salicylates and anacardic-acid

MUC1 is a transmembrane mucin that can promote cancer progression, and its upregulation correlates with a worse prognosis in colon cancer. We examined the effects of overexpression of MUC1 in colon cancer cells, finding that it induced epithelial to mesenchymal transition (EMT), including enhanced migration and invasion, and increased Akt phosphorylation. When the clones were treated with the aspirin metabolite salicylate, Akt phosphorylation was decreased and EMT inhibited. As the salicylate motif is necessary for the activity of the lysine acetyltransferase (KAT) inhibitor anacardic acid, we hypothesized these effects were associated with the inhibition of KAT activity. This was supported by anacardic acid treatment producing the same effect on EMT. In vitro KAT assays confirmed that salicylate directly inhibited PCAF/Kat2b, Tip60/Kat5 and hMOF/Kat8, and this inhibition was likely involved in the reversal of EMT in the metastatic prostate cancer cell line PC-3. Salicylate treatment also inhibited EMT induced by cytokines, illustrating the general effect it had on this process. The inhibition of both EMT and KATs by salicylate presents a little explored activity that could explain some of the anti-cancer effects of aspirin.

Topics: Anacardic Acids; Cell Line, Tumor; Cell Proliferation; Cell Survival; Colorectal Neoplasms; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; HT29 Cells; Humans; Lysine Acetyltransferases; Male; Mucin-1; Neoplasms; Phosphorylation; Prostatic Neoplasms; Proto-Oncogene Proteins c-akt; Salicylates

Lipoxygenases catalyze the oxidation of unsaturated fatty acids, such as linoleic acid, which play a crucial role in inflammatory responses. Selective inhibitors may provide a new therapeutic approach for inflammatory diseases. In this study, we describe the identification of a novel soybean lipoxygenase-1 (SLO-1) inhibitor and a potato 5-lipoxygenase (5-LOX) activator from a screening of a focused compound collection around the natural product anacardic acid. The natural product anacardic acid inhibits SLO-1 with an IC(50) of 52 μM, whereas the inhibitory potency of the novel mixed type inhibitor 23 is fivefold enhanced. In addition, another derivative (21) caused non-essential activation of potato 5-LOX. This suggests the presence of an allosteric binding site that regulates the lipoxygenase activity.

Topics: Anacardic Acids; Arachidonate 5-Lipoxygenase; Dose-Response Relationship, Drug; Enzyme Activation; Glycine max; Lipoxygenase; Lipoxygenase Inhibitors; Molecular Structure; Salicylates; Solanum tuberosum; Structure-Activity Relationship

Protein modification by small ubiquitin-related modifier proteins (SUMOs) controls diverse cellular functions. Dysregulation of SUMOylation or deSUMOylation processes has been implicated in the development of cancer and neurodegenerative diseases. However, no small-molecule inhibiting protein SUMOylation has been reported so far. Here, we report inhibition of SUMOylation by ginkgolic acid and its analog, anacardic acid. Ginkgolic acid and anacardic acid inhibit protein SUMOylation both in vitro and in vivo without affecting in vivo ubiquitination. Binding assays with a fluorescently labeled probe showed that ginkgolic acid directly binds E1 and inhibits the formation of the E1-SUMO intermediate. These studies will provide not only a useful tool for investigating the roles of SUMO conjugations in a variety of pathways in cells, but also a basis for the development of drugs targeted against diseases involving aberrant SUMOylation.

Topics: Anacardic Acids; Ginkgo biloba; Plant Extracts; Plant Leaves; Protein Binding; Salicylates; Small Molecule Libraries; Small Ubiquitin-Related Modifier Proteins; Structure-Activity Relationship; Ubiquitination

The defensive chemistry of two species of ants from Brunei in the genus Crematogaster (Physocrema group) has been investigated. Ants in this group release a white secretion from hypertrophied metapleural glands on their thorax when they are disturbed. Previously, one species in this group has been shown to produce alkylphenols and alkylresorcinols. In the present investigation, similar compounds along with salicylic acids and resorcylic acids that are anacardic acid and olivetolic acid homologs, respectively, are described from two species. The structures of these compounds were suggested by their spectroscopic data and confirmed by direct comparison with synthetic samples. Some of these compounds occur in lichens and have well documented physiological activities.

Topics: Anacardic Acids; Animals; Ants; Brunei; Exocrine Glands; Hydroxybenzoates; Lichens; Phenols; Salicylates; Species Specificity

The synergistic effects of 6-alk(en)ylsalcylic acids, also known as anacardic acids, in combination with methicillin against Staphylococcus aureus ATCC 33591 (MRSA) was investigated. The double bond in C15-anacardic acids is not essential in eliciting the antibacterial activity but is associated with increasing the activity. The synergistic effects decreased with increasing the number of double bonds in the alkyl chain. On the other hand, the antibacterial activity of anacardic acids possessing different alkyl chain lengths against the same MRSA strain was found to be a parabolic function of their lipophilicity and maximized with the alkyl chain length of C10 and C12. Notably, the synergistic effects were noted to increase with increasing the alkyl chain length.

Topics: Anacardic Acids; Anti-Bacterial Agents; Drug Synergism; Methicillin; Methicillin Resistance; Molecular Structure; Salicylates; Staphylococcus aureus

Anacardic acid, 6[8(Z), 11(Z), 14-pentadecatrienyl]salicylic acid, inhibits generation of superoxide radicals by xanthine oxidase. This inhibition does not follow a hyperbolic inhibition, depends on anacardic acid concentrations, but follows a sigmoidal inhibition. The inhibition was analyzed by using a Hill equation, and slope factor and EC(50) were 4.3+/-0.5 and 53.6+/-5.1 microM, respectively. In addition, anacardic acid inhibited uric acid formation by xanthine oxidase cooperatively. Slope factor and EC(50) were 1.7+/-0.5 and 162+/-10 microM, respectively. The results indicate that anacardic acid binds to allosteric sites near the xanthine-binding domain in xanthine oxidase. Salicylic acid moiety and alkenyl side chain in anacardic acid are associated with the cooperative inhibition and hydrophobic binding, respectively.

Topics: Anacardic Acids; Binding Sites; Enzyme Inhibitors; Flavin-Adenine Dinucleotide; Kinetics; Salicylates; Uric Acid; Xanthine; Xanthine Oxidase

Histone acetyltransferases (HATs) are a group of enzymes that play a significant role in the regulation of gene expression. These enzymes covalently modify the N-terminal lysine residues of histones by the addition of acetyl groups from acetyl-CoA. Dysfunction of these enzymes is often associated with the manifestation of several diseases, predominantly cancer. Here we report that anacardic acid from cashew nut shell liquid is a potent inhibitor of p300 and p300/CBP-associated factor histone acetyltranferase activities. Although it does not affect DNA transcription, HAT-dependent transcription from a chromatin template was strongly inhibited by anacardic acid. Furthermore, we describe the design and synthesis of an amide derivative N-(4-chloro-3-trifluoromethyl-phenyl)-2-ethoxy-6-pentadecyl-benzamide (CTPB) using anacardic acid as a synthon, which remarkably activates p300 HAT activity but not that of p300/CBP-associated factor. Although CTPB does not affect DNA transcription, it enhances the p300 HAT-dependent transcriptional activation from in vitro assembled chromatin template. However, it has no effect on histone deacetylase activity. These compounds would be useful as biological switching molecules for probing into the role of p300 in transcriptional studies and may also be useful as new chemical entities for the development of anticancer drugs.

Topics: Acetylation; Acetyltransferases; Amino Acid Sequence; Anacardic Acids; Anacardium; Antineoplastic Agents; Benzamides; Cell Cycle Proteins; Chromatin; Electrophoresis, Polyacrylamide Gel; Enzyme Inhibitors; HeLa Cells; Histone Acetyltransferases; Histones; Humans; Models, Molecular; Molecular Sequence Data; Molecular Structure; p300-CBP Transcription Factors; Plant Extracts; Recombinant Proteins; Salicylates; Seeds; Templates, Genetic; Transcription Factors; Transcription, Genetic

The structural and antibacterial activity relationship of 6-alk(en)ylsalicylic acids, also known as anacardic acids, was investigated against Gram-positive bacteria, emphasizing the methicillin resistant Staphylococcus aureus ATCC 33591 (MRSA) strain. The unsaturation in the alkyl side chain is not essential in eliciting activity but is associated with increasing the activity. The antibacterial activity of methicillin against MRSA strains was significantly enhanced in combination with C(12:0)-anacardic acid, and the fractional inhibitory concentration index for this combination was calculated as 0.281. It appears that biophysical disruption of the membrane (surfactant property) is due to the primary response to their antibacterial activity, while biochemical mechanisms are little involved. The compounds possessing the similar log P values exhibit similar activity.

Topics: Anacardic Acids; Anti-Bacterial Agents; Methicillin; Methicillin Resistance; Penicillin G; Salicylates; Staphylococcus aureus; Structure-Activity Relationship

Anacardic acid (6-pentadecylsalicylic acid), a major component of cashew nut shell liquid, consists of a heterogeneous mixture of monoenes, dienes, and trienes. The enes mixture of anacardic acid was hydrogenated to a saturated compound. Using saturated anacardic acid as a starting material, analogues of sildenafil [a potent phosphodiesterase-5 (PDE(5)) inhibitor and an orally active drug for the treatment of erectile dysfunction] were synthesized, to observe the effect of the pentadecyl side chain on PDE(5) inhibition. The synthesized compounds were characterized by spectral studies and tested for PDE(5) inhibition, and the results were compared with those obtained with sildenafil.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Anacardic Acids; Cyclic Nucleotide Phosphodiesterases, Type 5; Magnetic Resonance Spectroscopy; Mass Spectrometry; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Purines; Salicylates; Sildenafil Citrate; Structure-Activity Relationship; Sulfones

We have previously shown that anacardic acid has an uncoupling effect on oxidative phosphorylation in rat liver mitochondria using succinate as a substrate (Life Sci. 66 (2000) 229-234). In the present study, for clarification of the physicochemical characteristics of anacardic acid, we used a cyanine dye (DiS-C3(5)) and 9-aminoacridine (9-AA) to determine changes of membrane potential (DeltaPsi) and pH difference (DeltapH), respectively, in a liposome suspension in response to the addition of anacardic acid to the suspension. The anacardic acid quenched DiS-C3(5) fluorescence at concentrations higher than 300 nM, with the degree of quenching being dependent on the log concentration of the acid. Furthermore, the K(+) diffusion potential generated by the addition of valinomycin to the suspension decreased for each increase in anacardic acid concentration used over 300 nM, but the sum of the anacardic acid- and valinomycin-mediated quenching was additively increasing. This indicates that the anacardic acid-mediated quenching was not due simply to increments in the K(+) permeability of the membrane. Addition of anacardic acid in the micromolar range to the liposomes with DeltaPsi formed by valinomycin-K(+) did not significantly alter 9-AA fluorescence, but unexpectedly dissipated DeltaPsi. The DeltaPsi preformed by valinomycin-K(+) decreased gradually following the addition of increasing concentrations of anacardic acid. The DeltaPsi dissipation rate was dependent on the pre-existing magnitude of DeltaPsi, and was correlated with the logarithmic concentration of anacardic acid. Furthermore, the initial rate of DeltapH dissipation increased with logarithmic increases in anacardic acid concentration. These results provide the evidence for a unique function of anacardic acid, dissimilar to carbonylcyanide p-trifluoromethoxyphenylhydrazone or valinomycin, in that anacardic acid behaves as both an electrogenic (negative) charge carrier driven by DeltaPsi, and a 'proton carrier' that dissipates the transmembrane proton gradient formed.

Topics: Aminacrine; Anacardic Acids; Benzothiazoles; Carbocyanines; Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; Dose-Response Relationship, Drug; Fluorescent Dyes; Gramicidin; Hydrogen-Ion Concentration; Liposomes; Membrane Potentials; Models, Chemical; Molecular Structure; Salicylates; Spectrometry, Fluorescence; Valinomycin

11-Chloro-3-methoxy-2-undecenal was synthesized from 8-bromooctanol, and an annelation reaction with this aldehyde and ethyl acetoacetate proceeded to give the ethyl 6-(8-chlorooctyl)salicylate. Ethyl 6-(8-chlorooctyl)salicylate was converted to ethyl 6-(7-formylheptyl)-2-methoxybenzoate through the iodide after protection of the phenolic hydroxyl group. Finally, the Wittig reaction with the aldehyde and triphenylphosphonium iodides in the presence of BuLi gave the methoxybenzoates, and then treatments of these methoxybenzoates with BBr3 in CH2Cl2 and 10% NaOH in ethanol gave 6-18(Z),11(Z)-pentadecadienyllsalicylic acid (anacardic acid 3) and 6-[8(Z),11(Z),14-pentadecatrienyl]salicylic acid (anacardic acid 4) which were isolated from plants of the anacardiaceae.

Topics: Alkenes; Anacardic Acids; Salicylates; Spectrum Analysis

Anacardic acids are one of natural products found in not only the cashew nut shell oil but also the nut and fruit juice. The present study was conducted to investigate the uncoupling effect of anacardic acids on oxidative phosphorylation of rat liver mitochondria using succinate (plus rotenone) as a substrate. Four anacardic acids with C15:0, C15:1, C15:2 or C15:3 as an alkyl side chain exhibited uncoupling effects similar to the classical uncoupler, 2,4-dinitrophenol on ADP/O ratio, state 4 and respiratory control ratio (RCR). Anacardic acid with C15:1 side chain was most effective for uncoupling of these compounds. Salicylic acid, which has no alkyl side chain, exhibited a very weak uncoupling effect on oxidative phosphorylation. When the carboxyl group in anacardic acids was lost converting them to the corresponding cardanols, uncoupling activity dramatically decreased regardless of the number of double bonds in the long alkyl chain. These results suggest that the C15 alkyl side chain as well as the carboxyl group may play an important role in assisting the uncoupling activity of anacardic acids in liver mitochondria of animals. This study provides the first evidence of an uncoupling effect of anacardic acids on liver mitochondria

Topics: 2,4-Dinitrophenol; Anacardic Acids; Animals; In Vitro Techniques; Male; Mitochondria, Liver; Nuts; Oxidative Phosphorylation; Rats; Rats, Sprague-Dawley; Salicylates; Structure-Activity Relationship; Uncoupling Agents

Anacardic acids and (E)-2-hexenal characterized from the cashew Anacardium occidentale L. (Anacardiaceae) apple have been found to exhibit antibacterial activity against the Gram-negative bacterium Helicobacter pylori, which is now considered to cause acute gastritis. The same antibacterial compounds have also been found to inhibit urease (EC 3.5.1.5).

Topics: Aldehydes; Anacardic Acids; Enzyme Inhibitors; Helicobacter pylori; Microbial Sensitivity Tests; Rosales; Salicylates; Urease

A series of 6-oxa isosteres of anacardic acids (6-higher alkyl/alkenyl-2-hydroxybenzoic acids) was synthesised and several members were discovered to be among the most potent inhibitors (IC50 values < or = 5 microM) of the bacterial two-component regulatory systems, KinA/SpoOF and NRII/NRI, reported to date. The Gram-positive antibacterial activity in selected strains is also presented.

Topics: Anacardic Acids; Anti-Bacterial Agents; Bacteria; Enzyme Inhibitors; Histidine Kinase; Microbial Sensitivity Tests; Protein Kinase Inhibitors; Protein Kinases; Salicylates; Structure-Activity Relationship

Five compounds, which inhibited the amidolytic activity of soluble tissue factor/activated factor VII complex (sTF/VIIa), were isolated from two traditional Chinese medicinal plants commonly used in the treatment of cardiovascular and cerebrovascular diseases. The active compounds were found to be linolenic, linoleic, and oleic acids from roots of Salvia miltiorrhiza; and two anacardic acids, 6-(8'Z-pentadecenyl)- and 6-(10'Z-heptadecenyl)-salicylic acids, from leaves of Ginkgo biloba. The IC50 values were in the range 30-80 micromol/L. Palmitic acid, isolated from roots of Salvia miltiorrhiza, and 2-[(3',7',11',15'-tetramethyl)-2'E,6'E,10'E, 14'E-hexadecatetraenyl]-1,4-hydroquinone, isolated from the marine sponge Adocia viola, did not inhibit sTF/VIIa. Further expansion of the structure-activity relationship to include anacardic acids, 6-(8'Z,11'Z-heptadecadienyl)- and 6-(8'Z, 11'Z, 14'Z-heptadecatrienyl)-salicylic acids from leaves of Anacardium spondias, and other fatty acids demonstrated that at least one cis double bond was essential for inhibitory activity, and that fatty acids containing two or three cis double bonds were optimal. Evidence from preincubation studies implied that these fatty acids may exert their effect by binding to VIIa and consequently preventing binding of sTF to VIIa.

Topics: Anacardic Acids; Enzyme Inhibitors; Factor VIIa; Fatty Acids, Unsaturated; Humans; Plant Extracts; Plant Roots; Plants, Medicinal; Recombinant Proteins; Salicylates; Trypsin Inhibitors

The petroleum ether extract of cashewnut shell (Anacardium occidentale) was tested for its mutagenic, carcinogenic and cocarcinogenic potency. Mutagenicity tests using Salmonella typhimurium (Ame's test) Strains TA 1535, TA 100 and TA 98 showed that cashewnut shell liquid is non-mutagenic up to a concentration of 0.003% (in 0.1 ml DMSO) with and without metabolic activation (S 9 mixture). Carcinogenicity testing using murine (female Swiss albino mice) two stage skin tumourigenesis model revealed that cashewnut shell liquid has no tumour initiating potency at a concentration of 10% (in 0.2 ml acetone) while it may act as weak promoter (P < 0.05) at a concentration of 5% (in 0.2 ml acetone). Testing for cocarcinogenic potency of cashewnut shell liquid (2% and 5% in 0.2 ml acetone) demonstrated that it has no cocarcinogenic potency on mouse skin tumour model when applied along with 2 x 10(-6)% benzo(a)pyrene in acetone up to a period of 20 weeks.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Anacardic Acids; Animals; Carcinogenicity Tests; Carcinogens; Cocarcinogenesis; Female; Mice; Mutagenicity Tests; Neoplasms, Experimental; Plant Extracts; Plants, Toxic; Resorcinols; Salicylates; Salmonella typhimurium; Skin Neoplasms

Anacardic acids, a class of secondary compounds derived from fatty acids, are found in a variety of dicotyledonous families. Pest resistance (e.g., spider mites and aphids) in Pelargonium xhortorum (geranium) is associated with high levels (approximately 81%) of unsaturated 22:1 omega 5 and 24:1 omega 5 anacardic acids in the glandular trichome exudate. A single dominant locus controls the production of these omega 5 anacardic acids, which arise from novel 16:1 delta 11 and 18:1 delta 13 fatty acids. We describe the isolation and characterization of a cDNA encoding a unique delta 9 14:0-acyl carrier protein fatty acid desaturase. Several lines of evidence indicated that expression of this desaturase leads to the production of the omega 5 anacardic acids involved in pest resistance. First, its expression was found in pest-resistant, but not suspectible, plants and its expression followed the production of the omega 5 anacardic acids in segregating populations. Second, its expression and the occurrence of the novel 16:1 delta 11 and 18:1 delta 13 fatty acids and the omega 5 anacardic acids were specific to tall glandular trichomes. Third, assays of the recombinant protein demonstrated that this desaturase produced the 14:1 delta 9 fatty acid precursor to the novel 16:1 delta 11 and 18:1 delta 13 fatty acids. Based on our genetic and biochemical studies, we conclude that expression of this delta 9 14:0-ACP desaturase gene is required for the production of omega 5 anacardic acids that have been shown to be necessary for pest resistance in geranium.

Topics: Amino Acid Sequence; Anacardic Acids; Chromatography, Gas; DNA, Complementary; Escherichia coli; Fatty Acid Desaturases; Fatty Acids, Unsaturated; Gene Expression; Genes, Plant; Immunity, Innate; Mixed Function Oxygenases; Molecular Sequence Data; Plants; Recombinant Proteins; RNA, Messenger; Salicylates

The inhibitory and bactericidal activities of anacardic acid and totarol, alone and in combination with methicillin, were investigated against methicillin-resistant Staphylococcus aureus (MRSA). The growth of two MRSA strains was inhibited by 6 x 25 microg ml-1 of anacardic acid and 0 x 78 microg ml-1 of totarol. The time-kill curve study showed that these two compounds were bactericidal against MRSA. Anacardic acid killed MRSA cells more rapidly than totarol, and no viable cells were detected after being exposed to 6 x 25 microg ml-1 of anacardic acid for 6 h. Anacardic acid showed bactericidal activity against MRSA at any stage of growth, and also even when cell division was inhibited by chloramphenicol. In the combination studies, the minimal inhibitory concentration (MIC) of methicillin was lowered from 800 to 1 x 56 microg ml-1 for MRSA ATCC 33591, and from 800 to 6 x 25 microg ml-1 for MRSA ATCC 33592, by combining with 1/2 x MIC of anacardic acid. The time-kill curves demonstrated synergistic bactericidal activities for these combinations.

Topics: Abietanes; Anacardic Acids; Anti-Bacterial Agents; Chloramphenicol; Diterpenes; Drug Synergism; Enzyme Inhibitors; Methicillin; Methicillin Resistance; Microbial Sensitivity Tests; Penicillins; Salicylates; Staphylococcus aureus

Topics: Anacardic Acids; Brazil; Case-Control Studies; Dermatitis, Allergic Contact; Dermatitis, Occupational; Female; Hand Dermatoses; Humans; Plants, Toxic; Resorcinols; Salicylates

Anacardic acids, 2-methylcardols, and cardols isolated from various parts of the cashew [Anacardium occidentale] (Anacardiaceae) fruit have been found to exhibit tyrosinase inhibitory activity. Kinetic studies with the two principal active compounds, 6-[8(Z),11(Z),14-pentadecatrienyl]salicylic acid and 5-[8(Z),11(Z),14-pentadecatrienyl]resorcinol, have indicated that both of these phenolic compounds exhibit characteristic competitive inhibition of the oxidation of L-3,4-dihydroxyphenylalanine (L-DOPA) by mushroom tyrosinase.

Topics: Anacardic Acids; Basidiomycota; Kinetics; Levodopa; Monophenol Monooxygenase; Nuts; Oxidation-Reduction; Resorcinols; Salicylates; Structure-Activity Relationship

Bioassay-directed fractionation of the n-hexane extract of the stem of Rhus semialata Murr. var. roxburghii DC (Anacardiaceae) has led to the isolation of 6-pentadecylsalicylic acid. It showed antithrombin activity at 50 micrograms/ml in the amidolytic method. It also prolonged the clotting time in a dose-dependent manner in the clotting assay of thrombin-fibrinogen interaction.

Topics: Amino Acid Sequence; Anacardic Acids; Animals; Antithrombins; Cattle; Chromogenic Compounds; Magnetic Resonance Spectroscopy; Molecular Sequence Data; Molecular Structure; Plants, Medicinal; Salicylates