Synthesis of methyl ether analogues of sildenafil (Viagra) possessing tyrosinase inhibitory potential

The microwave-assisted synthesis and characterization of the ten new sildenafil (Viagra; 1) analogues 6-15 are described. A detailed structure-activity-relationship (SAR) study revealed that compounds 10 (= 4-ethoxy-N-hydroxy-3-(7-methoxy-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzenesulfonamide) and 12 (= S-(2-hydroxyethyl) 4-ethoxy-3-(7-methoxy-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzenesulfonothioate) are extremely potent mushroom tyrosinase inhibitors, with IC50 values (3.59 and 2.15 microM, resp.) below those of the standard inhibitors L-mimosine and kojic acid (IC50 = 3.68 and 16.67 microM, resp.). Compounds 10 and 12 are, thus, the currently most-effective inhibitors of tyrosinase, and bear great potential to be used for the treatment of various skin disorders such as hyperpigmentation, which is associated with high production of melanocytes.     

Antioxidant, cyclooxygenase and topoisomerase inhibitory compounds from Apium graveolens Linn. seeds

Cyclooxygenase inhibitory and antioxidant bioassay-directed extraction and purification of celery seeds yielded sedanolide (1), senkyunolide-N (2), senkyunolide-J (3), 3-hydroxymethyl-6-methoxy-2,3-dihydro-1H-indol-2-ol (4), L-tryptophan (6), and 7-[3-(3,4-dihydroxy-4-hydroxymethyl-tetrahydro-furan-2-yloxy)-4,5-dihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy]-5-hydroxy-2-(4-hydroxy-3-methoxy-phenyl)-chromen-4-one (7). The structures of compounds 1-7 were determined using spectroscopic methods. Compound 4 is reported here for the first time. At 250 pg ml(-1), compounds 1-4, 6 and 7 displayed prostaglandin H endoperoxide synthase-I (COX-I) and prostaglandin H endoperoxide synthase-II (COX-II) inhibitory activities at pH 7. The acetylated product (5) of compound 4 also inhibited COX-I and COX-II enzymes when tested at 250 microg ml(-1). Compounds 6 and 7 exhibited good antioxidant activity at concentrations of 125 and 250 microg ml(-1). Only compounds 1-3 exhibited topoisomerase-I and -II enzyme inhibitory activity at concentrations of 100, 200 and 200 microg ml(-1), respectively.     

New bisabolane sesquiterpenes and coumarin from Leontopodium longifolium

From the roots of Leontopotium longifolium, three new bisabolane sesquiterpenes, rel-(1S,4R,5S,6R)-4,5-diacetoxy-6-[(R)-1,5-dimethylhexa-3,5-dienyl]-3-methylcyclohex-2-enyl (Z)-2-methylbut-2-enoate (1), rel-(1S,4R,5S,6R)-4,5-diacetoxy-6-[(R)-5-hydroxy-1,5-dimethylhex-3-enyl]-3-methylcyclohex-2-enyl (Z)-2-methylbut-2-enoate (2), rel-(1R,2S,4R,5S)-4-acetoxy-2-[(R)-5-hydroxy-1,5-dimethylhex-3-enyl]-5-methylcyclohexyl (Z)-2-methylbut-2-enoate (3), and a new coumarin, 2,3-dihydro-5-hydroxy-2-(1-methylethenyl)-7H-pyrano[2,3-g][1,4]benzodioxin-7-one (4) together with nine known compounds have been isolated. The structures of these compounds were established by spectroscopic methods. Compounds 1 and 2 exhibited moderate cytotoxic activities against human promyelocytic leukemia (HL-60) cells.     

山竺果壳的化学成分

从山竺（Garcinia mangostana）果壳中分离得到6个化合物,通过MS,1D NMR以及与文献对照鉴定它们为4个[口山]酮类化合物：α-rnangostin（1）,β-mangostin（2）,γ-mangostin（3）,5,9-dihydroxy-8-methoxy-2,2-dimethyl-7-（3-methylbut-2-envl）-2H,6H-pyrano-[3,2-b]-xanthen-6-one（4）,以及表儿茶素（epicatechin,5）和一个双苄类化合物egonol（6）。其中化合物5和化合物6为首次从该植物中分离得到。对化合物1～5进行抗HIV-1 RT活性筛选结果表明,化合物2和化合物5在浓度200μg/ml的条件下,其对HIV-1 RT抑制率分别为41．97％和47．72％;同一实验结果显示化合物1,3和4没有抑制HIV-1 RT作用。     

Synthesis, antimycobacterial and antitumor activities of new (1,1-dioxido-3-oxo-1,2-benzisothiazol-2(3H)-yl)methyl N,N-disubstituted dithiocarbamate/O-alkyldithiocarbonate derivatives

Reaction of 2-chloromethylsaccharin with substituted potassium dithiocarbamates and substituted potassium dithiocarbonates furnished (1,1-dioxido-3-oxo-1,2-benzisothiazol-2(3H)-yl)methyl N,N-disubstituted dithiocarbamates (4-15) and (1,1-dioxido-3-oxo-1,2-benzisothiazol-2(3H)-yl)methyl O-alkyldithiocarbonates (16-20). The new derivatives were evaluated for in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv. Compounds 4-13, 15, and 16-20 described herein showed moderate to good inhibitory activity. In particular, seven analogs 4, 5, 6, 13, and 7, 8, and 12 exhibited excellent MIC values of 1.56 and 0.78 microg/mL, respectively. Compounds 4, 5, 10, 12, 13, and 16 were selected and screened for antitumor activity. Among the tested compounds, 4 and 5 were found to be cytotoxic, especially against leukemia cell lines CCRF-CEM, HL-60(TB), RPMI-8226, and SR with log10GI50 values lower than -6.69, and against non-small cell lung cancer NCI-H522 cell line with log10GI50 values lower than -6.31. Compound 10 was cytotoxic against leukemia cell line HL-60(TB), whereas 16 displayed favorable cytotoxicity against ovarian cancer cell line OVCAR-3 with log10GI50 values of -6.31 and -7.45, respectively.     

Synthesis of imidazoline and imidazo[2,1-c][1,2,4]triazole aryl derivatives containing the methylthio group as possible antibacterial agents

1-Arylimidazolidine-2-thiones (1a-g) were synthesized by the condensation reaction of N-arylethylenediamines with carbon disulfide in xylene medium. Their further alkylation with methyl iodide led to the formation of some biologically active 1-aryl-2-methylthio-imidazolines (2a-g). The 7-(4-methylphenyl)-3-methylthio-5H-6,7-dihydroimidazo[2,1-c][1,2,4]triazole (4b) was obtained by the alkylation of the respective 7-(4-methylphenyl)-2,5,6,7-tetrahydroimidazo[2,1-c][1,2,4]triazol-3(H)-thione (3b) with methyl iodide. Antimicrobial activities of 1-aryl-2-methylthio-imidazolines (2a-g) and the 7-(4-methylphenyl)-3- methylthio-5H-6,7-dihydroimidazo[2,1-c][1,2,4]triazole (4b) are presented. All tested compounds showed MIC in the range of 11.0-89.2 microM. Compounds 2a,e were found to be equipotent to chloramphenicol in vitro, whereas 2a,c,e-g and 4b showed superior activity (MIC) to ampicillin.     

3,4-Dihydronaphthalen-1(2H)-ones: novel ligands for the benzodiazepine site of alpha5-containing GABAA receptors

A series of substituted 3,4-dihydronaphthalen-1(2H)-ones with high binding affinity for the benzodiazepine site of GABAA receptors containing the alpha5-subunit has been identified. These compounds have consistently higher binding affinity for the GABAA alpha5 receptor subtype over the other benzodiazepine-sensitive GABAA receptor subtypes (alpha1, alpha2 and alpha3). Compounds with a range of efficacies for the benzodiazepine site of alpha5-containing GABAA receptors were identified, including the alpha5 inverse agonist 3,3-dimethyl-8-methylthio-5-(pyridin-2-yl)-3,4-dihydronaphthalen-1(2H)-one 22 and the alpha5 agonist 8-ethylthio-3-methyl-5-(1-oxidopyridin-2-yl)-3,4-dihydronaphthalen-1(2H)-one 19.     

Clitolactone: a banana slug antifeedant from Clitocybe flaccida

Clitolactone, 5-(chloromethyl)-3-methyl-2(5H)-furanone, was isolated from sporocaps of the mushroom Clitocybe flaccida. The structure was determined by HRMS, EIMS, (1)H & (13)C NMR, 2D (1)H-(13)C COSY and (1)H-(1)H COSY. This mushroom is not eaten by the banana slug Ariolimax columbianus (Gould), a mycophagist from the temperate rain forests of the Pacific Northwest. Clitolactone acts as an antifeedant because these slugs rejected 1.0 cm(2) pieces of lettuce treated with 25 μg of clitolactone.     

Two novel C29-5beta-sterols from the stems of Opuntia dillenii

Two novel C29-5beta-sterols, opuntisterol [(24R)-24-ethyl-5beta-cholest-9-ene-6beta,12alpha-diol] (1) and opuntisteroside [(24R)-24-ethyl-6beta-[(beta-d-glucopyranosyl)oxy]-5beta-cholest-9-ene-12alpha-ol] (2), together with nine known compounds, beta-sitosterol (3), taraxerol (4), friedelin (5), methyl linoleate (6), 7-oxositosterol (7), 6beta-hydroxystigmast-4-ene-3-one (8), daucosterol (9), methyl eucomate (10) and eucomic acid (11), were isolated from the stems of Opuntia dillenii collected in Guizhou Province, China. Their structures were elucidated mainly by spectroscopic analysis. The absolute configuration of 1 were deduced from comparative 1H NMR data of the (S)- and (R)-methoxyphenyl acetate derivatives. Compounds 6-8, 10 and 11 were isolated from O. dillenii for the first time.     

Biosynthetic studies on the alpha-glucosidase inhibitor acarbose: the chemical synthesis of isotopically labeled 2-epi-5-epi-valiolone analogs

2-epi-5-epi-valiolone is a cyclization product of the C(7) sugar phosphate, sedoheptulose 7-phosphate, involved in the biosynthesis of the aminocyclitol moieties of acarbose, validamycin, and pyralomicin. As part of our investigation into the pathway from 2-epi-5-epi-valiolone to the valienamine moiety of acarbose, we prepared 1-epi-5-epi-(6-(2)H(2))valiolol [(6-(2)H(2))-6], 5-epi-(6-(2)H(2))valiolol [(6-(2)H(2))-17], 1-epi-2-epi-5-epi-(6-(2)H(2))valiolol [(6-(2)H(2))-12] and 2-epi-5-epi-(6-(2)H(2))valiolamine [(6-(2)H(2))-11]. Compounds (6-(2)H(2))-6 and (6-(2)H(2))-17 were synthesized from 2,3,4,6-tetra-O-benzyl-D-glucopyranose in 10 and seven steps, respectively, whereas (6-(2)H(2))-12 and (6-(2)H(2))-11 were synthesized from 2,3,4,6-tetra-O-benzyl-D-mannopyranose in eight and 10 steps, respectively.     

Potential anti-allergic ent-kaurene diterpenes from the bark of Suregada multiflora

Two ent-kaurene diterpenes, ent-16-kaurene-3beta,15beta,18-triol (1) and ent-3-oxo-16-kaurene-15beta,18-diol (2), were isolated from a dichloromethane extract of the bark of Suregada multiflora along with five known diterpenes:ent-16-kaurene-3beta,15beta-diol (3), abbeokutone (4), helioscopinolide A (5), helioscopinolide C (6) and helioscopinolide I (7). Their structures were elucidated on the basis of spectroscopic analysis. Compounds 1-7 possessed appreciable anti-allergic activities in RBL-2H3 cells model with IC50 values ranging from 22.5 to 42.2 microM.     

Synthesis of new nucleoside analogues comprising a geminal difluorocyclopropane moiety as potential antiviral/antitumor agents

Geminal difluorocyclopropane analogues of nucleosides 7a-7e were synthesized. Compounds 7a and 7c-7e were obtained by alkylation of nucleic acid bases or their appropriate precursors with (cis)-1-benzyloxymethyl-2-bromomethyl-3,3-difluorocyclopropane+ ++ (8). Analogue 7b was prepared by hydrolysis of 2-amino-6-chloropurine derivative 7e. Compounds 7a-7d did not exhibit any antiviral activity against HCMV, HSV-1, HSV-2, EBV, VZV, HBV and HIV-1 or antitumor effects against murine leukemia L1210, mouse tumors PO3 or C38 and human tumor H15.     

Three new arylbenzofurans from Lavandula angustifolia and their bioactivities

Three new arylbenzofurans, 2-(7-methoxy-2-(4-methoxyphenyl)-3-methylbenzofuran-5-yl)ethanol (1), 4-(5-(2-hydroxyethyl)-7-methoxy-3-methylbenzofuran-2-yl)phenol (2), and 2-(6-methoxy-2-(4- methoxyphenyl)-3-methylbenzofuran-5-yl)ethanol (3), together with three known ones (4–6) were isolated from the whole plant of Lavandula angustifolia. Their structures were determined by means of HRESIMS and extensive 1D and 2D NMR spectroscopic studies. Compounds 1–3 and 5 were tested for their anti-tobacoo mosaic virus (TMV) activities, and Compounds 1–6 were tested for their cytotoxicity activities. In our assay, Compounds 1–3 showed high anti-TMV activity with inhibition rate of 38.2, 35.2, and 34.0%, which superior to positive control Ningnanmycin. Compounds 1–6 also showed weak inhibitory activities against some tested human tumor cell lines with IC50 values in the range of 2.2–8.2 μM.     

灵芝一共生真菌的发酵液化学成分研究

从灵芝一共生真菌 (CalcarisporiumarbusculaPreuss)的发酵液中分离得到 7个化合物 ,经波谱分析确定其结构分别为 :zythiostromicacidA(1) ,zythiostromolide(2 ) ,7,8 二甲基苯并 [g]蝶啶 2 ,4 (1H ,3H) 二酮 (7,8 dimethylbenzo[g]pteridine 2 ,4 (1H ,3H) dione ,3) ,麦角甾醇 (ergosterol,4 ) ,琥珀酸 (butane dioicacid ,5 ) ,狼毒甲素 (5 ,5’ [oxybis(methylene) ]bis 2 furancarboxaldehyde ,6 ) ,5 羟甲基糠醛 (5 hydrox ylmethyl 2 furancarboxaldehyde ,7)。 1,2 ,3首次从齿梗孢属真菌中分离得到。     

Synthesis of 1-Hydroxy-10-methyl-pyrimido [1, 6-C][1, 3]oxazine and the Oxazepine Derivative,Structural Mimicry of Anti-Constrained Acyclic Thymidine

Abstract

A number of pyrimido[1, 6-c][1, 3]oxazine and -oxazepine derivatives, mimicry analogs of anti-constrained acyclic thymidine, have been prepared via treatment of lithiated 5, 6-dimethyl-2, 4-dimethoxypyrimidine with benzylchloromethyl ether or oxiran to furnish 2, 4-dimethoxy-6-(1-benzyloxyethyl)-S-methylpyrimidine (2) and 2, 4-dimethoxy-6-(1-hydroxypropyl)-5-methylpyrimidine (8), respectively. Debenzylation of 2 afforded 2, 4-dimethoxy-6-(1-hydroxyethyl)-5-methylpyrimidine (3). Chloromethylation of 3 and 8 with paraformaldehyde and gaseous hydrogen chloride produced reactive chloromethyl ether intermediates which were converted to the cyclized products 9-methyl-(1H, 2H, 4H, 7H)-pyrimido[1, 6-c][1, 3]-oxazine (5) and -oxazepine (9)-6, 8-dione, respectively. By using selenium dioxide, allylic oxidation of 5 and 9 afforded the target compounds, a racemic mixture of (±)1-hydroxy-9-methyl-(1H, 2H, 4H, 7H)-pyrimido[1, 6-c][1, 3]-oxazine (6) and -oxazepine (10)-6, 8-dione, respectively. Compounds 5, 6, 7, 9, and 10 were evaluated for activity against human immunodeficiency virus (HIV), herpes simplex virus type 1 (HSV-1) and human cytomegalovirus (HCMV). All of these compounds were inactive.     

金顶侧耳次级代谢产物及抗氧化活性研究(英文)

采用硅胶柱色谱、ODS柱色谱、Sephadex LH-20柱色谱、HPLC等分离方法,对金顶侧耳大米发酵乙酸乙酯提取物进行分离;通过HR-ESI-MS、1H-NMR和13C-NMR等光谱学方法对其结构进行鉴定。并检测铁氰化钾还原能力、1,1-二苯基-2-苦基苯肼(DPPH)自由基清除能力和亚铁离子螯合能力。从金顶侧耳大米发酵粗提物中分离鉴定了吲哚甲醛、苯肽等6个化合物,吲哚甲醛为首次从该菌中分离得到,活性测试表明金顶侧耳粗提取物具有一定的还原能力,其大米发酵产物有可能开发成为一种新型功能性食品。     

Two Oxazolyl Compounds and a Monosubstituted α-Pyrone as Free-radical Scavengers Isolated from a Fungus

In the course of our screening for free radical scavengers, (1′E)-erythro-4-(3′,4′-dihydroxypentenyl)oxazole (1) (1′E,4′S)-4-(3′-oxo-4′-hydroxypentenyl)oxazole (2) and 6-pentyl-α-pyrone (3) were isolated from an unidentified fungal metabolite. These compounds, especially novel oxazolyl compound 2, inhibited the bactericidal effect of the Fenton reagent toward Bacillus subtilis. They and their acetylated compounds (diAc-1 and Ac-2) also showed inhibitory activity against linoleate autoxidation. Furthermore, 1–3 inhibited oxidative enzymes (soybean lipoxygenase and mushroom tyrosinase).

To investigate the radical scavenging mechanism of 3, two oxidized products (4 and 5) were isolated from the reaction mixture of 3 and the Fenton reagent. Compounds 4 and 5 seemed to be derived from 3 by scavenging the hydroxyl radical.     

Desmodianone H and uncinanone B,potential tyrosinase inhibitors obtained from Lespedeza maximowiczii by using bioactivity-guided isolation

A new bioactive compound, namely desmodianone H (1), and another known compound uncinanone B (2) were first isolated using bioactivity-guided isolation from the leaves of Lespedeza maximowiczii and structures were elucidated by comprehensive analysis of their nuclear magnetic resonance and mass spectrometry data. Compounds 1 and 2 exhibited strong inhibitory effects on mushroom tyrosinase activity.     

An Oxidized Ergosterol from <Emphasis Type="Italic">Pleurotus cystidiosus</Emphasis> Active Against Anthracnose Causing <Emphasis Type="Italic">Colletotrichum</Emphasis><Emphasis Type="Italic">gloeosporioides</Emphasis>

This study was undertaken to study the antifungal activity of Pleurotus cystidiosus against Colletotrichum gloeosporioides. This was achieved by fractionating the mushroom, P. cystidiosus initially to acetone (A), dichloromethane (D), and hexane (H) and studying the antifungal activity using the standard poisoned food technique. All the test solutions used were in the concentration of 20,000 ppm. The percentage inhibition of extracts A, D, and H was 12, 7, and 0.4%, respectively. Antifungal assay guided fractionation of the most active extract A resulted in four fractions; A1, A2, A3, and A4 having 12, 22, 0, and 17% percentage inhibitions, respectively. Fractions A2 and A4 were selected for further purifications. Normal phase column chromatography of A2 gave A2-1, A2-2, A2-3, and A2-4, with percentage inhibitions 7, 5, 26, and 13%, respectively. The fraction with the highest inhibitory activity (A2-3) was further separated using the Chromatotron and a single compound (A2-3-13) with 41% inhibition was isolated. Structure elucidation of this compound using 1D and 2D NMR spectroscopy proved this compound to be 3beta, 5alpha, 6beta-trihydroxyergosta-7,22-diene.     

Endoplasmic Reticulum (ER) Stress-Suppressive Compounds from Scrap Cultivation Beds of the Mushroom Hericium erinaceum

Four compounds were isolated from scrap cultivation beds of the mushroom, Hericium erinaceum. Compounds 1–4 were identified as methyl 4-hydroxy-3-(3-methylbutanoyl) benzoate, 2-chloro-1,3-dimethoxy-5-methylbenzene, methyl 4-chloro-3,5-dimethoxybenzoate, and 4-chloro-3,5-dimethoxybenzaldehyde by an interpretation of the NMR and MS data, respectively. This is the first reported isolation of 1 from a natural source. All the compounds showed protective activity against endoplasmic reticulum stress-dependent cell death.