Synthesis and evaluation of <Emphasis Type="Italic">p</Emphasis>-<Emphasis Type="Italic">N</Emphasis>,<Emphasis Type="Italic">N</Emphasis>-dialkyl substituted chalcones as anti-cancer agents

Several new N,N-dialkyl substituted chalcones (chalconoids or benzylideneacetophenones) have been synthesized via the condensation of corresponding N,N-dialkylbenzaldehyde with various aryl methyl ketones. All the chalcones have been synthesized from readily available and cheap starting materials under environmentally benign conditions in very high yields without work up and column chromatographic purification. Synthesized compounds have been tested for their biological activity against pathogenic microorganisms such as Escherichia coli, Bacillus subtilis, and Mycobacterium smegmatis. Anti-cancer activity of these compounds has also been tested against multiple myeloma (RPMI-8226) and human mammary adenocarcinoma (MCF-7) cell lines. The most hydrophilic molecules 23 and 24 showed very good anti-cancer activity against MCF-7 cell lines at low micro-molar concentrations. All the compounds have also been evaluated for their activity against Beta-secretase 1 enzyme. One of the synthesized compounds showed Beta-secretase 1 enzyme inhibition activity at micro-molar concentration.     

Synthesis and analgesic activity of <Emphasis Type="Italic">N</Emphasis>',<Emphasis Type="Italic">N</Emphasis>'-dialkylhydradizes of aliphatic carboxylic acids

A series of new N',N'-dialkylhydrazides of aliphatic carboxylic acids have been obtained. It is shown that some of these compounds possess central analgesic activity and exhibit low toxicity. N',N'-dialkylhydrazides of octanoic acid are of interest for further investigation in the search for new neurotropic agents.     

Diphenyl diselenide supplementation delays the development of <Emphasis Type="Italic">N</Emphasis>-nitroso-<Emphasis Type="Italic">N</Emphasis>-methylurea-induced mammary tumors

The effect of dietary diphenyl diselenide (1 ppm) on N-nitroso-N-methylurea (NMU)-induced mammary carcinogenesis was examined in female Wistar rats. Beginning at 5 weeks of age, the animals were fed with either control or diphenyl-diselenide-supplied diets until the end of the study (210 days). At 50 days of age, mammary tumor was induced by the administration of three doses of NMU (50 mg/kg body wt, intraperitoneally) once a week for 3 weeks. In experimental trials, latency to tumor onset was extended in rats fed with diet supplemented with diphenyl diselenide (P < 0.05). The incidence and frequency of tumors were significantly small in animals supplemented with diphenyl diselenide. However, the multiplicity of tumors was not altered by dietary diphenyl diselenide. Diphenyl diselenide supplementation also restored superoxide dismutase (SOD) activity and vitamin C levels altered in the NMU group (P < 0.05). Our results suggest that diphenyl diselenide can be considered a chemopreventive agent, even when supplemented at a relatively low concentration.     

New potential antihypoxants based on 2-ethyl-3-(<Emphasis Type="Italic">N</Emphasis>,<Emphasis Type="Italic">N</Emphasis>-dimethylcarbamoyloxy)-6-methylpyridine

It is established that succinic acid is capable of potentiating (synergism) the antihypoxic activity of 3-hydroxypyridine derivatives such as the succinate (Ia) and hydrochloride (Ib) of 3-(N,N-dimethylcarbamoyloxy)- 2-ethyl-6-methylpyridine. This effect makes it expedient to create new drugs containing a mixture of Ia or Ib and succinic acid derivatives that would possess antihypoxic, antiamnestic, and anticonvulsant activity. The antihypoxic activity of 3-hydroxypyridine drugs increases in the order emoxypin < mexidol < proxypin < Ia + succinic acid < Ib + succinic acid.     

<Emphasis Type="Italic">ent</Emphasis>-Abietane diterpenoids from <Emphasis Type="Italic">Isodon xerophilus</Emphasis>

Three new ent-abietanoids, named xerophilusins XIV–XVI, and four known analogues, as well as four known chemical constituents were isolated from the leaves of Isodon xerophilus. Their structures were elucidated by extensive spectroscopic studies, and comparison with literature data. In addition, the cytotoxic activity of the ent-abietanoids against chronic myelogenous leukemia (K562), stomach adenocarcinoma (MKN45), and hepatocellular carcinoma (HepG2) human cell lines was investigated and no activities were observed.     

<Emphasis Type="Italic">In Vitro</Emphasis> and <Emphasis Type="Italic">ex Vivo</Emphasis> Intestinal Tissue Models to Measure Mucoadhesion of Poly (Methacrylate) and <Emphasis Type="Italic">N</Emphasis>-Trimethylated Chitosan Polymers

No HeadingPurpose. The adhesion of a range of polymers based on poly(2-(dimethylamino-ethyl) methacrylate (pDMAEMA) was assessed using human mucus-secreting and non mucus-secreting intestinal cell monolayers, HT29-MTX-E12 (E12) and HT29 monolayers, as well as excised non-everted intestinal sacs from rats. Differentiation of mucoadhesion from bioadhesion was achieved by pre-treatment with the mucolytic agent, N-acetyl cysteine (NAC). Adherence of pDMAEMA polymers was compared to that obtained with the mucoadhesive, N-trimethylated chitosan (TMC).Methods. The quantity of adherent coumarin 343-conjugated polymers to HT29, E12, and intestinal sacs was measured by fluorescence. Confocal laser scanning microscopy (CLSM), light microscopy, and fluorescent microscopy were used to provide direct evidence. Measurements of transepithelial electrical resistance (TEER), permeability to FITC-dextran 4000 (FD-4), and the release of lactate dehydrogenase (LDH) were used to assess potential cytotoxicity of polymers.Results. Adherence of unquaternized and of 10%, 24%, and 32% methyl iodide-quaternized pDMAEMA polymers was measured in E12, HT29, and sacs. All pDMAEMA polymers showed significantly higher levels of adhesion to mucus (mucoadhesion) than to epithelium (bioadhesion). Colocalization of pDMAEMA with mucus was confirmed in E12 by microscopy. TMC showed equally high levels of mucoadhesion as unquaternized and 24% quaternized pDMAEMA, but displayed higher levels of bioadhesion. pDMAEMA-based polymers demonstrated lower levels of adherence to E12 and rat sacs in the presence of NAC, whereas adherence of TMC was unchanged. pDMAEMA significantly decreased the permeability of FD-4 across E12 monolayers and sacs and was less cytotoxic in E12 than in HT29. In contrast, TMC increased the permeability of FD-4 across E12 and sacs and was less cytotoxic in E12 than in HT29.Conclusions. Human mucus–producing E12 monolayers can be used to assess polymer mucoadhesion and give similar data to isolated rat intestinal sacs. pDMAEMA displayed similar levels of mucoadhesion and lower levels of bioadhesion than a chitosan derivative and it was not cytotoxic. pDMAEMA decreased FD-4 flux in the presence of mucus, whereas TMC increased it. The combination of mucus and methacrylate polymers appears to increase barrier function of the apical membrane.     

Identification of medicinal <Emphasis Type="Italic">Dendrobium</Emphasis> species by phylogenetic analyses using <Emphasis Type="Italic">matK</Emphasis> and <Emphasis Type="Italic">rbcL</Emphasis> sequences

Species identification of five Dendrobium plants was conducted using phylogenetic analysis and the validity of the method was verified. Some Dendrobium plants (Orchidaceae) have been used as herbal medicines but the difficulty in identifying their botanical origin by traditional methods prevented their full modern utilization. Based on the emerging field of molecular systematics as a powerful classification tool, a phylogenetic analysis was conducted using sequences of two plastid genes, the maturase-coding gene (matK) and the large subunit of ribulose 1,5-bisphosphate carboxylase-coding gene (rbcL), as DNA barcodes for species identification of Dendrobium plants. We investigated five medicinal Dendrobium species, Dendrobium fimbriatum, D. moniliforme, D. nobile, D. pulchellum, and D. tosaense. The phylogenetic trees constructed from matK data successfully distinguished each species from each other. On the other hand, rbcL, as a single-locus barcode, offered less species discriminating power than matK, possibly due to its being present with little variation. When results using matK sequences of D. officinale that was deposited in the DNA database were combined, D. officinale and D. tosaense showed a close genetic relationship, which brought us closer to resolving the question of their taxonomic identity. Identification of the plant source as well as the uniformity of the chemical components is critical for the quality control of herbal medicines and it is important that the processed materials be validated. The methods presented here could be applied to the analysis of processed Dendrobium plants and be a promising tool for the identification of botanical origins of crude drugs.     

Tissue distribution and elimination of <Emphasis Type="Italic">N</Emphasis>-methyl-<Emphasis Type="Italic">N</Emphasis>-2,4,6-tetranitroaniline (tetryl) in rats

The elimination of tetryl was studied using ring-labeled ¹⁴C-tetryl. Tetryl was given subcutaneously to male Sprague–Dawley rats at doses of 25, 100, and 300 mg kg⁻¹, and urine and feces were collected 24 h post-injection. Percent urinary elimination was observed to be 10.02 ± 2.48, 11.2 ± 1.66, and 13.24 ± 5.79 (mean ± SEM) respectively. Percent fecal elimination was 15.68 ± 6.13, 9.41 ± 1.52, and 8.45 ± 1.81 respectively. At 24 h post-injection, tissues from male Sprague–Dawley rats were collected from animals that received 100 mg kg^{−1 14}C-tetryl. Tetryl was found to be poorly absorbed with approximately 65% of the administered dose remaining at the site of subcutaneous injection. Blood was found to be the principal depot of radioactivity, followed by muscle, liver, and kidney. Analysis of the tissue to blood radioactivity ratio revealed that the liver had the highest ratio (1.2), followed by brain (0.45), kidney (0.38), and testes (0.35). All other tissues analyzed had ratios less than 0.30. Urine of animals receiving ¹⁴C-tetryl (100 mg kg⁻¹) was analyzed using HPLC coupled with UV detection (200–600 nm; 1.2 nm resolution). During HPLC analysis, 1 min fractions were collected and radioactivity measured. Two major peaks of radioactivity were identified at approximately 5 and 14 min retention times, respectively. The 14 min peak had the same retention time and UV spectrum as picric acid and 5 min peak had the same retention time and UV profile as picramic acid. The data presented demonstrates that that there is little retention of tetryl in specific tissue depots and that tetryl is eliminated in roughly equal amounts in both urine and feces. The major urinary metabolites identified picric acid and picramic acid (a known urinary metabolite observed in rabbits). From microsomal fraction studies, a major metabolite, NMPA, was identified. The formation of this metabolite was found to be dependent on at least two enzymes. One enzyme is dependent on NAD⁺ for NMPA formation and is likely to be NADP(H):quinone oxidoreductase. The second metabolite is NADP⁺ dependent and is probably related to NADPH:cytochrome-P450 reductase.     

A new <Emphasis Type="Italic">Erythrina</Emphasis> alkaloid from <Emphasis Type="Italic">Erythrina herbacea</Emphasis>

A new Erythrina alkaloid, 10-hydroxy-11-oxoerysotrine (1), has been isolated from the flowers of Erythrina herbacea together with five known compounds: erytharbine (2), 10,11-dioxoerysotrine (3), erythrartine (4), erysotramidine (5) and erysotrine-N-oxide (6). The structure of the new compound was elucidated on the basis of its spectral data, including 2-D NMR and mass (MS) spectra. The new compound is a rare C-10 oxygenated Erythrina alkaloid. The antioxidant activities of the isolated compounds 1–6 were evaluated by scavenging with peroxynitrite.     

Identification of <Emphasis Type="Italic">N</Emphasis>-arylsulfonylpyrimidones as anticancer agents

For confirming the role of five membered ring of imidazolidinone moiety of N-arylsulfonylimidazolidinones (7) previously reported with highly potent anticancer agent, a series of N-arylsulfonylpyrimidones (10a–g) and N-arylsulfonyltetrahydropyrimidones (11a–e) were prepared and their anti-proliferating activity was measured against human cancer cell lines (renal ACHN, colon HCT-15, breast MDA-MB-231, lung NCI-H23, stomach NUGC-3, and prostate PC-3) using XTT assay. Among them, 1-(1-acetylindolin-5-ylsulfonyl)-4-phenyltetrahydropyrimidin-2(1H)-one (11d, mean GI₅₀ = 3.50 µM) and ethyl 5-(2-oxo-4-phenyltetrahydropyrimidin-1(2H)-ylsulfonyl)-indoline-1-carboxylate (11e, mean GI₅₀ = 0.26 µM) showed best growth inhibitory activity against human cancer cell lines. Considering the activity results, N-arylsulfonyltetrahydropyrimidones (11) exhibited more potent activity compared to N-arylsulfonylpyrimidones (10) and comparable activity to N-arylsulfonylimidazolidinones (7). Especially, tetrahydropyrimidin-2(1H)-one analogs containing acylindolin-5-ylsulfonyl moiety at position 1 demonstrated their strong growth inhibitory activity against human cancer cell lines.     

<Emphasis Type="Italic">In Vitro</Emphasis> hepatoprotective compounds from <Emphasis Type="Italic">Suaeda glauca</Emphasis>

Bioassay-guided fractionation of the MeOH extract of Suaeda glauca yielded four phenolic compounds, methyl 3,5-di-O-caffeoyl quinate (1) and 3,5-di-O-caffeoyl quinic acid (2), isorhamnetin 3-O-beta-D-galactoside (3), and quercetin 3-O-beta-D-galactoside (4). Compounds 1 and 2 were hepatoprotective against tacrine-induced cytotoxicity in human liver-derived Hep G2 cells with the EC(50) values of 72.7+/-6.2 and 117.2+/-10.5 microM, respectively. Silybin as a positive control showed an EC(50) value of 82.4+/-4.1 microM.     

MDMA induces <Emphasis Type="Italic">Per1</Emphasis>, <Emphasis Type="Italic">Per2</Emphasis> and <Emphasis Type="Italic">c-fos</Emphasis> gene expression in rat suprachiasmatic nuclei

Rationale  

±3,4-Methylenedioxymethamphetamine (MDMA, ‘ecstasy’) is a psychoactive drug that has marked effects on the serotonergic system. Serotonergic agonists are known to interact with the circadian pacemaker located in the suprachiasmatic nuclei (SCN).     

Biologically active <Emphasis Type="Italic">C</Emphasis>-alkylated flavonoids from <Emphasis Type="Italic">Dodonaea viscosa</Emphasis>

A new C-alkylated flavonoid (5,7-dihydroxy-3′-(4″-acetoxy-3″-methylbutyl)-3,6,4′-trimethoxyflavone (1), along with two known C-alkylated flavonoids (5,7-dihydroxy-3′-(3-hydroxymethylbutyl)-3,6,4′-trimethoxyflavone (2), 5,7,4′-trihydroxy-3′-(3-hyroxymethylbutyl)-3,6-dimethoxyflavone (3) and two new source C-alkylated flavonoids (5,7-dihydroxy-3′-(2-hydroxy-3-methyl-3-butenyl)-3,6,4′-trimethoxyflavone (4), 5,7,4′-trihydroxy-3,6-dimethoxy-3′-isoprenyl-flavone (5) were isolated from the aerial parts of Dodonaea viscosa. The structures of all compounds were established on the basis of 1D and 2D NMR spectroscopy and mass spectrometry. The isolated compounds were evaluated for their inhibitory effect on urease and α-chymotrypsin enzyme. All the compounds (1–5) exhibited mild inhibition against urease but remained recessive in case of α-chymotrypsin.     

Biological activity of <Emphasis Type="Italic">Entada phaseoloides</Emphasis> and <Emphasis Type="Italic">Entada rheedei</Emphasis>

The aim of our study is to find functional compounds from natural resources. We focus on plants grown in tropical areas, especially Madagascar and Thailand, because they have unique flora and are expected to contain interesting compounds. We review the functional compounds of the seed kernels of Entada phaseoloides and E. rheedei and their biological activities such as anti-proliferation and melanogenesis inhibitory properties, etc.     

<Emphasis Type="Italic">NAT2</Emphasis>,<Emphasis Type="Italic"> CYP2C9</Emphasis>,<Emphasis Type="Italic"> CYP2C19</Emphasis>, and<Emphasis Type="Italic"> CYP2E1</Emphasis> genetic polymorphisms in anti-TB drug-induced maculopapular eruption

Purpose  

It has been suggested that drug-metabolizing enzymes might play important roles in the development of anti-tuberculosis drug (ATD)-induced maculopapular eruption (MPE), as in ATD-induced hepatitis. We investigated the associations between the genetic polymorphisms of drug-metabolizing enzymes and ATD-induced MPE.     

<Emphasis Type="Italic">Perilla frutescens</Emphasis> var. <Emphasis Type="Italic">frutescens</Emphasis> in northern Laos

Twenty-eight samples of mericarps of Perilla frutescens var. frutescens were collected through fieldwork performed in Phongsali and Xieng Khouang provinces in northern Laos. No perilla samples were collected from Savannakhet province in the south although more than 20 sites were investigated. Perilla plants are mostly grown mixed with dry-paddy rice by slash-and-burn cultivation in Laos. The most popular local name for perilla mericarps in the area was “Ma Nga Chan”. Weight of 1,000 grains and hardness of the mericarps were measured, and all mericarps were found to be large (weight of 1,000 grains around 2 g) and soft (limit load weight under 300 g), which were preferred for culinary use in Laos. The composition of the essential oils obtained from the herbaceous plants raised from the mericarps was divided into five types, perillaketone, elemicine plus myristicine, shisofuran, piperitenon, and myristicine, and GC–MS analysis of these Laotian perilla samples showed that they were similar to those of corresponding types of known Japanese perilla strains. One of the shisofuran-type perilla contained large amounts of putative α-naginatene, which is likely to be an intermediate of the biosynthesis of naginataketone. The farmers' indifference to the oil type of the leaf seems to leave Laotian perilla as a good genetic resource for studies of the biosynthesis of oil compounds.