New α-pyrone and phthalide from the Xylariaceae fungus

A new α-pyrone xylaripyrone A (1) and a new phthalide xylariphthalide A (2) were isolated from the Xylariaceae fungus (no. 63-19-7-3), along with four related known phthalides (3–6): 4-[(acetyloxy)methyl]-7-methoxy-6-methyl-1(3H)-isobenzofuranone (3), convolvulol (4), 7-methoxy-4,6-dimethyl-3H-isobenzofuran-1-one (5), and convolvulanic acid B (6). Their structures were determined on the basis of IR, MS, and NMR spectroscopic analyses.     

A new compound from an endophytic fungus Bambusicola massarinia

One new chromone, rel-(1S,2S,3S)-2,8-dihydroxy-6-methoxy-1,3-dimethyl-3,4-dihydro-1H-xanthen-9(2H)-one (1), together with one known compound wentiquinone A (2), were isolated from solid culture of endophytic fungus strain Bambusicola massarinia. The structures of all compounds were determined mainly by analysis of their NMR spectroscopic data. The relative configuration of compound 1 was determined by the single-crystal X-ray diffraction analyses.     

Sesquiterpenoids from Ferula fukanensis and their inhibitory effects on nitric oxide production

Six sesquiterpene derivatives, 2,3-dihydro-7-methoxy-2S*, 3R*-dimethyl-2-[4,8-dimethyl-3(E),7-nonadienyl]furo[3,2-c]coumarin (1) and 2,3-dihydro-7-methoxy-2R*,3R*-dimethyl-2-[4,8-dimethyl-3(E),7-nonadienyl]furo[3,2-c]coumarin (2), nerolidol (3), 1-(2,4-dihydroxyphenyl)-3,7,11-trimethyl-3-ninyl-6(E),10-dodecadien-1-one (4), 1-(2,4-dihydroxyphenyl)-3,7-dimethyl-3-vinyl-8-(4-methyl-2-furyl)-6(E)-octen-1-one (5) and dshamirone (6) were isolated from an 80% aqueous methanol extract of the roots of Ferula fukanensis. The sesquiterpenoids inhibited nitric oxide (NO) production and inducible NO synthase gene expression by a murine macrophage-like cell line (RAW 264.7) [1], which was activated by lipopolysaccharide and recombinant mouse interferon-.     

Two new lignans from Phyllanthus amarus

Two new lignans, 3-(3,4-dimethoxy-benzyl)-4-(7-methoxy-benzo[1,3]dioxol-5-yl-methyl)-dihydrofuran-2-one (1) and 4-(3,4-dimethoxy-phenyl)-1-(7-methoxy-benzo[1,3]dioxol-5-yl)-2,3-bis-methoxymethyl-butan-1-ol (2), were isolated from the leaves of Phyllanthus amarus and their structures were established by spectral analysis. Additionally, eight known lignans were also isolated and characterized.     

Dihydroayapin,a New Coumarin Compound from Dendrobium Densiflorum

Abstract

A new coumarin named dihydroayapin (1) together with seven known compounds were isolated from the stems of Dendrobium densiflorum. On the basis of physicochemical and spectral evidences, the structure of 1 was established as 6,7-methylenedioxy-3,4-dihydrobenzopyran-2-one.     

Two new isoprenyl chalcones from Hedysarum gmelinii

Two new isoprenyl chalcones, 1-[2,4-dihydroxy-3-(2-hydroxy-3-methyl-3-butenyl)phenyl]-3-(2,2-dimethyl-2H-benzopyran-6-yl)-2-propen-1-one (1) and 1-[4-hydroxy-2-(1-hydroxy-1-methyl-ethyl)-2,3-dihydro-benzofuran-5-yl]-3-[3-(3-methyl-2-butenyl)-4-hydroxy-phenyl]-2-propen-1-one (2), named hedysarumine A and hedysarumine B, along with a known isoprenyl chalcone paratocarpin E (3) were isolated from the roots of Hedysarum gmelinii for the first time. Their structures were elucidated based on NMR and MS spectral analyses.     

Three new alkaloids from the seeds of Nigella glandulifera

Three new alkaloids namely 8-(4-hydroxyphenyl)-6-methoxy-3,4-dihydroisoquinolin-1(2H)-one (1), 4-aminonigellidine (2), and N-[(4-hydroxy-2-isopropyl-5-methyl)]phenylurea (3), along with six known ones (4–9), were isolated from the seeds of Nigella glandulifera. The structures of 1–3 were determined through spectroscopic analyses (HRESIMS, 1D/2D NMR). Compound 1 was a rare isoquinolinone alkaloid with phenyl substituted at C-8.     

A novel 3,4-dihydronaphthalen-1(2H)-one with spiro-butyrolactone and a new isocoumarin isolated from the endophytic fungus Phoma sp. YN02-P-3

A novel 3,4-dihydronaphthalen-1(2H)-one with spiro-butyrolactone phomol (1) and a new isocoumarin phomasatin (2), together with two known compounds (3–4) were isolated from the solid culture of the endophytic fungus Phoma sp. YN02-P-3. Their structures including the absolute configurations were characterized on the basis of extensive 1D, 2D NMR (HSQC, HMBC, NOESY), MS, and CD spectral data. Compound 1 showed selective cytotoxic activity against HL-60 cell line with the IC₅₀ value of 29.05 μM.     

Chemical constituents from the culture of the fungus Hericium alpestre

Two new compounds herialpins A–B (1–2), along with eleven known compounds, were isolated from the culture of fungus Hericium alpestre. The structures were elucidated by 1D and 2D NMR data, ESI-MS and X-ray crystallographic analysis. Compounds 1–2 were assayed for their cytotoxicity against three tumor cell lines compared with the known compound 3. Compounds 1 and 2 were found with modest activity, while compound 3 exhibits stronger selective inhibitory activity against A549 and HT-29 cells with IC₅₀ values of 15.1 and 20.1 μmol/L, respectively. The pyrano[3,4-g]chromene-4,6-dione moiety in compound 3 should be responsible for the stronger selective inhibitory activity.     

Prenylated xanthones: antiproliferative effects and enhancement of the growth inhibitory action of 4-hydroxytamoxifen in estrogen receptor-positive breast cancer cell line

The effects of three prenylated xanthones on the in vitro growth of estrogen-dependent ER (+) MCF-7 (breast), estrogen-independent ER (−) MDA-MB-231 cells (breast), and NCI-H460 (non-small cell lung) were investigated in a complete and/or steroid-free medium. 3,4-Dihydro-12-hydroxy-2,2-dimethyl-2H,6H-pyrano[3,2-b]xanthen-6-one (4), the most potent against the ER(+) MCF-7 cell line (GI₅₀ = 5 μM), showed an enhancement in the anti-estrogenic effect of 4-hydroxytamoxifen in this ER(+) cell line.     

Four homoisoflavonoids isolated from traditional Chinese medicine: “Gan Luo Xin”

Two new homoisoflavonoids, ( ± )-5,7-dihydroxy-8-methyl-3-(2′,4′-dihydroxybenzyl) chroman-4-one (1) and ( ± )-5,7-dihydroxy-6,8-dimethyl-3-(2′,4′-dihydroxybenzyl) chroman-4-one (2), along with two known homoisoflavonoids, 5,7-dihydroxy-6-methyl-3-(2′,4′-dihydroxybenzyl)chroman-4-one (3) and disporopsin (4), were isolated from the EtOAc extract of traditional Chinese medicine – “Gan Luo Xin.” Their structures were determined on the basis of spectroscopic analysis (UV, IR, HR-ESI-MS, 1D NMR, and 2D NMR).     

Two new polyprenylated acylphloroglucinols from Hypericum scabrum

Two new polyprenylated acylphloroglucinols, (1S,32R,5S,6R,7R)-6-((R)-3,4-di-hydroxy-4-methylpentyl)-2-(2-hydroxypropan-2-yl)-7-isobutyryl-6-methyl-5,9-bis(3-methylbut-2-en-1-yl)-4,5,6,7-tetrahydro-2H-32,7-methanocycloocta[b]furan-8,10(3H)-dione (1) and (4R,5R,7R)-4-((R)-3,4-dihydroxy-4-methylpentyl)-2,2,4-trimethyl-5,7-bis(3-methyl-but-2-en-1-yl)-7-(5-methylhex-4-enoyl)-4,5,6,7-tetrahydrobenzofuran-3(2H)-one (2) were isolated from Hypericum scabrum. The structures were elucidated by means of spectroscopic methods, including MS, IR, NMR, OR, and CD.     

Two new acorane sesquiterpenes from <Emphasis Type="Italic">Illicium henryi</Emphasis>

Two new acorane sesquiterpenes, 10-hydroxyacoronene (1) and 1β-isopropyl-4β-methyl-9β-hydroxy spiro[4.5]dec-6-en-8-one (2), one new natural product, 4-hydroxy-4, 6-dimethyl-1-tetralone (3), and one known acorane sesquiterpene, acoradiepoxide (4) were isolated from the twigs and leaves of Illicium henryi. The structures of the new compounds were elucidated primarily on the basis of analysis of spectroscopic data. In addition, the inhibitory effect on NO production of these compounds were tested. Compounds 1 and 4 exhibited slight inhibitory effects on NO production with IC₅₀ values of 82.4 μg/mL and 76.5 μg/mL, respectively.     

Carboxymethyl flavonoids and a monoterpene glucoside from <Emphasis Type="Italic">Selaginella moellendorffii</Emphasis>

A new dihydroflavone, 5-carboxymethyl-7,4′-dihydroxyflavonone (1), and its glucoside 5-carboxymethyl-7,4′-dihydroxyflavonone-7-O-β-d-glucopyranoside (2), and one new monoterpene glucoside, (4Z,6E)-2,7-dimethyl-8-hydroxyocta-4,6-dienoic acid 8-O-β-d-glucopyranoside (3), were isolated from the whole plants of Selaginella moellendorffii. Their structures were determined by spectroscopic methods and chemical transformation. Compound 2 was evaluated for the ability to enhance glucose consumption in normal and insulin-resistant L6 muscle cells induced by high concentrations of insulin and glucose. Glucose consumption in insulin-resistant cells (but not in normal cells) was increased 15.2 ± 3.3% (p < 0.01) by compound 2 at a concentration of 0.1 μM in the presence of insulin (1 nM).     

Pyrido[3,4-d]pyrimidin-4(3H)-one metabolism mediated by aldehyde oxidase is blocked by C2-substitution

1.?We have previously described C8-substituted pyrido[3,4-d]pyrimidin-4(3H)-one derivatives as cell permeable inhibitors of the KDM4 and KDM5 subfamilies of JmjC histone lysine demethylases.

2.?Although exemplar compound 1 exhibited moderate clearance in mouse liver microsomes, it was highly cleared in vivo due to metabolism by aldehyde oxidase (AO). Similar human and mouse AO-mediated metabolism was observed with the pyrido[3,4-d]pyrimidin-4(3H)-one scaffold and other C8-substituted derivatives.

3.?We identified the C2-position as the oxidation site by LC-MS and ¹H-NMR and showed that C2-substituted derivatives are no longer AO substrates.

4.?In addition to the experimental data, these observations are supported by molecular modelling studies in the human AO protein crystal structure.     

Geraniinic acid derivative from the leaves of Phyllanthus reticulatus

Chemical constituents as well as cytotoxic and insecticidal activity of the crude methanol extract from the leaves of Phyllanthus reticulatus Poir. (Euphorbiaceae) were investigated. (5R*,6R*)-4,6-Dimethoxycarbonyl-5-[2′,3′,4′-trihydroxy-6′-(methoxycarbonyl) phenyl]-5,6-dihydro-2H-pyran-2-one (1) along with 3,4,3′-tri-O-methylellagic acid, and methyl gallate were isolated from the dichloromethane extract. Determination of their structures was based on spectroscopic analysis. Compound 1 possessed a very weak insecticidal activity against Spodoptera frugiperda (Sf9) with an IC₅₀ value of 27.27?μg/mL.     

Synthesis and anti-HIV activity of 4-[(1,2-dihydro-2-oxo-3H-indol-3-ylidene) amino]-N(4,6-dimethyl-2-pyrimidinyl)-benzene sulfonamide and its derivatives

4-[(1,2-Dihydro-2-oxo-3H-indol-3-ylidene) amino]-N(4,6-dimethyl-2-pyrimidinyl)-benzene sulphonamide and its derivatives were synthesized by reaction of isatin and its derivatives with sulphadimidine. Their chemical structures have been confirmed by IR, ¹H NMR data and elemental analysis. Investigation of anti-HIV activity of compounds were tested against replication of HIV-1 (IIIB) and HIV-2 (ROD) strains in acutely infected MT-4 cells and the activity compared with standard azidothymidine. Among the compounds tested, 4-[(1,2-dihydro-2 oxo-3H-indol-3-ylidene)amino]-N(4,6-dimethyl-2-pyrimidinyl)-benzene sulphonamide and its N-acetyl derivative were the most active compounds.     

A new chromone and a new aliphatic ester isolated from Daldinia eschscholtzii

Abstract

A new chromone and a new aliphatic ester were isolated from the EtOAc extract of myceliums of Daldinia eschscholtzii. Their structures were elucidated as (R)-5-hydroxy-8-methoxy-2-methylchroman-4-one (1) and (E)-6-(non-3-en-1-yl) -2H-pyran-2-one (2) by interpretation of the spectroscopic evidence.     

Application of structure–metabolism relationships in the identification of a selective endothelin A antagonist,BMS-193884, with favourable pharmacokinetic properties

1.?Based on binding affinity, 2′-amino-N-(3,4-dimethyl-5-isoxazolyl)-4′-(2-methylpropyl)[1,1′-biphenyl]-2-sulfonamide (2) was identified as an initial lead in a programme to identify selective endothelin (ET) receptor antagonists. However, the compound was extensively metabolized in preclinical animal species and human in vitro systems due to oxidative biotransformation.

2.?To optimize this structural class, the site of metabolism of 2 was determined. This allowed for focussed structure–activity and structure–metabolism studies aimed at finding more metabolically stable analogues that maintained potency. New analogues were screened for their ET binding characteristics and their stability in rat and human liver microsomes.

3.?The use of the microsomal stability screen was tested by the determination of the pharmacokinetic parameters of select analogues. A good correlation was found between reduced rates of rat microsomal metabolism and reduced clearance in the rat.

4.?N-(3,4-dimethyl-5-isoxazolyl)-4′-(2-oxazolyl)[1,1′-biphenyl]-2-sulfonamide (3) was identified as an analogue with improved in vitro properties and further studies revealed that the compound had improved pharmacokinetic properties.

5.?N-[[2′-[[(3,4-dimethyl-5-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1′-biphenyl]-2-yl]methyl]acetamide (4) was subsequently identified as a compound with superior in vitro properties compared with compound 3, but when tested in vivo it had a substantially increased rate of clearance. Further studies demonstrated that the clearance of this closely related structural analogue was not dictated by metabolic processes, but was mediated by transport-mediated direct biliary excretion.

6.?The utility of screening for in vitro liver microsomal stability as part of the lead optimization process for compounds with metabolic liabilities was shown. It was also shown that relatively small molecular changes can dramatically change the disposition of closely related analogues and care must be used when screening for a single property.     

Manuifolin Q,an unusual 4-aryl-substituted isoflavan from Maackia tenuifolia

Manuifolin Q (1), an unusual 4-aryl-substituted isoflavan, was isolated from the roots of Maackia tenuifolia. Its absolute configuration was determined as (3R,4R)-3,4-trans-7,2′-dihydroxy-4′-methoxy-4-[(2,4-dihydroxy-5-(1,1-dimethyl-2-propenyl)]-phenyl-isoflavan, on the basis of spectroscopic analysis.