Synthesis and potential antidiabetic and lipid-lowering activities of putative asperidine B and its desmethyl analogue.

Putative asperidine B is an unnatural 2,6-disubstituted piperidin-3-ol and a structural isomer of (+)-preussin, a well-known pyrrolidin-3-ol alkaloid. This work reports the first enantioselective synthesis of putative asperidine B and its desmethyl analogue via a chiron approach starting from d-isoascorbic acid as well as evaluation of their free-radical scavenging, antidiabetic, and anti-hyperlipidemic activities. Both putative asperidine B and its desmethyl analogue markedly reduced the total reactive oxygen species (ROS) without cytotoxicity in hepatocellular carcinoma (HepG2) cells. The desmethyl analogue was a potent inducer for two antioxidant gene expression, glutathione peroxidase and superoxide dismutase, whereas putative asperidine B only induced superoxide dismutase. In addition, putative asperidine B exerted potent antidiabetic activity via α-glucosidase inhibition (IC50 = 0.143 ± 0.001 mg/mL) comparable to that of acarbose, an antidiabetic drug. Consistent with the parent asperidine B (preussin), both putative asperidine B and its desmethyl analogue inhibited cholesterol absorption in the intestinal Caco-2 cells. These novel and promising antioxidant, antidiabetic, and lipid-lowering effects of piperidin-3-ols could offer a starting point for this class of compounds for obesity and diabetic drug discovery.

Direct synthesis of tetrahydropyran-4-ones via O3ReOH-catalyzed Prins cyclization of 3-chlorohomoallylic alcohols.

A new variation of Prins cyclization to directly and stereoselectively synthesize cis-2,6-disubstituted tetrahydropyran-4-ones from 3-chlorohomoallylic alcohols and aldehydes catalyzed by perrhenic acid is reported. The reaction is generally compatible with a range of aliphatic and aromatic aldehydes and 24 examples of tetrahydropyran-4-one products have been prepared in moderate to good yields. This methodology highlights the use of simple starting materials and commercially available aqueous perrhenic acid as a catalyst for Prins cyclization reactions to directly synthesize 2,6-disubstituted tetrahydropyran-4-ones.

Cholesterol-Lowering Effects of Asperidine B, a Pyrrolidine Derivative from the Soil-Derived Fungus Aspergillus sclerotiorum PSU-RSPG178: A Potential Cholesterol Absorption Inhibitor.

Isolated secondary metabolites asperidine B (preussin) and asperidine C, produced by the soil-derived fungus Aspergillus sclerotiorum PSU-RSPG178, were found to exhibit inhibitory effects against 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase and oxidative stress in an in vitro assay. Whether or not the known pyrrolidine asperidine B and the recently isolated piperidine asperidine C have lipid-lowering effects remains unknown. Thus, this study aimed to investigate the hypocholesterolemic effects of asperidines B and C and identify the mechanisms involved in using in vitro, ex vivo, and in vivo models. The results show that both compounds interfered with cholesterol micelle formation by increasing bile acid binding capacity, similar to the action of the bile acid sequestrant drug cholestyramine. However, only asperidine B, but not asperidine C, was found to inhibit cholesterol uptake in Caco-2 cells by up-regulating LXRα without changing cholesterol transporter NPC1L1 protein expression. Likewise, reduced cholesterol absorption via asperidine-B-mediated activation of LXRα was also observed in isolated rat jejunal loops. Asperidine B consistently decreases plasma cholesterol absorption, similar to the effect of ezetimibe in rats. Therefore, asperidine B, the pyrrolidine derivative, has therapeutic potential to be developed into a type of cholesterol absorption inhibitor for the treatment of hypercholesterolemia.

Total Synthesis and Biological Evaluation of Mutolide and Analogues.

The convergent total syntheses of three 14-membered macrolide natural products, mutolide, nigrosporolide and (4S,7S,13S)-4,7-dihydroxy-13-tetradeca-2,5,8-trienolide have been achieved. The key synthetic features include Shiina macrolactonization to assemble the 14-membered macrocyclic core, Wittig or Still-Gennari olefination and selective reduction of propargylic alcohol to construct the E- or Z-olefins. Cross metathesis was also highlighted as an efficient tool to forge the formation of E-olefin. The three synthetic macrolides were evaluated for their cytotoxic activity against three human cancer cell lines as well as for inhibitory effect on CFTR-mediated chloride secretion in human intestinal epithelial (T84) cells. Mutolide displayed significant cytotoxic activity against HCT116 colon cancer cells with an IC50 of ∼12 µM as well as a potent CTFR inhibitory effect with an IC50 value of ∼1 µM.

Unified synthesis and cytotoxic activity of 8-O-methylfusarubin and its analogues.

A simple and unified synthesis of four related pyranonaphthoquinone natural products, e.g. 8-O-methylfusarubin, 8-O-methylanhydrofusarubin, fusarubin and anhydrofusarubin, is reported. The key synthetic features include the precedented Diels-Alder cycloaddition to assemble the naphthalene skeleton, selective formylation and acetonylation and intramolecular acetalization to construct the pyran ring. Manipulation of the oxidation state of the naphthoquinone core was performed to construct the two analogues, fusarubin and anhydrofusarubin. This work also highlights an unprecedented directing effect of the hydroxymethylene group in the selective hypervalent iodine-mediated quinone oxidation. The four synthetic compounds were evaluated for their in vitro cytotoxic activities against six human cancer cells. 8-O-Methylfusarubin was the most potent analogue and displayed excellent cytotoxic activity against MCF-7 breast cancer cells with an IC50 value of 1.01 µM with no cytotoxic effect on noncancerous Vero cells, which could potentially be a promising lead compound for anti-breast cancer drug discovery.

A fungal metabolite zearalenone as a CFTR inhibitor and potential therapy of secretory diarrheas.

Overstimulation of CFTR-mediated Cl- secretion plays an important role in the pathogenesis of secretory diarrheas, which remain an important global health problem. This study aimed to identify inhibitors of CFTR-mediated Cl- secretion from a library of fungus-derived compounds and to evaluate their pharmacological properties and anti-diarrheal utility. We identified zearalenone, 7'-dehydrozearalenone and 8'-hydroxyzearalenone isolated from the seagrass-derived fungus Fusarium sp. PSU-ES123 as inhibitors of CFTR-mediated Cl- secretion in human intestinal epithelial (T84) cells. Being the most potent fungal metabolite capable of inhibiting CFTR-mediated Cl- secretion, zearalenone reversibly inhibited CFTR Cl- channel activity in T84 cells with an IC50 of ∼0.5 µM. Functional and biochemical analyses and molecular docking studies indicate that zearalenone binds to the ß-estradiol binding sites in the ATP-binding pockets on NBD1 and NBD2 of CFTR. Mechanisms of CFTR inhibition by zearalenone do not involve activation of phosphodiesterases, protein phosphatases, multidrug-resistance protein 4 and AMP-activated protein kinases. Importantly, zearalenone significantly inhibited cholera toxin (CT)-induced Cl- secretion in T84 cells and blocked CT-induced intestinal fluid secretion in mice. Collectively, our study indicates that zearalenone represents the first class of fungus-derived CFTR inhibitors. Further development of this class of compounds may provide an effective treatment of secretory diarrheas.

γ-Butenolide and furanone derivatives from the soil-derived fungus Aspergillus sclerotiorum PSU-RSPG178.

Chromatographic separation of the broth extract of the soil-derived fungus Aspergillus sclerotiorum PSU-RSPG178 resulted in isolation of four γ-butenolide-furanone dimers, aspersclerotiorones A-D, a furanone derivative, aspersclerotiorone E, and two γ-butenolide derivatives, aspersclerotiorones F and G, together with six known compounds, penicillic acid, dihydropenicillic acid, 5,6-dihydro-6-hydroxypenicillic acid, 6-methoxy-5,6-dihydropenicillic acid, coculnol and (4R,5R)-4,5-dihydroxy-3-methoxy-5-methylcyclohex-2-en-1-one. Their structures were determined by spectroscopic evidence. For aspersclerotiorones A and B, the structures were confirmed by single-crystal X-ray diffraction crystallography. Penicillic acid displayed weak antibacterial activity against Staphylococcus aureus and Escherichia coli with equal MIC values of 128 µg/mL, and it was noncytotoxic towards African green monkey kidney fibroblast cells.

Synthesis and cytotoxic activities of semisynthetic zearalenone analogues.

Zearalenone is a ß-resorcylic acid macrolide with various biological activities. Herein we report the synthesis and cytotoxic activities of 34 zearalenone analogues against human oral epidermoid carcinoma (KB) and human breast adenocarcinoma (MCF-7) cells as well as noncancerous Vero cells. Some zearalenone analogues showed moderately enhanced cytotoxic activities against the two cancer cell lines. We have discovered the potential lead compounds with diminished or no cytotoxicity to Vero cells. Preliminary structure-activity relationship studies revealed that the double bond at the 1' and 2' positions of zearalenone core was crucial for cytotoxic activities on both cell lines. In addition, for zearalenol analogues, the unprotected hydroxyl group at C-2 and an alkoxy substituent at C-4 played key roles on cytotoxic effects of both cell lines.

Tetrahydroanthraquinone and xanthone derivatives from the marine-derived fungus Trichoderma aureoviride PSU-F95.

Trichodermaquinone (1) and trichodermaxanthone (2) were isolated from the marine-derived fungus Trichoderma aureoviride PSU-F95 together with eleven known compounds. The structures were interpreted by spectroscopic methods. Known coniothranthraquinone 1 and emodin displayed strong antibacterial activity against methicillin-resistant Staphylococcus aureus with the MIC values of 8 and 4 µg/mL, respectively.

Symmetric macrocycles by a Prins dimerization and macrocyclization strategy.

A tandem dimerization/macrocyclization reaction utilizing the Prins cyclization has been developed. This reaction develops molecular complexity through the formation of highly substituted dimeric tetrahydropyran macrocycles. Mild conditions utilizing rhenium(VII) catalysts were explored for aromatic substrates, while harsher Lewis acidic conditions were used for aliphatic substrates. Both aldehydes and acetals are shown to be viable substrates for this reaction.

Rhenium(VII) catalysis of Prins cyclization reactions.

The rhenium(VII) complex O3ReOSiPh3 is a particularly effective catalyst for Prins cyclizations using aromatic and alpha,beta-unsaturated aldehydes. The reaction conditions are mild, and the highly substituted 4-hydroxytetrahydropyran products are formed stereoselectively. Rhenium(VII) complexes appear to spontaneously form esters with alcohols and to directly activate electron-rich alcohols for solvolysis. Re2O7 and perrhenic acid are equally effective in catalyzing these cyclizations.

Benzopyran, biphenyl, and tetraoxygenated xanthone derivatives from the twigs of Garcinia nigrolineata.

One new benzopyran, nigrolineabenzopyran A (1), two new biphenyls, nigrolineabiphenyls A and B (2, 3), and four new tetraoxygenated xanthones, nigrolineaxanthones T-W (4-7), were isolated from the crude methanol extract of the twigs of Garcinia nigrolineata along with 11 known xanthones. The xanthones isolated from the twigs as well as those from the stem bark were evaluated for antibacterial activity against methicillin-resistant Staphylococcus aureus. Nigrolineaxanthone F, latisxanthone D, and brasilixanthone showed significant activity, with an equal MIC value of 2 microg/mL.