Antiallergic agents from natural sources 9. Inhibition of nitric oxide production by novel chalcone derivatives from Mallotus philippinensis (Euphorbiaceae)

Three novel chalcone derivatives, mallotophilippens C (1), D (2) and E (3) were isolated from the fruits of Mallotus philippinensis MUELL. ARG. These compounds were identified, using chemical and spectral data, as 1-[6-(3,7-dimethyl-octa-2,6-dienyl)-5,7-dihydroxy-2,2-dimethyl-2H-chromen-8-yl]-3-(4-hydroxy-phenyl)-propenone, 3-(3,4-dihydroxy-phenyl)-1-[6-(3,7-dimethyl-octa-2,6-dienyl)-5,7-dihydroxy-2,2-dimethyl-2H-chromen-8-yl]-propenone and 1-[5,7-dihydroxy-2-methyl-6-(3-methyl-but-2-enyl)-2-(4-methyl-pent-3-enyl)-2H-chromen-8-yl]-3-(3,4-dihydroxy-phenyl)-propenone, respectively. They inhibited nitric oxide (NO) production and inducible NO synthase (iNOS) gene expression by a murine macrophage-like cell line (RAW 264.7), which was activated by lipopolysaccharide (LPS) and recombinant mouse interferon-gamma (IFN-gamma). Furthermore, they downregulated cyclooxygenase-2 (COX-2) gene, interleukin-6 (IL-6) gene and interleukin-1beta (IL-1beta) gene expression. These results suggest that they have anti-inflammatory and immunoregulatory effects.     

5-Demethoxyfumagillol, a potent angiogenesis inhibitor isolated from Aspergillus fumigatus

A novel angiogenesis inhibitor, 5-demethoxyfumagillol (1), was obtained by isolation, purification and saponification of cultured broth of Aspergillus fumigatus. The structure was assigned as (3R,4R,6R)-4-[(2R,3R)-2-methyl-3-(3-methyl-but-2-enyl)-oxiranyl]-1-oxa-spiro[2,5]octan-6-ol (1) by spectroscopic analysis and confirmed by independent synthesis from fumagillol (3). In addition, 6-O-(chloroacetylcarbamoyl)-5-demethoxyfumagillol (7) showed a potential anti-angiogenic activity in CAPE cells in vitro.     

Multiple pathways in the synthesis of new annelated analogues of 6-benzyl-1-(ethoxymethyl)-5-isopropyluracil (emivirine)

Condensation of 3-(3,5-dimethylphenyl)-2-oxocyclopentanecarboxamide (11) with oxalyl chloride and condensation of ethyl 2-benzylamino-5-methyl-3-phenylcyclopent-1-enecarboxylate (17a) with trimethylsilyl isothiocyanate gave 7-(3,5-dimethylphenyl)-6,7-dihydro-5H-cyclopenta[e][1,3]oxazine-2,4-dione (12) and 1-benzyl-5-methyl-7-phenyl-2-thioxo-1,2,3,5,6,7- hexahydrocyclopentapyrimidin-4-one (18a), respectively. Acid catalyzed ring-closure of 6-(4-methyl-1-phenylpent-3-enyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (26) and radical mediated ring-closure of 1,3-bis(benzyloxymethyl)-5-bromo-6-(1-phenylbut-3-enyl)-1H-pyrimidine-2,4- dione (32a) gave 5,5-dimethyl-8-phenyl-5,6,7,8-tetrahydro-1H-quinazoline-2,4- dione (28) and 1,3-bis(benzyloxymethyl)-5-methyl-7-phenyl-1,5,6,7- tetrahydrocyclopentapyrimidine-2,4-dione (33), respectively. Annelated emivirine analogues 7-(3,5-dimethylphenyl)-1- ethoxymethyl-1,5,6,7-tetrahydrocyclopentapyrimidine-2,4-dione (4), 1-ethoxymethyl-5,5-dimethyl-8-phenyl-5,6,7,8-tetrahydro-1H-quinazoline- 2,4-dione (5) and 1-ethoxymethyl-5-methyl-7-phenyl-1,5,6,7- tetrahydrocyclopentapyrimidine-2,4-dione (6) were obtained in few steps from 12, 28 and 18a/33, respectively. These new analogues can be considered as conformationally locaTed analogues of emivirine. However, the compounds 4 6 showed lower activities against HIV-1 than emivirine and it is concluded that the locked conformation disfavours activity against HIV-1.     

4H-Chromenone Glycosides from Eranthis hyemalis (L.) SALISBURY

Investigation of the tubers of Eranthis hyemalis (Ranunculaceae) afforded six chromenone glycosides. Their structures have been elucidated mainly by spectroscopic (FAB-MS, 2D-NMR techniques) and chemical methods (acidic and enzymatic hydrolysis) as 9-{[(β-D -glucopyranosyl)oxy]methyl}-8,11-dihydro-5-hydroxy-2-methyl-4H-pyrano[2,3-g][1]benzoxepin-4-one ( 1 ), 9-{[(β-D -gentiobiosyl)oxy]methyl}-8,11-dihydro-5-hydroxy-2-methyl-4H-pyrano[2,3-g][1]benzoxepin-4-one( 2 ), 9-{[(β-D -glucopyranosvl)oxy]melhyl}-8,11-dihydro-5-hydroxy-2-(hydroxy-methyl)-4H-pyrano[2,3-g][1]benzoxepin-4-one( 3 ), 8-{(2E)-4-[(β-D -glucopyranosyl)oxy]-3-methylbut-2-enyl}-5,7-dihydroxy-2-methyl-4H-1-benzopyran-4-one ( 4 ), 8-{(2E)-4-[(β-D -glucopyranosyi)oxy]-3-methylbut-2-enyl}-5,7-dihydroxy-2-(hydroxymethyl)-4H-1-benzopyran-4-one ( 5 ), and 7-{[(β-D -glucopyranosy1)oxy]methyl}-2,3-dihydro-2-(l-hydroxy-1-methylethyl)-4-methoxy-5H-furo[3,2-g][1]benzopyran-5-one ( 6 ). Compound 2 exhibited negative inotropic activity.     

Fischer iondolization and its related compounds—X: Application of the advanced fischer indolization of a 2-methoxyphenylhydrazone derivative to syntheses of some naturally occurring 6-substituted indoles

Two naturally occurring 6-substituted indoles, 6-(3-methylbuta-1,3-dienyl)indole (2) and 6-(3-methyl-2-butenyl)indole (5), were synthesized by using an advanced Fischer indolization of a 2-methoxyphenylhydrazone derivative.     

Synthesis of Urinary Metabolites of Retinoic Acid

Urinary metabolites 5-methyl-5-[2-(2,6,6-trimethyl -3-oxo-1-cyclohexen-1-yl)-vinyl]-2-tetrahydrofuranone (1) and 5-[2-(6-hydroxymethyl-2, 6-dimethyl-3-oxo-1- cyclohexen-1-yl)vinyl]-5-methyl-2-tetrahydrofuranone (2) of retinoic acid have been synthesized from 4-[2,2,6-trimethyl-3-(tetrahydro-2 H -pyran-2-yl)oxy-1-cyclohexen-1-yl]-3-buten-2-one (4) and methyl 2-(3,3-ethylenedioxy-1-butenyl)-1, 3-dimethyl-4-oxo-2-cyclohexene-1-carboxylate (5) .     

Studies on the synthesis of heterocyclic compounds. Part IV. Further investigation of the pschorr reaction with some pyrazole derivatives

Thermal decomposition of the diazonium sulfate derived from N-methyl-(1-phenyl-3-methylpyrazol-5-yl)-2-aminobenzamide afforded products formulated as 1-phenyl-3-methyl[2]benzopyrano[4,3-c]pyrazol-5-one (yield 10%), 1,4-dimethyl-3-phenylpyrazolo[3,4-c]isoquinolin-5-one (yield 10%), N-methyl-(1-phenyl-3-methylpyrazol-5-yl)-2-hydroxybenzamide (yield 8%) and 4′-hydroxy-2,3′-dimethyl-1′-phenylspiro[isoindoline-1,5′-[2]-pyrazolin]-3-one (yield 20%). Decomposition of the diazonium sulfate derived from N-methyl-(1,3-diphenylpyrazol-5-yl)-2-aminobenzamide gave products formulated as 7,9-dimethyldibenzo[e,g]pyrazolo[1,5-a][1,3]-diazocin-10-(9H)one (yield 8%), 4-methyl-1,3-diphenylpyrazolo[3,4-c]isoquinolin-5-one (yield 7%) and 4′-hydroxy-2-methyl-1′,3′-diphenylspiro[isoindoline-1,5′-[2]pyrazolin]3-one (yield 10%). The spiro compounds 6a,b underwent thermal and acid-catalysed conversion into the hitherto unknown 2-benzopyrano[4,3-c]pyrazole ring system 7a,b in good yield. Analytical and spectral data are presented which supported the structures proposed.     

Stereoselective synthesis of cyclohexa-2,4-dien-1-ones and cyclohex-2-en-1-ones from phenols

A convenient synthetic method for the synthesis of substituted cyclohex-2-en-1-ones by the direct alkylation of phenols has been developed. Furthermore, enantiomerically enriched 2,6-dimethyl-6-(3-methylbut-2-enyl)-cyclohexa-2,4-dienone was prepared by the deprotonation of 2,6-dimethylphenol with a sparteine–lithium complex followed by alkylation with 1-chloro-3-methylbut-2-ene. 2,6-Dimethyl-6-(3-methyl-but-2-enyl)-cyclohex-2-enone was prepared from the corresponding cyclohexa-2,4-dien-1-one by selective hydrogenation of the 4,5-double bond. The method was extended to 2-methyl-naphthalen-1-ol and 1-methyl-naphthalen-2-ol resulting in 2-(R)-methyl-2-(3-methylbut-2-enyl)-2H-naphthalen-1-one and 1-(S)-methyl-1-(3-methylbut-2-enyl)-1H-naphthalen-2-one, respectively.     

Eine Synthese methylierter Epoxyhydroazulenone durch intramolekulare [4 + 3]-Cycloaddition einer aus 1,1-Dichloro-6-(3-methylfur-2-yl)hexan-2-on erzeugten Oxyallyl-Zwischenstufe

A synthesis of Methylated Epoxyhydroazulenones by Intramolecular [4 + 3] Cycloaddition of an Oxyallyl Intermediate, Generated from 1,1-Dichloro-6-(3-methyl-2-furyl)hexan-2-one (Z)-3-Methylpent-2-en-4-yn-1-ol ( 7 ) was transformed to 2-(4-chlorobutyl)-3-methylfuran ( 4b ) and 2-(but-3-enyl)-3-methylfuran ( 10a ) by C-alkylation and 5-exo-dig cyclization. The Grignard derivative formed from 4b gave 1,1-dichloro-6-(3-methylfur-2-yl)hexan-2-onc ( 1b ) on reaction with dichloroacetyl chloride. This dichloromethyl ketone undergoes a base-induced cyclization to form diastereoisomeric 7-chloro-1,2,3,6,7,8a-hexahydro-4-methyl-8H-3a,6-epoxyazulen-8-ones ( 3bα and 3bβ ) by way of an intramolecular [4+3] cycloaddition of an oxyallyl intermediate 2b. By dechlorination and hydrogenation of 3bβ , the tricyclic hydroepoxyazulenones 18 and 19 have been synthesized.     

In vitro cytotoxicity activity on several cancer cell lines of acridone alkaloids and N-phenylethyl-benzamide derivatives from Swinglea glutinosa (Bl.) Merr

The methanol extract from the stems and fruits of Swinglea glutinosa (Rutaceae) afforded 11 known acridone alkaloids and three N-phenylethyl-benzamide derivatives, glycocitrine-IV, 1,3,5-trihydroxy-4-methoxy-10-methyl-2,8-bis(3-methylbut-2-enyl)acridin-9(10H)-one, 1,3,5- trihydroxy-2,8-bis(3-methylbut-2-enyl)-10-methyl-9-acridone, citbrasine, citrusinine-II, citrusinine-I, 5-dihydroxyacronycine, pyranofoline, 3,4-dihydro-3,5,8-trihydroxy-6-methoxy-2,2,7-trimethyl-2H-pyrano[2,3-a]acridin-12(7H)-one, 2,3-dihydro-4,9-dihydroxy-2-(2-hydroxy-propan-2-yl)-11-methoxy-10-methylfuro[3,2-b]acridin-5(10H)-one, bis-5-hydroxyacronycine, N-(2-{4-[(3,7-dimethylocta-2,6-dien-1-yl)oxy]phenyl}ethyl)benzamide, N-(2-{4-[(3,7-dimethyl-4-acethyl-octa-2,6-dien-1-yl)oxy]phenyl}ethyl)benzamide, and severine acetate. All compounds isolated were examined for their activity against three cancer cell lines: human lung carcinoma (COR-L23), human breast adenocarcinoma (MCF7), human melanoma (C32), and normal human fetal lung cell line, MRC-5. The acridones tested exhibited weak cytotoxicity but the amides showed moderate nonselective cytotoxic activity.     

Synthesis of optically active (+)-19-nortestosterone by asymmetric bis-annulation reaction

Michael reaction of 1,7-pctadien-3-one with 2-methylcyclopentane-1,3-dione, followed by intramolecular aldol condensation promoted by L-amino acids produced the optically active (+)-4-(3-butenyl)-7a-methyl-5,6,7,7a-tetrahydroindane-1,5-dione in high chemical and optical yields. The PdCl₂-catalyzed oxidation of the terminal double bond gave the methyl ketone, which had 76% optical purity and was made 100% optically pure by recrystallization. Then aldol condensation afforded the tricyclic ketone, which was alkylated with 3-butenyl iodide to afford (?)-3β-t-butoxy-2,3,3a,4,5,7,8,9,9aβ,9bα-decahydro-6-(3-butenyl)-3aβ-methyl-1H-benz[e]inden-7-one. The synthesis of this compound means the total synthesis of (+)-19-nortestosterone.     

Antiangiogenic polyketides from Peperomia dindygulensis Miq

Two new polyketides: 2Z-(heptadec-12-enyl)-4-hydroxy-3,4,7,8-tetrahydro-2H-chromen-5(6H)-one (1) and 2-(heptadec-12-enyl)-5-hydroxy-5,6,7,8-tetrahydrochromen- 4-one (2), together with eleven known compounds: 4-hydroxy-2-[(3,4-methylenedioxy- phenyl)tridecanoyl] cyclohexane-1,3-dione (3), oleiferinone (4), 4-hydroxy-2-[(3,4- methylenedioxyphenyl)undecanoyl]cyclohexane-1,3-dione (5), 4-hydroxy-2-[(11-phenyl- undecanoyl)cyclohexane-1,3-dione (6), proctorione C (7), surinone C (8), 5-hydroxy- 7,8,4'-trimethoxyflavone (9), 5-hydroxy-7,8,3',4'-tetramethoxyflavone (10), 5-hydroxy- 7,3',4'-trimethoxyflavone (11), 5,8-dihydroxy-7,3',4'-trimethoxyflavone (12) and cepharanone B (13) were isolated from the whole plant of Peperomia dindygulensis Miq. Their structures were elucidated by spectroscopic methods, including 2D-NMR techniques. Compounds 2, 3, 5 and 8 inhibited human umbilical vein endothelial cell (HUVEC) proliferation and compounds 5 and 8 sharply suppressed HUVEC tube formation.     

Identification and biological activity of microbial metabolites of xanthohumol

Microbial transformation of xanthohumol using the culture broth of Cunninghamella echinulata NRRL 3655 afforded (2S)-8-[4"-hydroxy-3"-methyl-(2"-Z)-butenyl]-4',7-dihydroxy-5-methoxyflavanone (5) and (2S)-8-[5"-hydroxy-3"-methyl-(2"-E)-butenyl]-4',7-dihydroxy-5-methoxyflavanone (6). Xanthohumol (1) and flavanone 6 as well as (E)-2"-(2"'-hydroxyisopropyl)-dihydrofurano[2",3":4',3']-2',4-dihydroxy-6'-methoxychalcone (2), (2S)-2"-(2"'-hydroxyisopropyl)-dihydrofurano[2",3":7,8]-4'-hydroxy-5-methoxyflavanone (3) obtained with Pichia membranifaciens showed antimalarial activity against Plasmodium falciparum.     

Formation and structure elucidation of two novel spiro[2H-indol]-3(1H)-ones

The molecular structures of two byproducts 1,1'-diphenyl-3',4'-dihydrodispiro[indole-2,2'-furan-5',2'-indole]-3,3'(1H, 1'H)-dione (3) and 1,5'-diphenyl-4',5'-dihydro-3'H-spiro[indole-2,2'-pyrano[3,2-b]indol]-3(1H)-one (4), which accompanied the rearrangement of 3-hydroxy-3-methyl-1-phenylquinoline-2,4(1H,3H)-dione (1) to 2-hydroxy-2-methyl-1-phenyl-1,2-dihydro-3H-indol-3-one (2), have been elucidated by NMR, MS, and X-ray diffraction.     

Piperidine-mediated synthesis of thiazolyl chalcones and their derivatives as potent antimicrobial agents

A series of new thiazolyl chalcones, 1-[2-amino-4-methyl-1,3-thiazol-5-yl]-3-aryl-prop-2-en-1-one were prepared by piperidine mediated Claisen-Schmidt condensation of thiazolyl ketone with aromatic aldehyde. These chalcones on cyclisation gave 2-amino-6-(2-amino-4-methyl-1,3-thiazol-5-yl)-4-aryl-4H-pyridine-3-carbonitrile and 2-amino-6-(2-amino-4-methyl-1,3-thiazol-5-yl)-4-aryl-4H-pyran-3-carbonitrile. The result showed that the compounds exhibited marked potency as antimicrobial agents.     

Bildung von 5,6-Dihydro-1,3(4H)-thiazin-4-carbonsäure-estern aus 4-Allyl-1,3-thiazol-5(4H)-onen

Formation of Methyl 5,6-Dihydro-l, 3(4H)-thiazine-4-carboxyiates from 4-Allyl-l, 3-thiazol-5(4H)-ones . The reaction of N-[1-(N, N-dimethylthiocarbamoyl)-1-methyl-3-butenyl]benzamid ( 1 ) with HCl or TsOH in MeCN or toluene yields a mixture of 4-allyl-4-methyl-2-phenyl-1,3-thiazol-5(4H)-one ( 5a ) and allyl 4-methyl-2-phenyl-1,3-thiazol-2-yl sulfide ( 11 ; Scheme 3). Most probably, the corresponding 1,3-oxazol-5(4H)-thiones B are intermediates in this reaction. With HCl in MeOH, 1 is transformed into methyl 5,6-dihydro-4,6-dimethyl-2-phenyl-1,3(4H)-thiazine-4-carboxylate ( 12a ). The same product 12a is formed on treatment of the 1,3-thiazol-5(4H)-one 5a with HCl in MeOH (Scheme 4). It is shown that the latter reaction type is common for 4-allyl-substituted 1,3-thiazol-5(4H)-ones.     

Manganese(III)-mediated intermolecular cyclization reactions of alkenes and active methylene compounds

The reactions of 1,1-diphenylethene, 1,1-bis(4-chlorophenyl)ethene, 1,1-bis(4-methylphenyl)ethene, and 1,1-bis(4-methoxyphenyl)ethene with 3,5-diacetyl-2,6-heptanedione in the presence of manganese(III) acetate in acetic acid at 80° yielded 4,6-diacetyl-8,8-diaryl-1,3-dimethyl-2,9-dioxabicyclo[4.3.0]non-3-enes (41-48%), 5-acetyl-2,2-diaryl-6-methyl-2,3-dihydrobenzo[b]furans (20–21%), 3-acetyl-5,5-diaryl-2-methyl-4,5-dihydrofurans (5–10%), and benzophenones (3–7%). Similarly, the reactions of 1,1-diarylethenes with dimethyl 2,4-diacetyl-1,5-pentanedioate or diethyl 2,4-diacetyl-1,5-pentanedioate gave the corresponding 4,6-bis(alkoxycarbonyl)-8,8-diaryl-1,3-dimethyl-2,9-dioxabicyclo[4.3.0]non-3-enes in moderate yields.     

南海红树林内生真菌No．ZZF71代谢产物研究

由于海洋环境的特殊性和微生物在生态系统的功能,海洋微生物已经发展出独特的代谢方式,提供了在陆地微生物中未遇到过的代谢产物。研究海洋微生物的活性物质,不但能发现结构新颖的化合物,丰富和发展有机化学理论,而且为寻找新的强效活性药物及其它有用物质提供了一个重要途径[1     

Nitrate and perchlorate salts of a silver(I) complex from 5-methyl-2-(2,3-diaza-4-(5-methyl-2-thienyl)buta-1,3-dienyl)thiophene

Bis(5-methyl-2-(2,3-diaza-4-(5-methyl-2-thienyl)buta-1,3-dienyl)thiophene) silver(I) complex was synthesized in high yield by refluxing 5-methyl-2-(2,3-diaza-4-(5-methyl-2-thienyl)buta-1,3-dienyl)thiophene (L) with silver nitrate or silver perchlorate in anhydrous acetonitrile. The product thus formed was well characterized by NMR, IR, UV–Vis and mass spectroscopies as well as elemental analysis and electrochemical analysis. Molecular structures of compounds L, [L₂Ag]NO₃ and [L₂Ag]ClO₄ were determined by single crystal X-ray diffraction analysis. It was found that the C=N double bond of the ligand rotated during the course of ligand coordination in the case of the perchlorate salt but not in the case of the nitrate salt.     

液质联用同时测定大鼠尿液中6种苯二氮卓类药物

建立高效液相色谱串联质谱法同时测定大鼠尿液中的6种苯二氮卓类药物(BZDs).以乙酸乙酯为萃取溶剂,经液-液萃取前处理后检测.以地西泮为内标,流动相为甲醇-0.01％甲酸+5 mmol/L甲酸铵,梯度洗脱,柱温为40℃;流速为0.3 mL/min;进样量为2 μL,质谱采用电喷雾离子源正离子模式(ESI+).8-溴-1...