Inhibitory effect of the compounds from the water extract of Curcuma longa on the production of PGE2 and NO in a macrophage cell line stimulated by LPS

ABSTRACT

We wished to search for the compounds contributing to the anti-inflammatory effects of the water extract of Curcuma longa (WEC). WEC was fractioned and the fractions were evaluated with regard to their inhibitory effect on the production of nitric oxide (NO) from the macrophage cell line stimulated by lipopolysaccharide. Compounds in the active fractions were isolated and identified. One isolated compound was identified as new: (6S)-2-methyl-5-hydroxy-6-(3-hydroxy-4-methylphenyl)-2-heptene-4-one (1). Four isolated compounds were identified as known: (6S)-2-methyl-6-(4-hydroxyphenyl)-2-heptene-4-one (4), bisabolone-4-one (5), curcumenone (6), and turmeronol A (8). Three isolated compounds were not identified their stereostructures but their planar structures: 2-methyl-6-(4-hydroxymethyl-phenyl)-2-heptene-4-one (2), 2-methyl-6-(2,3-epoxy-4-methyl-4-cyclohexene)-2-heptene (3), and 4-methylene-5-hydroxybisabola-2,10-diene-9-one (7). Compounds 1, 4, 7 and 8 inhibited production of prostaglandin E2 and NO. Others inhibited NO production only. These results (at least in part) show the active compounds contributing to the anti-inflammatory effects of WEC, and may be useful for elucidating its various beneficial physiologic effects.     

5′-Nor Carbocyclic Ribavirin

Abstract

An efficient synthesis of 5′-nor carbocyclic ribavirin (4) is described in 13 steps from conveniently available (+)-(1R,4S)-4-hydroxy-2-cyclopenten-1-yl acetate (6). Compound 4 was evaluated against the following viruses: herpes simplex type 1 and 2, vaccinia, cowpox, smallpox, Ebola, hepatitis B, hepatitis C, adenovirus type 1, influenza A (H1N1 and H3N2), influenza B, parainfluenza type 3, Pichinde, Punta Toro A, respiratory syncytial, rhinovirus type 2, Venezuelan equine encephalitis, yellow fever, and West Nile. No activity was found nor was there any cytotoxicity to the viral host cells.     

Synthesis and Antiviral Activity of C-5 Substituted Analogues of D4T Bearing Methylamino- or Methyldiamino-Linker Arms

Abstract

A general strategy is reported for the preparation of C-5-methylamino- or methyldiamino-d4T analogues of “different sizes”. Reactions of the 2′,3′-didehydro-2′,3′-dideoxy-C-5 hydroxymethyl precursor (7) with either polymethylene diamines (n = 6, 8, 10 and 12) or propargylamine proceed regioselectively via subtitution reactions at the C-5 position of uracil. The compounds were evaluated for antiviral activity and cytotoxicity. No significant activity was observed for compounds 9, 11, and 13, but 10 and 12 exhibited a weak activity against HIV-1.     

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.     

Synthesis and Biological Activity of Modified Thiopyrimidine Nucleosides

Abstract

N³ -β-D-glucopyranosyl, galactopyranosyl and xylopyranosyl 6-methyl-2-methylthiouracil and their 5-bromo derivatives have been synthesized by coupling an a-acetobromosugar with the corresponding thiouracil. The new modified thiouridine analogues were evaluated for their inhibitory activity against Human Immunodeficiency Virus (HIV) replication in MT-4 cells as well as for their cytotoxicity.     

Synthesis,physiochemical property and antimicrobial activity of novel quaternary ammonium salts

Twenty-four novel 5-phenyl-1,3,4-oxadiazole-2-thiol (POT) analogues, benzo[d]oxazole-2-thiol, benzo[d]thiazole-2-thiol and 5-methyl-1,3,4-thiadiazole-2-thiol-substituted N,N-bis(2-hydroxyethyl) quaternary ammonium salts (QAS) (5a-d, 6a-d, 7a-d, 10a-d, 13a-d, 16a-d) were prepared and characterised by FTIR, NMR and elemental analysis. Part of target compounds (5d, 6d, 7d, 10d, 13d, 16d) displayed potent antimicrobial effect against ten common pathogens (S. aureus, α-H-tococcus, β-H-tococcus, E. coli, P. aeruginosa, Proteus vulgaris, Canidia Albicans, Cytospora mandshurica, Physalospora piricola, Aspergillus niger) and had relatively low cytotoxity against two human cell lines (HaCat and LO2). TEM and SEM images of E. coli and S. aureus morphologies treated with 7d showed that the antibacterial mechanism might be the QAS fixing on cell wall surfaces and puncturing to result in the release of bacterial cytoplasm. This study provides new information of QAS, which could be used to design novel antimicrobial agents applied in clinic or agriculture.     

The chemical constituents of Piper kadsura and their cytotoxic and anti-neuroinflammtaory activities

The n-hexane and CHCl₃ soluble fractions of the MeOH extract of the aerial parts of Piper kadsura were found to potently inhibit nitric oxide (NO) production in LPS-activated BV-2 cells, a microglial cell line. From the active fractions, a new stereoisomer of guaiane sesquiterpene, 1α,5β-guai-4(15)-ene-6β,10β-diol, kadsuguain A (1) and a new cyclohexadienone, kadsuketanone A (2), together with twelve known compounds (3–14) were isolated. The structures of these compounds were elucidated by extensive NMR spectral studies. The absolute configuration of 2 was determined by circular dichroism (CD) spectra. Compounds 2, 6, and 11–14 significantly inhibited both nitric oxide (NO) and prostaglandin E₂ (PGE₂) production in the LPS-activated microglia cells. In addition, compounds 4, 6, and 11–14 exhibited cytotoxicity against the A549, SK-OV-3, SK-MEL-2, and HCT15 human tumour cells.     

Activity-guided isolation of antileishmanial compounds from Piper hispidum

The bioassay-guided purification of the ethanolic extract from the leaves of Piper hispidum led to the isolation of one new amide, N-2-(3′,4′,5′-trimethoxyphenyl)ethyl-2-hydroxybenzamide (1) as well as two known chalcones 2′-hydroxy-3′,4′,6′-trimethoxychalcone (2); 2′,4′-dihydroxy-6′-methoxychalcone (cardamonin, 3) and one known flavanone, 5,7-dihydroxyflavanone (Pinocembrin, 4). Their structures were elucidated on the basis of spectroscopic data, including homo- and heteronuclear correlation NMR experiments (COSY, HSQC and HMBC) and comparison with data reported in the literature. The isolated compounds were tested against Leishmania amazonensis axenic amastigotes. The results showed that the known chalcone 2 exhibited the most potent antileishmanial activity with an IC₅₀ of 0.8 μM (amphotericin B: IC₅₀ = 0.2 μM) but was shown to exhibit mild cytotoxicity.     

铁皮石斛内生真菌次生代谢产物研究

为了解铁皮石斛(Dendrobium officinale)内生真菌Phyllosticta aristolochiicola的次生代谢产物,从该真菌中分离得到15个化合物,经波谱分析分别鉴定为N-methyl-2-pyrolidinone (1)、环-(甘氨酸-L-脯氨酸)(2)、环-(D-丙氨酸-L-脯氨酸)(3)、环-(L-缬氨酸-L-脯氨酸)(4)、环-(L-亮氨酸-L-脯氨酸)(5)、cyclo-(L-Leu-D-4-hydroxyprolinyl)(6)、环-(L-苯丙氨酸-L-脯氨酸)(7)、环-(L-苯丙氨酸-L-4-羟基脯氨酸)(8)、环-(L-酪氨酸-L-脯氨酸)(9)、环-(L-苯丙氨酸-L-亮氨酸)(10)、啤酒甾醇(11)、对羟基苯乙醇(12)、对羟基苯乙酸(13)、(2S,3R)-1-(4-羟基苯基)丁烷-2,3-二醇(14)和(2R,3S)-1-苯基丁烷-2,3-二醇(15)。采用MTS法检测抗肿瘤活性表明,化合物2、10和14对HL-60、A-549、SMMC-7721、MCF-7和SW-480细胞株具有一定的抑制活性。     

Phytochemical and Bioactivity Studies on Constituents of the Leaves of Vitex Quinata

A phytochemical investigation of the leaves of Vitex quinata (Lour.) F.N. Williams (Verbenaceae), guided by a cytotoxicity assay against the MCF-7 human breast cancer cell line, led to the isolation of a new δ-truxinate derivative (1) and a new phytonoic acid derivative (2), together with 12 known compounds. The structures of the new compounds were determined by spectroscopic methods as dimethyl 3,4,3′,4′-tetrahydroxy-δ-truxinate (1) and methyl 10R-methoxy-12-oxo-9(13),16E-phytodienoate (2), respectively. In a cytotoxicity assay, (S)-5-hydroxy-7,4′-dimethoxyflavanone (3) was found to be the sole active principle, with ED₅₀ values of 1.1–6.7 μM, respectively, when tested against a panel of three human cancer cells. Methyl 3,4,5-O-tricaffeoyl quinate (4) showed activity in an enzyme-based ELISA NF-κB p65 assay, with an ED₅₀ value of 10.3 μM.     

Synthesis of trans-4-Amino-1-hydroxy-2-methyl-2-butene from Isoprene

A novel synthetic pathway to trans-4-amino-1-hydroxy-2-methyl-2-butene (7), a useful synthetic intermediate of zeatin, is presented here. On selective monophthalimide formation, the trans-1, 4-dibromo-2-methyl-2-butene (10) prepared from isoprene (1) predominantly gives trans-1-bromo-2-methyl-4-phthalimido-2-butene (11). The compound (11) is converted to 7 via trans-1-acetoxy-2-methyl-4-phthalimido-2-butene (6). The overall yield of 7 from 1 is 33.6%. Base-catalyzed hydrolysis of 11 also gives 7 directly. Zeatin can be prepared by the condensation of 7 with 6-chloropurine.     

Synthesis,characterization, antiamoebic activity and cytotoxicity of new pyrazolo[3, 4-d]pyrimidine-6-one derivatives

A new series of pyrazolo[3,4-d]pyrimidine-6-one derivatives (2a–2j) were prepared by using the Biginelli multicomponent cyclocondensation of 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one (1a), different aromatic aldehydes, and urea with a catalytic amount of HCl at reflux temperature. These compounds were characterized by IR, ¹H NMR, ¹³C NMR, and Mass spectral data. In vitro antiamoebic activity was performed against HM1:IMSS strain of Entamoeba histolytica. The results showed that the compounds 2b, 2i, and 2j with IC₅₀ values of 0.37 µM, 0.04 µM, and 0.06 µM, respectively, exhibited better antiamoebic activity than the standard drug metronidazole (IC₅₀?=?1.33 µM). The toxicological studies of these compounds on human breast cancer MCF-7 cell line showed that the compounds 2b, 2i, and 2j exhibited >80% viability at the concentration range of 1.56–50 µM.     

Cytotoxic activity of withanolides isolated from Tunisian Datura metel L

Withanolide-type steroids, withametelin Q (1) and 12α-hydroxydaturametelin B (2) along with three known withanolides, were isolated from leaves of Datura metel L. (Solanaceae). The respective structures, characterized mainly by NMR spectroscopy, were identified as (20R,22R,24R)-21,24-epoxy-1α,3β-dihydroxywitha-5,25(27)-dienolide-3-O-β-d-glucopyranoside (1) and (20R,22R,24R)-12α,21,27-trihydroxy-1-oxowitha-2,5,24-trienolide-27-O-β-d-glucopyranoside (2). The cytotoxicity of isolated compounds was evaluated against human lung carcinoma cells (A549) and human colorectal adenocarcinoma cells (DLD-1), respectively. Compound 2 exhibited cytotoxicity against A549 and DLD-1 cell lines, with IC₅₀ values of 7 and 2.0 μM, respectively. However, for compounds 6 and 7, cytotoxicities were higher against DLD-1 cells with IC₅₀ values of 0.6 and 0.7 μM. Both compounds blocked the cell cycle in the S-phase and induced apoptosis.     

薏苡糠壳的化学成分及其种子萌发活性研究

为了解薏苡(Coix lachryma-jobi)糠壳的化学成分,利用多种柱色谱技术对其乙醇提取物乙酸乙酯萃取部位进行分离,经波谱数据分析鉴定了15个化合物,分别为香豆酸(1)、香豆酸甲酯(2)、2-羟乙基-香豆酸酯(3)、咖啡酸甲酯(4)、阿魏酸甲酯(5)、(E)-3-(4-甲氧基苯基)丙烯酸(6)、2,3-二羟基-...     

Synthesis and Antiviral Activity of Carbocyclic Nucleosides Incorporating a Modified Cyclopentane Ring. Part 3: Adenosine and Uridine Analogues

Abstract

Six new carbocyclic nucleosides were prepared by mounting a purine (compounds 4–6), 8-azapurine (7 and 8) or undine (9) base on the ammo group of (1S,3R)-3-amino-2,2,3-trimethylcyclopentylmethanol (10). At subtoxic concentrations, compounds 5-9 showed at best marginal antiviral activity.     

Synthesis,anti-inflammatory,analgesic and antioxidant activities of some tetrasubstituted thiophenes

Sets of tetrasubstituted thiophene esters 4a-4g, 5a-5f and 6a-6e were synthesized by reaction of 1-(α-Carbomethoxy-β-aminothiocrotonoyl)-aryl/aroyl amines (3) with 3-(bromoacetyl)coumarin, 1,4-dibromodiacetyl and chloroacetone respectively. The compound 3 were synthesized by nucleophilic addition of aryl/aroylisothiocyanate and enamine (2). The synthesized targeted compounds (4a-4g, 5a-5f and 6a-6e) were evaluated for their in vivo anti-inflammatory activity in carrageenin-induced rat hind paw oedema model at three graded doses employed at 10, 20 and 40 mg/kg body weight using mefanamic acid, ibuprofen and in vivo analgesic activity in acetic acid induced writhing response model at 10 mg/kg dose using ibuprofen as standard drug. The compounds 4a-4f, 5c, 5f, 6c and 6e were evaluated for their in vitro antioxidant nitric oxide radical scavenging assay at the concentrations of 5, 10, 15, 20, 25, 30 and 35 μg/mL using ascorbic acid as standard drug. Among all the targeted compounds 4c showed maximum anti-inflammatory activity of 71% protection at 10 mg/kg and 77% protection at 20 mg/kg to inflamed paw and analgesic activity of 56% inhibition and also maximum in vitro nitric oxide radical scavenging activity having IC₅₀ value 31.59 μg/mL.     

Synthesis and Antimicrobial Activity of Optically Active trans-Cycloheximide Isomers

Optically active tiraras-cycloheximide isomers such as cycloheximide [(2S,4S,6R,αR)-form (1)], naramycin B[(25,4S,6RαR)-form(4)], and new stereoisomers (2S,4S,6S,αS)-form (8) and (2S,4S,6R,αS)-from (9) were synthesized by an aldol condensation of trans-2,4-dimethyl-l-cyclohexanone (5b), with 4-(2-oxoethyl)-2,6-piperidinedione(6). The antimicrobial activity of trans- cycloheximide isomers (1, 4, 8, and 9) was examined against S. cerevisiae and P. oryzae. The stereoisomers 1 and 4 exhibited marked antimicrobial activity against both microorganisms as compared with their C- α-epimers 8 and 9.     

Biotransformation of mestanolone and 17-methyl-1-testosterone by Rhizopus stolonifer

Abstract

Microbial transformation of mestanolone (1) using the plant pathogenic fungus, Rhizopus stolonifer, resulted in the production of two known metabolites, identified as 11α-hydroxymestanolone (3) and 6α-hydroxymestanolone (4). Transformation of 17-methyl-1-testosterone (2) by R. stolonifer yielded two known metabolites, methandrostenolone (5) and 11α,17β- dihydroxy-androsta-1,4-diene-3-one (6). These transformations included α-hydroxylations at C-11 and C-6, dehydrogenation at C-4, androsta and a demethylation at C-17 positions. Structures of transformed products were determined using spectroscopic techniques.     

Synthesis and biological evaluation of novel series of aminopyrimidine derivatives as urease inhibitors and antimicrobial agents

A novel series of carbazole substituted aminopyrimidines (5a-p) were synthesized and screened for their in vitro urease inhibition and antimicrobial activity. Among the compounds, 4-(2,4-dichlorophenyl)-6-(9-methyl-9H-carbazol-3-yl)-pyrimidin-2-amine (5i) was found to be the most potent showing urease inhibitory activity with an IC₅₀ value 19.4?±?0.43 µM. Compounds 5c, 5g, 5j and 5o showed good activity against all selected bacterial strains and compounds 5b, 5c, 5m and 5o showed good activity against selected fungal strains. All the compounds were subjected for ADME predictions by computational method.     

ACYCLIC NUCLEOSIDE/NUCLEOTIDE ANALOGUES WITH AN IMIDAZOLE RING SKELETON

Syntheses of a few acyclic nucleoside and acyclic nucleoside phosphonate analogues containing an imidazole ring have been reported. These analogues include methyl 1-(2-hydroxyethoxymethyl)imidazole-4,5-dicarbo-xylate (1), 4,5-dicarbamoyl-1-(2-hydroxyethoxymethyl)imidazole (2), 4,5-dicya-no-1-(2-hydroxyethoxymethyl)imidazole (4), Methyl 1-(2-bromoethoxymethyl)- imidazole-4,5-dicarboxylate (7), 4,5-dicyano-(2-bromoethoxymethyl)imidazole (8), and Methyl 1-(2-phosphonomethoxyethyl)imidazole (10). Also reported are a few potential prodrugs of the above compounds, including the acetyl derivatives 5 and 6 (of 1 and 4, respectively), and the diethyl phosphonate ester 9 (of 10). In addition, the corresponding benzyl-protected precursors 11 and 12 (of 1 and 4, respectively), along with their common hydrolysis product, 1-(2-benzyloxy-ethoxymethyl)-4,5-imidazoledicarboxylic acid (3), are reported. Another potential prodrug included in the list is 1-(2-acetoxyethyl)-4,5-dicyanoimidazole (15). The compounds were screened for in vitro antiviral activity against a wide variety of herpes and respiratory viruses. The most active compound was the phosphonate analogue 9 which exhibited an anti-measles virus activity with an EC₅₀ of <2.5 μg/mL and an SI value of > 176.