N-(2,4,5-Trihydroxyphenehtyl)normetazocine, a potential irreversible inhibitor of the narcotic receptor.

The reaction of N-2,4,5-tribenzyloxyphenyl)ethyl methanesulfonate, prepared in a seven-step sequence, with normetazocine followed by hydrogenolysis of the benzyloxy-protecting groups, gave N-(2,4,5-trihydroxyphenethyl)normetazocine. This compound was prepared to study the effect of a narcotic analgesic containing a functional group which could be activated in situ to a moiety potentially capable of reacting irreversibly with the narcotic receptor. This 6-hydroxydopamin derivative of normetazocine did not prove to be a useful affinity label. Its low toxicity could indicate the necessity for the formation of an aminochrome system for the expression of toxicity by 6-hydroxydopamine.     

3,4,5-三甲氧基氯苄的合成

3,4,5-三甲氧基苯甲醛经硼氢化钠还原得到的3,4,5-三甲氧基苄醇由浓盐酸氯化得到3,4,5-三甲氧基氯苄,总收率67%.     

A naphthoquinone derivative, shikonin, has insulin-like actions by inhibiting both phosphatase and tensin homolog deleted on chromosome 10 and tyrosine phosphatases

The 1,4-naphthoquinone derivative, shikonin, has been shown to increase glucose uptake by adipocytes and myocytes with minor effects on protein tyrosine phosphorylation in the cells (Biochem Biophys Res Commun 292:642-651, 2002). The present study was performed to examine the mechanism of this action of shikonin. Shikonin inhibited the phosphatidylinositol 3,4,5-triphosphate (PtdIns-3,4,5-P3) phosphatase activity of recombinant phosphatase and tensin homolog deleted on chromosome 10 (PTEN) with an IC50 value of 2.7 microM. Shikonin induced marked accumulation of PtdIns-3,4,5-P3 and activation of protein kinase B (PKB) in Chinese hamster ovary cells expressing insulin receptors. In addition to its effect on PTEN, shikonin was found to inhibit several protein phosphatases in cell-free systems. Its effect on tyrosine phosphorylation in intact cells was far weaker than that of pervanadate, a widely used tyrosine phosphatase inhibitor, despite the observation that the effect of shikonin on PKB was more potent than that of pervanadate. These results suggested that the inhibition of PTEN provides a clue to its potent insulin-like actions. We also found that naphthoquinones, including 1,2-naphthoquinone, inhibit PTEN in the cell-free system, which suggested that the effect on PTEN (and thus the effect on phosphatidylinositol 3-kinase signaling) should be taken into account when examining the pharmacological actions of naphthoquinone derivatives.     

Metabolism of alkenebenzene derivatives in the rat III. Elemicin and isoelemicin

1. The metabolites of elemicin (3,4,5-trimethoxyallylbenzene) and isoelemicin (3,4,5-trimethoxypropenylbenzene) in the rat were identified by g.l.c.-mass spectrometry.

2. The major metabolic reactions of elemicin follow the cinnamoyl pathway or the epoxide-diol pathway. The former route gives 3-(3,4,5-trimethoxyphenyl)propionic acid and its glycine conjugate as major urinary metabolites, whereas 3-(3,4,5-trimethoxyphenyl)propane-1,2-diol is the most prominent metabolite of the latter route. Small amounts of the epoxide of the 3-O-demethylated derivative of elemicin were identified in the urine.

3. Isoelemicin was metabolized by both aforementioned pathways; the cinnamoyl pathway predominated and 3-(3,4,5-trimethoxyphenyl)propionic acid was the major urinary metabolite.

4. All of the acidic metabolites detected were C₆-C₃ derivatives and further oxidation to benzoic acid derivatives did not occur.

5. Most of the urinary metabolites were also found in the bile, but in different relative amounts.     

CARBOXYLIC TERMINAL DETERMINATION IN SIMPLER PEPTIDES BY SELECTIVE REDUCTION OF CARBOXYLIC GROUP BY SODIUM DIHYDRO BIS-(2-METHOXYETHOXY) ALUMINATE

The terminal carboxylic group in acylamino acids and peptides is selectively reduced by sodium dihydro bis-(2-methoxyethoxy) aluminate to alcoholic group. On hydrolysing the reduced acylamino acids or peptides, the original carboxy terminal amino acid is liberated as amino alcohol which can be easily identified. The reaction of reduced N-acylamino alcohol with carbonyl diimidazole yields an N-acyl-2-oxazolidone derivative from which the N-acyl group is easily removed producing 2-oxazolidone. The possibility of selective cleavage of the terminal amino alcohol and its characterisation as 2-oxazolidone derivative has been investigated.     

Phenylpropane glycosides from Juniperus phoenicea

Juniperoside, a new 9-O[beta- D-glucopyranoside]-3,4,5-trimethoxycinnamyl alcohol has been isolated along with the 9- O-[alpha-L-arabinofuranosyl-(1-->6)-beta- D-glucopyranoside]cinnamyl alcohol (rosarin) and coumarin 7- O-beta- D-glucopyranoside (skimmin) from the acetone extract of the aerial parts of Juniperus phoenicea L. The structure elucidation of these natural products was achieved mainly by mass and NMR spectroscopy.     

New constituents of Leontopodium alpinum and their in vitro leukotriene biosynthesis inhibitory activity

Phytochemical investigations of the roots of Leontopodium alpinum Cass. resulted in the isolation and structure elucidation of six novel compounds and two known compounds. Novel constituents could be identified as the polyacetylenes 1-acetoxy-3-angeloyloxy-(4 E,6 E)-tetradeca-4,6-diene-8,10,12-triyne and its (6 Z)-isomer, the kaurenic acid derivative methyl ent-7alpha,9alpha-dihydroxy-15beta-[(2 Z)-2-methyl-but-2-enoyloxy]kaur-16-en-19-oate, the bisabolane derivative (1 R*,3 S*,4 R*,6 S*)-9-(acetoxy)-4-hydroxy-1-[(2Z)-2-methylbut-2-enoyloxy]bisabol-10(11)-ene and the lignans [(2 S,3 R,4 R)-4-(3,4-dimethoxybenzyl)-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran-3-yl]-methyl-(2 Z)-2-methylbut-2-enoate and its 3,4,5-trimethoxybenzyl derivative. Known compounds, reported here for the first time for the genus Leontopodium, were identified as ent-kaur-16-en-19-oic acid and T-cadinol. The obtained compounds were tested together with 15 previously described compounds of L. alpinum in an ex vivo leukotriene biosynthesis inhibition assay. The highest activities were determined for the bisabolane derivates (IC50: 7.7 to 11.4 microM), one lignan (IC50: 10.7 microM) and the ent-kaurenoate (IC50: 10.4 microM).     

Antimalarial agents from plants. III. Trichothecenes from Ficus fistulosa and Rhaphidophora decursiva

Bioassay-directed fractionation of an extract prepared from the dried leaves and stem barks of Ficus fistulosa Reinw. ex Blume (Moraceae) led to the isolation of verrucarin L acetate (1), together with 3alpha-hydroxyisohop-22(29)-en-24-oic acid, 3beta-gluco-sitosterol, 3,4-dihydro-6,7-dimethoxyisocarbostyril, 3,4,5-trimethoxybenzyl alcohol, alpha-methyl-3,4,5-trimethoxybenzyl alcohol, indole-3-carboxaldehyde, palmanine, and aurantiamide acetate. Roridin E (2) was identified in a subfraction from the dried leaves and stems of Rhaphidophora decursiva Schott (Araceae). Verrucarin L acetate and roridin E were characterized as macrocyclic trichothecene sesquiterpenoids and found to inhibit the growth of Plasmodium falciparum with IC 50 values below 1 ng/ml.     

Synthesis and anticancer activities of 4-oxobenzopyrano[2,3-d]pyrimidines

Several 2-aryl-4-oxoxbenzopyrano[2,3-d]pyrimidines have previously been shown to exhibit in vivo antitumor activity in mice with P388 lymphocytic leukemia. In the present study, a series of novel substituted benzopyrano[2,3-d]pyrimidines have been prepared and tested for cytotoxic activity against a panel of cancer cell lines including the P388 lymphocytic leukemia cell line. The unsubstituted parent compound, some methoxylated derivatives and a cyclohexyl derivative all exhibited potent cytotoxic activity (IC50 values 0.3-0.64 microM). A number of derivatives, including the unsubstituted parent pyrimidine, were shown to cause a significant perturbation in cell cycle kinetics with an observed 2- to 3-fold increase in cells in the G2/M phase of the cell cycle. Furthermore, a polymethoxylated derivative, 2-(3,4,5-trimethoxyphenyl)-9-methoxy-4-oxo-2,3-dihydrobenzopyrano[ 2,3-d]pyrimidine 13, was shown to be selectively active against a number of human ovarian cell lines.     

Synthesis of 4-Alkylpyrazoles as Inhibitors of Liver Alcohol Dehydrogenase

Theoretical studies by shape analysis of the molecular electrostatic potential on the van der Waals surfaces of a set of 4-alkylpyrazoles predicted 4-isopentyl derivative as a good inhibitor of liver alcohol dehydrogenase. Thus, the new 4-isopentyl and the already known 4-octylpyrazole have been prepared by a novel route. The isopentyl derivative has been tested as inhibitor of horse liver alcohol dehydrogenase giving the result predicted by the theoretical studies.     

Spectrophotometric and liquid chromatographic determination of trimebutine maleate in the presence of its degradation products

Three methods are presented for the determination of trimebutine maleate (TM) in the presence of its degradation products. The first method was based on a high performance liquid chromatographic (HPLC) separation of TM from its degradation products using an ODS column at ambient temperature with a mobile phase consisting of acetonitrile-5 mM heptane sulfonic acid disodium salt (45:55, v/v, pH 4) with UV detection at 215 nm. The second method depends on using first derivative spectrophotometry (1D) by measurement of the amplitude at 252.2 nm. The third method depends on using first derivative of the ratio spectrophotometry (1DD) by measurement of the amplitude at 282.4 nm where a normalized spectrum of 3,4,5-trimethoxy benzoic acid is used as divisor. The proposed HPLC and 1D methods were used to investigate the kinetics of acidic and alkaline degradation processes. The pH-rate profile of degradation of TM in Britton-Robinson buffer solutions within the pH range 2-11.9 was studied.     

Oxidative metabolism of mescaline in the central nervous system—V: In vitro deamination of mescaline to 3,4,5-trimethoxy-benzoic acid

3,4,5-Trimethoxy-benzoic acid (3,4,5-TMBA) besides 3,4,5-trimethoxy-phenylacetic acid (3,4,5-TMPAA) is formed from mescaline during its incubation with preparations of different mouse tissues. Brain has the highest capacity to form 3,4,5-TMBA among the tissues so far studied. The enzyme system which catalyses the oxidative deamination of mescaline to 3,4,5-TMBA is localized in the nuclear and microsomal fractions of brain. Oxygen, NAD(P)H and unidentified factors of the high speed supernatant of brain extract are necessary for optimal reaction conditions. 3,4,5-TMBA formation was inhibited by SKF 525-A, but not by MAO and DAO inhibitors. The similarities and dissimilarities of the enzymic deamination of amphetamine and mescaline are discussed.     

3,4,5-Tricaffeoylquinic Acid Inhibits the Lipopolysaccharide-Stimulated Production of Inflammatory Mediators in Keratinocytes

Background and Purpose: Microbial product lipopolysaccharide (LPS) has been shown to be involved in the pathogenesis of inflammatory skin diseases. Caffeoyl derivatives have demonstrated anti-inflammatory and antioxidant effects. However, the effect of 3,4,5-tricaffeoylquinic acid (3,4,5-triCQA) on the production of microbial product-induced inflammatory mediators in keratinocytes has not yet been studied. Experimental Approach: Using human keratinocytes, we investigated the effect of 3,4,5-triCQA on the LPS-stimulated production of inflammatory mediators in relation to the nuclear factor (NF)-?B, Akt and ERK pathways. Results: 3,4,5-triCQA inhibited the LPS-induced expression of Toll-like receptor 4, and the production of cytokines and chemokines in keratinocytes. 3,4,5-triCQA, Bay 11-7085, A?t inhibitor and ERK inhibitor each attenuated the LPS-induced production of inflammatory mediators by inhibiting the NF-?B, Akt and ERK pathways. Conclusions and Implications: 3,4,5-triCQA may attenuate the LPS-stimulated production of inflammatory mediators in keratinocytes by suppressing the Toll-like receptor 4 expression-mediated activation of the Akt, ERK and NF-?B pathways. 3,4,5-triCQA may exert a preventive effect against microbial product-induced inflammatory skin diseases.     

Synthesis and biological evaluation of 2- and 3-aminobenzo[b]thiophene derivatives as antimitotic agents and inhibitors of tubulin polymerization

Two new series of inhibitors of tubulin polymerization based on the 2-amino-3-(3,4,5-trimethoxybenzoyl)benzo[b]thiophene molecular skeleton and its 3-amino positional isomer were synthesized and evaluated for antiproliferative activity, inhibition of tubulin polymerization, and cell cycle effects. Although many more 3-amino derivatives have been synthesized so far, the most promising compound in this series was 2-amino-6-methyl-3-(3,4,5-trimethoxybenzoyl)benzo[b]thiophene, which inhibits cancer cell growth at subnanomolar concentrations and interacts strongly with tubulin by binding to the colchicine site.     

4(H)-1,2,4-triazole derivatives with expected biological activity. Part IV. Synthesis of substituted 3,4,5-triaryl-1,2,4-triazoles.

A series of 23 3,4,5-triaryl-1,2,4-triazoles with various substituents in one, two, or all three aromatic rings were prepared for screening tests as potential antibacterial, mostly antituberculotic agents. The synthesis, depending on the nature and position of the substituents, was accomplished by one of the following methods; (A) condensation of symmetrically substituted bis(alpha-chlorobenzylidene)hydrazine with an aniline derivative; (B) reaction of an aniline derivative with a symmetrical diaroylhydrazine in the presence of PCL3; (C) direct condensation of aroylhydrazine with an appropriately substituted N-phenylbenzimidoyl chloride. The latter method was considered to be most advantageous; it warranted highest yield and purity of the products and made it possible to prepare triazoles with three different aryl groups.     

Role of intracellular Ca2+ on histamine release from rat peritoneal mast cells.

The benzoic acid derivative 8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate hydrochloride (TMB-8) strongly inhibited histamine release from rat peritoneal mast cells induced by various secretagogues. TMB-8 also inhibited Ca2+ mobilization from intracellar Ca2+ stores. However, histamine release induced by compound 48/80 (condensation product of N-methyl-p-methoxy-phenethylamine and formaldehyde) was not affected by TMB-8. These results indicate that Ca2+ mobilization is necessary to elicit the release of histamine from mast cells.     

Antitumor activity of substituted E-3-(3,4,5-trimethoxybenzylidene)-1,3-dihydroindol-2-ones1

The design and synthesis of anticancer E-3-(3,4,5-trimethoxybenzylidene)-1,3-dihydroindol-2-ones is reported. Strong COMPARE correlations among the cell line responses suggest that these compounds may be acting similarly through a combination of different mechanisms of action. The 5-methoxy derivative (2h) was the most active compound with a mean pGI50 of 6.34, and it is now under review by Biological Evaluation Committee of the National Cancer Institute for possible further studies.     

The complexity of PTEN: mutation, marker and potential target for therapeutic intervention

Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is a phosphatase that removes phosphates primarily from lipids. It has also been called mutated in multiple advanced cancers 1 and transforming growth factor-beta regulated epithelial cell-enriched phosphatase 1. The best described substrate of PTEN is phosphatidyliniositol (3,4,5)-tris-phosphate [PtdIns(3,4,5)P3]. PTEN removes the phosphate in PtdIns(3,4,5)P(3) to generate PtdIns(4,5)P(2). PTEN serves to counter-balance the effects of phosphoinositide 3' kinase, which normally adds a phosphate to PtdIns(4,5)P(2) to generate PtdIns(3,4,5)P(3). PtdIns(3,4,5)P(3) recruits kinases such as phosphoinositide-dependent kinase 1, which in turn phosphorylate Akt, which phosphorylates other downstream proteins involved in regulation of apoptosis and cell-cycle progression. PTEN removal of the phosphate from PtdIns(3,4,5)P(3) inhibits this pathway by preventing localisation of proteins with pleckstrin homology domains to the cell membrane. Alterations of the PTEN gene are associated with cancer and other diseases. Novel therapeutic approaches have been developed to counteract the deletion/mutation of PTEN in human cancer. This review will discuss the role of PTEN in signal transduction and cancer as well as pharmacological approaches to combat PTEN loss in human cancer.     

Novel bronchodilators: synthesis, transamination reactions, and pharmacology of a series of pyrazino[2,3-c][1,2,6]thiadiazine 2, 2-dioxides

The synthesis, pharmacological evaluation, and structure-activity relationships of a new class of bronchodilator agents, derivatives of pyrazino[2,3-c][1,2,6]thiadiazine 2,2-dioxides are described. The compounds were prepared by reaction of 3,4,5-triamino-1,2, 6-thiadiazine 1,1-dioxide with suitable 1,2-dicarbonyl compounds or alpha-hydroxyiminoketones and subsequent N-alkylation. A transamination procedure for synthesizing derivatives with different substituents at the 4-amino group is reported for the first time. The pyrazino[2,3-c][1,2,6]thiadiazine derivatives were screened for tracheal relaxing activity in vitro, and the active compounds were evaluated in vivo in guinea pigs as bronchodilator agents in comparison to theophylline. Among the compounds studied, the most interesting properties were displayed by the 4-amino-1-ethyl-6-methyl derivative (21). The toxicological evaluation of this derivative is also reported.     

Ethanol-induced alteration of dopamine metabolism in rat liver

Ethanol alters the metabolism of dopamine such that the final product is no longer predominantly the acid, 3,4-dihydroxyphenylacetic acid (DOPAC), but is a mixture of the acid and the alcohol derivative, 3,4-dihydroxyphenylethanol (DOPET). The ratio of DOPAC/DOPET produced in rat liver slices incubationed with [ethylamine-2-¹⁴C]dopamine hydrochloride in the absence of ethanol is ca. 10, while in the presence of ethanol it is 0.25. Addition of alcohol dehydrogenase (ADH) inhibitors prevents the alteration in metabolism. Changing the NAD/NADH ratio of the liver cytosol by adding lactate to the incubation medium does not cause an alteration in the metabolism of dopamine. Acetaldehyde addition in the presence or absence of ADH inhibitors does not enhance the production of the alcohol derivative, though there was a small decrease in DOPAC levels. Thus, neither the decreased liver cytosol NAD/NADH ratio nor the preferential oxidation of acetaldehyde over 3,4-dihydroxyphenyl acetaldehyde (DOPAL) can explain the ethanol-induced alteration in dopamine metabolism. 3-Etiocholan-3β-o1-17-one, an alternative substrate for ADH, whose product of oxidation is neither a substrate nor an inhibitor of aldehyde dehydrogenase, mimics the effect of ethanol such that in its presence the metabolism of dopamine to its alcohol derivative is enhanced. An increased reduction of DOPAL by the NADPH-dependent aldehyde reductase cannot explain the dramatic enhancement of DOPET formation observed in the presence of ethanol or the sterol because the NADPH/ NADP ratio is normally very high in the liver. Due to the unique enzyme mechanism of ADH, in which the rate-limiting step of the reaction is the release of NADH from the enzyme, a finite concentration of the enzyme-NADH complex will exist during alcohol metabolism. We propose that the biogenic aldehyde binds to this form of ADH and is reduced.