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.     

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).     

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.     

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.     

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.     

<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 <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.     

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.     

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">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.     

<Emphasis Type="Italic">In Vitro</Emphasis> antioxidant and anti-inflammatory activities of Jaceosidin from <Emphasis Type="Italic">Artemisia princeps</Emphasis> Pampanini <Emphasis Type="Italic">cv.</Emphasis> Sajabal

Oxidized low-density lipoprotein (oxLDL) plays a key role in the inflammatory processes of atherosclerosis. Jaceosidin isolated from the methanolic extracts of the aerial parts of Artemisia princeps Pampanini cv. Sajabal was tested for antioxidant and anti-inflammatory activities. Jaceosidin inhibited the Cu²⁺-mediated LDL oxidation with IC₅₀ values of 10.2 μM in the thiobarbituric acid-reactive substances (TBARS) assay as well as the macrophage-mediated LDL oxidation. The antioxidant activities of jaceosidin were exhibited in the conjugated diene production, relative electrophoretic mobility, and apoB-100 fragmentation on copper-mediated LDL oxidation. Jaceosidin also inhibited the generation of reactive oxygen species (ROS) concerning in regulation of NF-κB signaling. And jaceosidin inhibited nuclear factor-kappa B (NF-κB) activity, nitric oxide (NO) production, and suppressed expression of inducible nitric oxide synthase (iNOS) in lipopolysaccharide (LPS)-induced RAW264.7 macrophages.     

Modification of the effects of 5-methoxy-<Emphasis Type="Italic">N</Emphasis>,<Emphasis Type="Italic">N</Emphasis>-dimethyltryptamine on exploratory behavior in rats by monoamine oxidase inhibitors

RATIONALE: Methylphenidate, which is used to treat attention deficit/hyperactivity disorder, increases extracellular dopamine by inhibiting the dopamine transporter. Methylphenidate has an abuse potential, and there are increasing reports of recreational use of methylphenidate. Little work has examined methylphenidate self-administration in rodent models. OBJECTIVES: This work characterized intravenous methylphenidate self-administration in rats, determined whether dopamine mediates its reinforcing effects and examined the influence of route of administration on the ability of methylphenidate to reinstate extinguished drug-seeking behaviour. MATERIALS AND METHODS: Rats were trained to self-administer methylphenidate (0.25 mg per infusion) via an intravenous catheter according to a fixed ratio 1 (FR1) or progressive ratio (PR) schedule. The effects of manipulating the dose of methylphenidate and of treatment with the dopamine D1 receptor antagonist SCH23390 or the dopamine D2 receptor antagonist eticlopride (both at 0.01 and 0.03 mg/kg) were examined. Finally, the ability of noncontingent administrations of methylphenidate (intraperitoneal [IP] or gavage) to reinstate extinguished drug-seeking behaviour was examined. RESULTS: Rats readily self-administered methylphenidate dose dependently on FR1 and PR schedules. Treatment with SCH23390 or eticlopride increased the number methylphenidate infusions taken by rats on the FR1 schedule and reduced breaking points on the PR schedule. Following extinction of drug-seeking behaviour, methylphenidate reinstated responding and was more effective at doing so when administered IP. CONCLUSION: These results demonstrate that intravenous methylphenidate is a reinforcer and that its reinforcing efficacy is related to increased dopamine activity at D1 and D2 receptors. Methylphenidate reinstates drug-seeking behaviour; the route of administration modifies this response suggesting that pharmacokinetic factors are important in determining methylphenidate-induced reinstatement.     

<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.