Β-resorcylic Acid Research Articles

β-Resorcylic Acid Lactones from a Paecilomyces Fungus

Six new beta-resorcylic acid lactones (1-6), named paecilomycins A-F, and five known compounds, aigilomycin B (7), zeaenol (8), aigialomycin D (9), aigialomycin F (10), and aigialospirol, were isolated from the mycelial solid culture of Paecilomyces sp. SC0924. Their structures were elucidated by extensive NMR analysis, single-crystal X-ray study, and chemical correlations. Compounds 5 and 10 exhibited antiplasmodial activity against Plasmodium falciparum line 3D7 with IC(50) values of 20.0 and 10.9 nM, respectively, and compounds 5-7 showed moderate activity against the P. falciparum line Dd2.

Cannabidiolic Acid as a Selective Cyclooxygenase-2 Inhibitory Component in Cannabis

In the present study it was revealed that cannabidiolic acid (CBDA) selectively inhibited cyclooxygenase (COX)-2 activity with an IC(50) value (50% inhibition concentration) around 2 microM, having 9-fold higher selectivity than COX-1 inhibition. In contrast, Delta(9)-tetrahydrocannabinolic acid (Delta(9)-THCA) was a much less potent inhibitor of COX-2 (IC(50) > 100 microM). Nonsteroidal anti-inflammatory drugs containing a carboxyl group in their chemical structures such as salicylic acid are known to inhibit nonselectively both COX-1 and COX-2. CBDA and Delta(9)-THCA have a salicylic acid moiety in their structures. Thus, the structural requirements for the CBDA-mediated COX-2 inhibition were next studied. There is a structural difference between CBDA and Delta(9)-THCA; phenolic hydroxyl groups of CBDA are freed from the ring formation with the terpene moiety, although Delta(9)-THCA has dibenzopyran ring structure. It was assumed that the whole structure of CBDA is important for COX-2 selective inhibition because beta-resorcylic acid itself did not inhibit COX-2 activity. Methylation of the carboxylic acid moiety of CBDA led to disappearance of COX-2 selectivity. Thus, it was suggested that the carboxylic acid moiety in CBDA is a key determinant for the inhibition. Furthermore, the crude extract of cannabis containing mainly CBDA was shown to have a selective inhibitory effect on COX-2. Taken together, these lines of evidence in this study suggest that naturally occurring CBDA in cannabis is a selective inhibitor for COX-2.

Geochemical Transformation of Trichloroacetic Acid to Chloroform in Fresh Waters – The Results Based Upon Laboratory Experiments

In order to explore the geochemical transformation of trichloroacetic acid to chloroform in fresh waters, an experimental study by using laboratory microcosms was performed. The study confirmed the abiotic transformation of TCA to chloroform with various rate constants, ranging from approx. 3.29×10−4 day−1 to 4.41×10−4 day−1, in different fresh waters at 25± 1 ∘C. Also, an induction period (5–6 days) was observed before apparent degradation of TCA. Of the four geochemical factors including pH, oxygen, humic substances and ferric ion, the influence of lake HA, extracted from East Lake, on the transformation has been proven to be more substantial. Several model substances of HA, such as acetic acid, citric acid and β-Resorcylic acid etc., were also found to promote chloroform formation. Whilst, the results of pH effect experiments showed that higher yields of chloroform released from TCA solution occurred in the intensified alkaline media (pH = 10), an unusual condition in environment, indicating the limited effect of pH on the transformation under prevailing conditions in natural waters. According to our study, a mathematic model was built and successfully used to simulate TCA transformation to chloroform in fresh waters. Mathematic simulation demonstrates that the rates of decay for chloroform formation, after induction time, are mainly owing to rapid TCA degradation. In addition, biotic experiments indicated that fresh water algae affect TCA transformation to chloroform in varying degrees. The blue alga Anabaena cylindrica remarkably promoted chloroform formation, in weak acid media (pH = 6.5). While, the green alga Chlorella vulgari seems to indistinctively affect chloroform formation, whether in alkaline or weak acidic media. Enzyme or other byproducts of alga, such as citric acid, might play roles in the TCA transformation.

Antibacterial Activities of Naturally Occurring Compounds against Antibiotic-Resistant Bacillus cereus Vegetative Cells and Spores, Escherichia coli, and Staphylococcus aureus

After demonstrating the lack of effectiveness of standard antibiotics against the acquired antibiotic resistance of Bacillus cereus (NCTC 10989), Escherichia coli (NCTC 1186), and Staphylococcus aureus (ATCC 12715), we showed that the following natural substances were antibacterial against these resistant pathogens: cinnamon oil, oregano oil, thyme oil, carvacrol, (S)-perillaldehyde, 3,4-dihydroxybenzoic acid (β-resorcylic acid), and 3,4-dihydroxyphenethylamine (dopamine). Exposure of the three pathogens to a dilution series of the test compounds showed that oregano oil was the most active substance. The oils and pure compounds exhibited exceptional activity against B. cereus vegetative cells, with oregano oil being active at nanogram per milliliter levels. In contrast, activities against B. cereus spores were very low. Activities of the test compounds were in the following approximate order: oregano oil > thyme oil ≈ carvacrol > cinnamon oil > perillaldehyde > dopamine>β-resorcylic acid. The order of susceptibilities of the pathogens to inactivation was as follows: B. cereus (vegetative) ≫S. aureus ≈ E. coli ≫ B. cereus (spores). Some of the test substances may be effective against antibiotic-resistant bacteria in foods and feeds.

Separation and Determination of Phenolcarboxylic Acids by Capillary Zone Electrophoresis with Dynamic Preconcentration on Hypercrosslinked Polystyrene

The sorption of phenolcarboxylic acids in the batch and dynamic modes on MN-200 hypercrosslinked polystyrene was studied. Conditions of the separation of phenolcarboxylic acids by capillary zone electrophoresis were optimized. The time of the analysis of a ten-component mixture including salicylic, 4-hydroxybenzoic, β-resorcylic, protocatechuic, gallic, syringic, caffeic, ferulic, benzoic, and cinnamic acids is no longer than 15 min. A procedure is described for the dynamic group preconcentration of phenolcarboxylic acids on a microcolumn filled with MN-200 and the subsequent determination of individual compounds in the eluate by capillary zone electrophoresis; performance characteristics are presented.

Hydrogen peroxide scavenging, antioxidant and anti-radical activity of some phenolic acids

Some water-soluble phenolic acids were investigated as antioxidants, scavengers of hydrogen peroxide (H 2O 2) and scavengers of 1,1-diphenyl-2-picrylhydrazyl radical (DPPH •). The strongest antioxidant, scavenging of H 2O 2 and DPPH • radical activity was exhibited by 3,4,5-trihydroxybenzoic (gallic) acid and 1,2,3-trihydroxybenzene (pyrogallol) with three hydroxyl groups bonded to the aromatic ring in an ortho position in relation to each other. Phenolic acids with two hydroxyl groups bonded to aromatic ring in the ortho position, such as 3,4-dihydroxycinnamic (caffeic), 3,4-dihydroxybenzoic (protocatechuic) and 2,3-dihydroxybenzoic ( o-pyrocatechuic) acids, showed strong antioxidant and anti-radical activity; however, it was lower than that of 3,4,5-trihydroxybenzoic acid or 1,2,3-trihydroxybenzene. 3,5-Dihydroxybenzoic (α-resorcylic) and 2,4-dihydroxybenzoic (β-resorcylic) acids with two hydroxyls bonded in the meta position in relation to each other showed moderate antioxidant and low DPPH • and hydrogen peroxide scavenging activity. Compounds with one hydroxyl group such as 3-hydroxybenzoic, 4-hydroxyphenylacetic and 2-hydroxybenzoic (salicylic) acids, exhibited the lowest anti-radical and antioxidant activity. The results obtained show that the antioxidant and anti-radical activity of phenolic acids correlated positively with the number of hydroxyl groups bonded to the aromatic ring. The model of an ortho substitution of hydroxyl groups to the aromatic ring seems to be adequate for antioxidant and H 2O 2 or DPPH • scavenging activity of phenolic acids.

Analysis of sugar acids by capillary electrophoresis with indirect UV detection. Application to samples of must and wine.

A study has been conducted of the separation of sugar acids (gluconic, galacturonic and glucuronic acids) by capillary electrophoresis using indirect UV detection. We have tested various background electrolytes: p-hydroxibenzoic acid, sorbic acid, potassium hydrogen phthalate, protocatechuic acid, α-resorcylic acid and β-resorcylic acid. The choice between these electrolytes was made on the basis of studies of electrophoretic mobility and absorbance values at the wavelengths of our CE system. Of all the electrolytes tested, it was found that β-resorcylic acid best met the required characteristics. The best separation of the three acid was achieved with a time of 8 min, for an electrolyte consisting of 5 mM β-resorcylic acid, 1 mM TTAOH (pH 3.0), indirect detection at 214 nm, -20 kV of run voltage and capillary of 60 cm length and 75 µm i.d. It was found that the proposed method is applicable to samples of both must and wine, and that the samples do not require any prior treatment apart from centrifugation (only in the case of must), filtration and dilution in suitable proportion.

Kinetic model for phenolic compound oxidation by Fenton's reagent

A kinetic model is developed for the oxidation of phenolic compounds by Fenton's reagent. In the first stage a rigorous kinetic model is applied to calculate the different kinetic rate constants for the oxidation process of p-hydroxybenzoic acid. In a second phase a competitive method is applied to calculate these kinetic constants for another 10 phenolic compounds present in agroindustrial and pulp paper wastewaters. These 10 phenolic compounds were: β-resorcylic acid, 3-(4-hydroxyphenyl)-propionic acid, ferulic acid, protocatechuic acid, caffeic acid, p-coumaric acid, vanillic acid, syringic acid, veratric acid and 3,4,5-trimethoxybenzoic acid.

Comparison of quercetin and a non-orthohydroxy flavonol as antioxidants by competing in vitro oxidation reactions.

Two structurally related flavonols, quercetin and morin, along with protocatechuic acid (PA), beta-resorcylic acid (DHBA), and phloroglucinol carboxylic acid (PCA), which represent quercetin and morin degradation products, were assessed with respect to their antioxidant potency by chemical comparisons in competing oxidation reactions. The measurement of the antioxidant capacity was performed with the beta-carotene bleaching method, and the compounds were also tested with respect to their abilities to prevent lipid, protein, and DNA oxidation. The effect of concentration was also considered. The results obtained strongly suggested that quercetin is a powerful antioxidant in every system used, whereas morin is a much weaker antioxidant and in some cases may also have pro-oxidant action. PA and PCA were always inferior antioxidants compared to the parent molecule quercetin; DHBA and PCA exhibited activities comparable to that of morin in reaction comparisons.

Syntheses of β-resorcylic acid derivatives, novel potato micro-tuber inducing substances isolated from Lasiodiplodia theobromae

Abstract The syntheses of β-resorcylic acid derivatives 1 and 2, isolated from fungus Lasiodiplodia theobromae, and their dimethyl ethers were accomplished. (R)-(−)-1,3-Butanediol was used as a chiral source of the side chain C6-synthon. The dianion of the benzoic acid moiety was alkylated with C6-bromide to give the desired skeleton. Several β-resorcylic acid derivatives including 1 and 2 were synthesized via hydrogenation, lactonization, demethylation and esterification. The (R)-configuration of the stereogenic center in the side chain was proved by this synthesis. It is confirmed that two phenolic hydroxy groups are required for 1 and 2 to exhibit potato micro-tuber inducing activity.

Total Synthesis of Biologically Active Compounds Related to Plant Disease and the Physiological Function.

Total synthesis of biologically active compounds related to plant disease and the physiological function has been accomplished. Coronatine, its related compounds, β-resorcylic acid derivatives, decumbic acid, aliphatic δ-lactones, cepaciamides, and piscidic acids, were selected as the synthetic targets. In these syntheses, the chiral pool method and catalytic asymmetric synthesis were also applied to introduce the requisite stereogenic centers. Combination of the two methods made it possible to synthesize a sufficient amount of the required enantiomers and diastereomers for biological studies.

Kinetics of the reaction between ozone and phenolic acids present in agro-industrial wastewaters

The kinetics of the ozonation of three phenolic acids is investigated from ozone absorption experiments in a semi-continuous reactor. After the evaluation of stoichiometric ratios for the individual reactions between ozone and each phenolic acid, the oxidation of p-hydroxybenzoic acid by ozone is performed in a first stage. The influence of the operating variables on the degradation process is established, and the application of a mass transfer with chemical reaction model based on the film theory leads to the determination of the reaction orders and kinetic rate constants. The experimental absorption rates obtained agree well with those calculated theoretically. In the second stage, a mixture of ferulic acid (4-hydroxy-3-methoxycinnamic acid), β-resorcylic acid (2,4-dihydroxybenzoic acid) and p-hydroxybenzoic acid is ozonated under different experimental conditions. The kinetic study is performed by means of a competitive method that takes p-hydroxybenzoic acid as reference compound. The application of this model allows to determine the kinetic rate constants for each compound, which are correlated as a function of pH and temperature. The results obtained support that the kinetic regime of absorption is fast and pseudo-first order with respect to ozone, a condition required by the competitive method used.

Valuation of Phytotoxic Activity of Naturally Occurring Phenolic Compounds.

Relative phytotoxic activity of 21 phenolic compounds previously reported as allelochemicals was evaluated with aqueous solution test and soil incorporation test. At 1.0mM, aqueous solutions of juglone, coumarin, t-cinnamic acid, o-hydroxy-phenylacetic acid and 3-phenylpropionic acid were most inhibitory to the radicle elongation of lettuce (Lactuca sativa) and Japanese barnyard millet (Echinochloa utilis), followed by salicylic acid, β-resorcylic acid and benzoic acid (Fig. 1). The effect greatly decreased at 0.1mM for all compounds except juglone. Lettuce was more susceptible than E. utilis. The most effective 8 compounds were then incorporated in soil and bioassayed using germinating lettuce (Fig. 2). Inhibitory activity on lettuce radicle elongation was highest in juglone, followed by coumarin, as in the solution test. The effect on 14 plant species of soil-incorporated coumarin and juglone was also determined. Although juglone fatally inhibited radicle elongation of all test species at 2.0μmol/g soil, phytotoxic activity of coumarin at 2.0μmol/g soil differed greatly among the species, and the activity of both compounds at 0.2 and 0.4μmol/g soil also differed among them (Fig. 3). In this case the sensitivity of test plants did not relate to the family of species, but seemed to have some relationships with their seed size. The larger seed species tended to be less sensitive to both compounds, while sensitivity of the small seed species varied over a wide range (Fig. 4).

Plasmodium berghei mouse model: antimalarial activity of new alkaloid salts and of thiosemicarbazone and acridine derivatives.

Sixteen compounds were synthesized and evaluated on Plasmodium berghei in CD1 mouse. The nature of the salt associated to the active principle can give some advantages in the field of activity, bioavailability and toxicity. beta-Resorcylic acid was chosen in this study because of its previously described antimalarial activity and its expected enhancement of quinine antimalarial activity. While treatment with subcutaneous quinine sulphate at 1 mmol/kg cured 6/10 mice, quinine beta-resorcylate cured all the mice under identical conditions. Although such a result appeared promising, in vitro investigation should be performed to draw clear conclusions regarding a synergy between quinine and beta-resorcylate. Cinchonidine beta-resorcylate was also active; all mice were cured at 1 mmol/kg and the mean survival time was 13.8 +/- 2.4 days after a subcutaneous treatment at 0.5 mmol/kg in a single dose. In the series of acridines, (N-alpha, sigma-dioxopentyl)-5-amino-1,2,3,4-tetrahydroacridine cured all mice at 50 mumol/kg under the same conditions. The maximum tolerated doses in mice ranged from 100 to 150 mumol/kg for these acridine derivatives. The chemotherapeutic index of (N-alpha, sigma-dioxopentyl)-5-amino-1,2,3,4-tetrahydroacridine was estimated at 2-3. Other salts expected to reduce the toxicity, such as alpha-ketoglutarate and p-chlorophenoxyacetate, did not enhance the activity of the active principles. These results prompt us to further investigations including plasma kinetic evaluation in rats and in vitro on Plasmodium falciparum.

Radicol, a microbial cell differentiation modulator, inhibits in vivo angiogenesis

Angiogenesis plays a significant role in various pathological states, including the progressive growth of solid tumors, rheumatoid arthritis, psoriasis, and diabetic retinopathy, in addition to its crucial role in embryonic development. Recent studies have revealed that an angiogenesis inhibitor is efficaciuos for these so-called angiogenic diseases. In the previous studies, we found that retinoids and vitamin D 3 analogs, which are known to exhibit cell differentiation-modulating activity, effectively inhibit angiogenesis in vivo, thus forming the basis of our working hypothesis that a modulator of cell differentiation is capable of affecting angiogenesis. In this study, to verify this hypothesis further, radicicol (syn. monorden; 5-chloro-6-(7,8-epoxy-10-hydoxy-2-oxo-3,5-undecadi enyl)-β-resorcylic acid μ-lactone), a microbial cell differentiation modulator from a fungus, a strain of Neocosmospora tenuicristata, was examined for its anti-angiogenic activity in a bioassay system involving chorioallantoic membranes of growing chick embryos. The microbial cell differentiation modulator dose dependently inhibited embryonic angiogenesis, The ID 50 value being 200 ng/egg. Radicicol also inhibited both the proliferation of and plasminogen activator production by vascular endothelial cells in the nM concentration range in a concentration-dependent manner, suggesting the possible involvement of these inhibitory effects in the anti-angiogenic action of the microbial product. These results indicate that radicicol might be a potential drug for treating different angiogenesis-dependent diseases, such as solid tumors, psoriasis, rheumatoid arthritis, and diabetic retinopathy.

Tamoxifen prevents induction of hepatic neoplasia by zeranol, an estrogenic food contaminant.

Zeranol (alpha-zearalanol) is a beta-resorcylic acid lactone (RAL) that has estrogen activity. It is synthesized by molds and is difficult to avoid in human food products. We tested the ability of this mycoestrogen to damage the liver of the Armenian hamster, a rodent that is especially sensitive to hepatotoxic effects of exogenous estrogens. Zeranol induced acute hepatotoxicity and, subsequently, hepatic carcinogenesis; both effects were blocked by tamoxifen, suggesting estrogen receptor mediation. Because zeranol is acting alone as a primary initiator of hepatic neoplasms, this model provides an unusual opportunity to study the pathogenesis of estrogen-initiated tumorigenesis.

Oral zeranol shortens the prolonged bleeding time of uremic rats

Intravenous conjugated estrogens reduce the prolonged bleeding time in uremic patients and in a rat model of uremia. However, estrogens have major side effects related to their hormonal activity. We investigated whether a beta-resorcylic acid lactone, zeranol (a compound with close spatial similarity to estrogens but with a weak estrogenic activity), improves primary hemostasis in uremic rats and whether the effect is mediated by estrogen receptors. The results showed that single oral administration of zeranol significantly (P less than 0.01) shortened the bleeding time of uremic rats, 20 mg/kg being the minimum effective dose. This effect was long-lasting (72 hours). The dose of 30 mg/kg zeranol reproduced the pattern observed after 20 mg/kg but bleeding time values were still significantly (P less than 0.01) shortened 96 hours after the administration. No changes in hematocrit, platelet and leukocyte count, and serum creatinine were detected after zeranol administration. When uremic rats were pre-treated orally with two estrogen receptor antagonists, tamoxifen and clomiphene (3 mg/kg), zeranol did not shorten the bleeding time, thus suggesting that the hemostatic effect of zeranol was due to an estrogen receptor-mediated mechanisms. These results might have important future implications for the management of uremic bleeding in humans.

Régioselectivité de la propargylation, par des ions carbéniums organométalliques, d'aromatiques polysubstitués; application aux dérivés du zéranol

The selective attachment of propargyl Co 2(CO) 6 groups at polysubstituted arene rings has been studied in zeranol, β-resorcylic acid and 6-methyl-β-resorcyclic acid series.

Influence of electrostatic effect on the stability of mixed-ligand complexes: Uranyl-complexone-phenol/phenolic acid ternary systems

The formation constants (logKMALMA) of the complexes of the type (UO2.A.L] (whereA = IMDA, NTA or EDTA;L = catechol, resorcinol, phloroglucinol, pyrogallol, β-resorcylic acid or protocatechuic acid) have been determined potentiometrically at 25°C and ionic strength,I = 0·2 (mol dm−3, NaClO4) using the Irving-Rossotti approach. The formation constants of the binary complexes (logKKMAKM) have been found to lie in the sequence IMDA NTA > EDTA. due to the electrostatic effect.

Friedel-Crafts Polymers. 8. Friedel-Crafts Polycondensation of β-Resorcylic Acid or Resorcinol with p-Xylylene Dichloride, p,p′-Dichloromethyldiphenyl Ether, and p,p′-Dichloroacetyldiphenyl Ether

Abstract Friedel-Crafts polycondensation of β-resorcylic acid (BRA) with p-xylylene dichloride (PXDC) or 4,4′-dichloromethyldiphenyl ether (DDE) in dioxane could be effected without simultaneous decarboxylation of BRA. The similar polycondensation of BRA with PXDC, DDE, or 4,4′-dichloroacetyldiphenyl ether (DADE) in nitrobenzene or in the absence of solvent at 150°C was associated with decarboxylation of BRA. Polymers having structures isomeric with those of the polycondensation product of BRA formed with subsequent in situ decarboxylation were prepared by Friedel-Crafts polycondensation of resorcinol with the above dichlorides. All the polymer samples were characterized, and those with related structures were compared. The ion-exchange properties of the polymer sample prepared from BRA and DDE in dioxane were studied.