C(2), pleurocybellone A(3), dihydrohypnophilin(4), cucumin F(5), antrodin A(6), 10α-hydroxyamorphan-4-en-3-one(7), and connatusin A(8). Compounds 1- 8 were firstly found from the genus Cerrena. All isolated sesquiterpenoids were evaluated for in vitro cytotoxic activities against HepG-2, SF-268, MCF-7 and NCI-H460 tumor cell lines. Compounds 1-3 showed inhibitory activities against the four tumor cell lines with IC50 values ranging from 20.33 to 63.13 µmol•L⁻¹.

Dichotocejpins A-C: New Diketopiperazines from a Deep-Sea-Derived Fungus Dichotomomyces cejpii FS110.

Three new diketopiperazines, dichotocejpins A-C (1-3), together with eight known analogues (4-11), were isolated from the culture of the deep-sea sediment derived fungus Dichotomomyces cejpii FS110. Their structures, including absolute configurations, were elucidated by a combination of HRESIMS, NMR, X-ray crystallography, and ECD calculations. Compounds 4-6, 10-11 showed significant cytotoxic activities against MCF-7, NCI-H460, HepG-2, and SF-268 tumor cell lines. Compound 1 exhibited excellent inhibitory activity against α-glucosidase with an IC50 of 138 µM.

Perangustols A and B, a pair of new azaphilone epimers from a marine sediment-derived fungus Cladosporium perangustm FS62.

A pair of new azaphilone epimers, perangustols A-B (1-2), and two new natural products (3-4), together with two known metabolites (5-6) were isolated from the culture of the marine sediment-derived fungus Cladosporium perangustum FS62. The structures of these compounds were established on the basis of extensive spectroscopic analysis. The isolated compounds (1-6) were evaluated for their cytotoxic activities against the SF-268, MCF-7, NCI-H460, and HepG-2 tumor cell lines. Nonetheless, no significant activity was observed.

Two new xyloketals from the endophytic fungus Endomelanconiopsis endophytica derived from medicinal plant Ficus hirta.

Chemical examination of the liquid culture of Endomelanconiopsis endophytica A326 isolated from the Chinese folk medicine Ficus hirta resulted in the isolation of two new xyloketals named xyloketals K and L (1-2) and three known analogs (3-5) including a new natural product (5). Their structures were determined on the basis of extensive spectroscopic analysis. All compounds were evaluated for their cytotoxic activities against the SF-268, MCF-7, NCI-H460, and HepG-2 tumor cell lines. Nonetheless, no significant activity was observed.

Cytotoxic trichothecene macrolides from the endophyte fungus Myrothecium roridum.

A new cytotoxic roridin-type trichothecene macrolide named epiroridin acid (1) and two known compounds epiroridin E (2) and mytoxin B (3) were isolated from the liquid culture of Myrothecium roridum A553, which was isolated from the medicinal plant Pogostemon cablin. The structure of the new macrolide (1) was elucidated by extensive spectroscopic measurements (UV, IR, MS, and 1D and 2D NMR) analyses. All isolated compounds (1-3) were evaluated for their cytotoxic activities against SF-268, MCF-7, NCI-H460, and HepG-2 tumor cell lines. The new compound (1) exhibited well cytotoxicity against the four selected tumor cell lines.

Two New Cinnamyl Isovalerate Derivatives from Sabina gaussenii.

Chemical investigation of the 90% acetone extract of the branches and leaves of Sabina gaussenii led to the isolation of two new cinnamyl isovalerate derivatives (1-2) and eighteen known compounds (3-20). Their structures were determined mainly by means of MS, 1D- and 2D-NMR data, and this is the first time these compounds have been reported from this plant. The biological activity test results indicated that the 90% acetone extract showed cytotoxicity against the human lung adenocarcinoma (A549) cell line (IC50 = 0.98 ± 0.1 µg/mL), compound 6 showed cytotoxicities against human cervical carcinoma (HeLa) (IC50 = 0.4 ± 0.1 µM ) and human gastric carcinoma (BGC-823) (IC50 = 0.9 ± 0.2 µM) cancer cell lines, and compound 19 showed cytotoxicities against HeLa (IC50 = 1.5 ± 0.4 µM), BGC-823 (IC50 = 7.0 ± 0.8 µM ), and A549 (IC50 = 10.6 ± 1.5 µM ) cancer cell lines.

New Cembrane-Type Diterpenoids from the South China Sea Soft Coral Sarcophyton ehrenbergi.

Chemical investigation on the soft coral Sarcophyton ehrenbergi collected from the Xisha Islands of the South China Sea have led to the isolation of eight cembranoids including five new ones, sarcophytonoxides A-E (1-5). The structures of new cembranoids (1-5) were determined by spectroscopic analysis and comparison of the NMR data with those of related analogues. The cytotoxicities of compounds 1-8 against human ovarian cancer cell line A2780 were also evaluated.

Two Trichothecene Mycotoxins from Myrothecium roridum Induce Apoptosis of HepG-2 Cells via Caspase Activation and Disruption of Mitochondrial Membrane Potential.

Trichothecene mycotoxins are a type of sesquiterpenoid produced by various kinds of plantpathogenic fungi. In this study, two trichothecene toxins, namely, a novel cytotoxic epiroridin acid and a known trichothecene, mytoxin B, were isolated from the endophytic fungus Myrothecium roridum derived from the medicinal plant Pogostemon cablin. The two trichothecene mytoxins were confirmed to induce the apoptosis of HepG-2 cells by cytomorphology inspection, DNA fragmentation detection, and flow cytometry assay. The cytotoxic mechanisms of the two mycotoxins were investigated by quantitative real time polymerase chain reaction, western blot, and detection of mitochondrial membrane potential. The results showed that the two trichothecene mycotoxins induced the apoptosis of cancer cell HepG-2 via activation of caspase-9 and caspase-3, up-regulation of bax gene expression, down-regulation of bcl-2 gene expression, and disruption of the mitochondrial membrane potential of the HepG-2 cell. This study is the first to report on the cytotoxic mechanism of trichothecene mycotoxins from M. roridum. This study provides new clues for the development of attenuated trichothecene toxins in future treatment of liver cancer.

Two New Secondary Metabolites from the Endophytic Fungus Endomelanconiopsis endophytica.

Two new secondary metabolites, endomeketals A-B (1-2), a new natural product (3), and a known compound (4) were isolated from the ethyl acetate extract of the endophytic fungus Endomelanconiopsis endophytica A326 derived from Ficus hirta. Their structures were determined on the basis of extensive spectroscopic analysis. All compounds were evaluated for their cytotoxic activities against SF-268, MCF-7, NCI-H460, and HepG-2 tumor cell lines. However, no compound showed cytotoxic activity against these human tumor cell lines.

[Study on cytotoxic secondary metabolites of endophytic fungus Diaporthe longicolla A616 from Pogostemon cablin].

To study active secondary metabolites of endophytic fungus Diaporthe longicolla A616 isolated from Pogostemon cablin. Ten compounds were isolated from fermentation product of the strain 616 by silica gel, reverse phase silica gel, Sephadex-LH20, HPLC and so on. Their structures were identified as 1,3-diamino-1,3-dimethylurea(1),(7R,9R)-7-hydroxy-9-propyl-5-nonen-9-olide(2), Ergosta-5,7,22-trien-3ß-ol(3),(22E,24R)-ergosta-4,6,8(14)-22-tetraen-3-one(4),(22E,24R)-3ß,5α-dihydroxy-6ß-ergosta-7,22-diene(5), citreoisocoumarin(6), glycerol monolinoleate(7), 1-(2-hydroxyethoxy)ethyl(E)-octadec-9-enoate(8), cyclo-(L-Pro-L-Ala)(9), cyclo(L)-Pro-(L)-Val(10), respectively, based on extensive spectroscopic analysis and literature comparisons. Compounds 6-10 were isolated from the genus Diaporthe for the first time. All isolated compounds were evaluated for in vitro cytotoxic activities against SF-268, MCF-7, NCI-H460 and HepG-2 tumor cell lines. Compounds 4 and 5 showed potent growth inhibitory activities against the four cell lines with IC50 values of 5.3, 6.5, 12.2, 6.1µmol•L⁻¹ and 8.2, 5.2, 6.1, 9.4µmol•L⁻¹, respectively.

Isolation and cytotoxicity evaluation of taxanes from the barks of Taxus wallichiana var. mairei.

Fifteen taxanes (1-15) including a new taxane glucoside, 7ß,9α,10ß-triacetoxy-13α-hydroxy-5α-O-(ß-d-glucopyranosyl)taxa-4(20),11-diene (1), were isolated from the barks of Taxus wallichiana var. mairei. Compounds 1-15 representing three sub-types of 6/8/6-taxane were evaluated in vitro for anti-proliferative activity against a panel of parental and drug-resistant cancer cells. Potent compounds were found while several exhibited selective cytotoxicity. Especially, 3, 8, and 10 showed selective inhibition to breast carcinoma cell line MCF-7, while 13 selectively inhibited taxol resistant human ovarian carcinoma cell line A2780/TAX (IC50=0.19µM), being more potent than the clinical drugs taxol (IC50=4.4µM) and docetaxol (IC50=0.42µM), and less cytotoxic to mouse embryonic fibroblast cell line NIH-3T3, a cell line close to normal cell line. The possible P-glycoprotein evasion mechanism of 13 against A2780/TAX and the preliminary structure-activity relationships (SARs) of this group of compounds were also discussed.

Neolignans from Aristolochia fordiana Prevent Oxidative Stress-Induced Neuronal Death through Maintaining the Nrf2/HO-1 Pathway in HT22 Cells.

Bioassay-guided fractionation of the ethanolic extract of the stems of Aristolochia fordiana led to the isolation of six new dihydrobenzofuran neolignans (1-3 and 7-9), three new 2-aryldihydrobenzofurans (4-6), a new 8-O-4' neolignan (10), and 14 known analogues (11-24). The structures of compounds 1-10 were established by spectroscopic methods, and their absolute configurations were determined by analyses of the specific rotation and electronic circular dichroism data. The neuroprotective effects of compounds 1-24 against glutamate-induced cell death were tested in hippocampal neuronal cell line HT22. Compounds 17 and 20-24 exhibited moderate neuroprotective activity by increasing the endogenous antioxidant defense system. In addition, the neolignans activated the Nrf2 (nuclear factor E2-related factor 2) pathway, resulting in the increase of the expression of endogenous antioxidant protein HO-1 (heme oxygenase-1). The active compounds also preserved the levels of antiapoptotic protein Bcl-2 (B cell lymphoma/leukemia-2), which was decreased by glutamate. Collectively, these results suggested that the active neolignans protect neurons against glutamate-induced cell death through maintaining the Nrf2/HO-1 signaling pathway as well as preserving the Bcl-2 protein and might be promising novel beneficial agents for oxidative stress-associated diseases.