Alkyl Gallates Research Articles

REACTION OF ALKYL GALLATES WITH DIPHENYL PICRYLHYDRACYL RADICALS IN SDS MICELLES

Diphenylpicrylhydracyl is a stable free radical that readily reacts with phenol groups. In the present work we have measured the reaction of DPPH with three alkyl gallates of different hydrophobicity: methyl gallate, propyl gallate, and octyl gallate. Experiments were carried out in acetate buffer (pH 5.0) in presence of several SDS concentrations. At surfactant concentrations higher than 20 mM, the gallates are almost totally associated to the micellar pseudophase. Under these conditions the rate of the reaction becomes almost independent of the length of the alkyl group. This indicates that the average localization of the gallate reactive group is almost independent of the solute hydrophobicity.

Arginine-Assisted Solubilization System for Drug Substances: Solubility Experiment and Simulation

The poor aqueous solubility of drug substances hampers their broader applications. This paper describes a de novo strategy to increase the aqueous solubility of drug substances using an arginine-assisted solubilization system (AASS) with alkyl gallates as model drug substances. Solubility experiments of alkyl gallates showed that arginine greatly increases the aqueous solubility of different alkyl gallates, whose aqueous solubilities differ widely. In contrast, lysine showed marginal effects on alkyl gallates solubility. Molecular dynamic simulation indicated a greater interaction of arginine with alkyl gallates than that of lysine, which reflects favorable interaction between the guanidinium group of arginine and the aromatic ring of alkyl gallates. Such interaction apparently disrupts association of alkyl gallate molecules, leading to solubilization. These results indicate AASS as a promising approach to solubilize poorly soluble drug substances containing aromatic ring structures.

Multifunctional Antioxidant Activities of Alkyl Gallates

A series (C 1 to C 16 ) of alkyl gallates was tested for their antioxidant activity for food protection and human health. One molecule of alkyl gallate, regardless of alkyl chain length, scavenges six molecules of 1,1-diphenyl-2- picrylhydrazyl (DPPH). Alkyl gallates inhibited the linoleic acid peroxidation catalyzed by soybean lipoxygenase-1 (EC 1.13.11.12, Type 1) without being oxidized. The progress curves for enzyme reactions were recorded by both spectropho- tometric and polarographic methods and the inhibitory activity was a parabolic function of their lipophilicity (log P) and maximized with alkyl chain length between C 12 and C 16 . Tetradecanyl (C 14 ) gallate exhibited the most potent inhibition with an IC 50 of 0.06 µM. The inhibition kinetics of dodecyl gallate (C 12 ) revealed competitive and slow-binding inhibi- tion. Alkyl gallates chelate transition metal ions and this chelation ability should be of considerable advantage as antioxi- dants. Additionally, gallic acid was found to inhibit superoxide anion generated by xanthine oxidase (EC 1.1.3.22) but did not inhibit enzymatically catalyzed uric acid formation.

2P242 アルキルガレートとリン脂質膜の結合に関する定量的解析(生体膜・人工膜-構造・物性,第48回日本生物物理学会年会)

2P242 アルキルガレートとリン脂質膜の結合に関する定量的解析(生体膜・人工膜-構造・物性,第48回日本生物物理学会年会)

Inhibitive Effects of Alkyl Gallates on Hyaluronidase and Collagenase

A series of the gallate esters of n-alkanols (C(1)-C(12)) was examined to determine their inhibitory activities against hyaluronidase and collagenase. Hexyl, heptyl, octyl, nonyl, and decyl gallates inhibited both hyaluronidase and collagenase, and the most potent inhibitor was octyl gallate against both enzymes. Octyl 3,5-dihydroxybenzoate showed inhibitory effects on hyaluronidase, whereas collagenase was inhibited by octyl 3,4-dihydroxybenzoate.

Production of Phenols and Alkyl Gallate Esters by Rhodobacter sphaeroides OU5

Rhodobacter sphaeroides OU5 grows phototrophically with generation doubling time of 18 h on L-phenylalanine when used as sole source of nitrogen. Phenols accumulated in the medium and gallate (0.5 mM) was identified as one of the major product. The others namely protocatechuate (0.2 mM) and caffeate (0.1 mM) and also three putative phenol alkyl esters were identified using Liquid chromatography-mass spectroscopy (LC-MS) analysis from the culture supernatant. Rhodobacter sphaeroides OU5 strain could explain its capability to produce the bioactive compounds during the growth. This study sheds production of bioactive and their biological exploring molecules.

Triple Combinations of Lower and Longer Alkyl Gallates and Oxacillin Improve Antibiotic Synergy against Methicillin-Resistant Staphylococcus aureus

Using liposome systems, we found that gallates with short alkyl chains were located in the external medium and those with longer alkyl chains were located in the surface region of lipid bilayer. Combinations of these gallates remarkably reduced oxacillin MICs against methicillin-resistant Staphylococcus aureus to below the antibiotic breakpoint (< or = 2 microg/ml).

Relation between lipophilicity of alkyl gallates and antifungal activity against yeasts and filamentous fungi

The antifungal activity of a complete series of 15 n-alkyl gallates and six analogues acting against a representative panel of opportunistic pathogenic fungi was studied in order to analyze their role in: the importance of the fungi tested, the importance of the hydroxyls, the influence of the chain length and the hydrophobicity of the compounds. It was demonstrated that dermatophytes were the most susceptible species and that hydroxyls appear to be necessary but not sufficient for the activity. When the log P of each gallate was calculated and related to the different values of MIC against Microsporum gypseum it was observed that hexyl, heptyl, octyl and nonyl gallates exhibit a significant positive deviation from the curve corresponding to a polynomial equation obtained for the other gallates. This suggests that these compounds have a further mode of action besides their hydrophobicity, possibly the inhibition of some enzyme involved in ergosterol biosynthesis.

Structure-Activity Relationship of Bis-Galloyl Derivatives Related to (-)-Epigallocatechin Gallate

Green tea and (-)-epigallocatechin gallate (EGCG: one of main components of green tea) are well known to have preventive activities against human cancers. Previously, using a galloyl group as a core structure derived from EGCG, we developed alkyl gallate and gallamide derivatives, which showed strong antiproliferative activity towards human leukemia HL-60 cells by inducing apoptosis. Here, as a further structural development study, we planned to introduce an additional galloyl group into alkyl gallates and gallamides. According to this strategy, various bisgallate and bisgallamide derivatives were synthesized and tested for antiproliferative activity towards HL-60 cells. In gallamide derivatives having a short alkyl chain, the additional galloyl group enhanced the antiproliferative activity. In contrast, in the gallate derivatives, the additional galloyl group had no effect on the antiproliferative activity.

Antiviral Activity of Lauryl Gallate against Animal Viruses

Background Antiviral compounds are needed in the control of many animal and human diseases. Methods We analysed the effect of the antitumoural drug lauryl gallate on the infectivity of the African swine fever virus among other DNA (herpes simplex and vaccinia) and RNA (influenza, porcine transmissible gastroenteritis and Sindbis) viruses, paying attention to its effect on the viability of the corresponding host cells. Results Viral production was strongly inhibited in different cell lines at non-toxic concentrations of the drug (1–10 μM), reducing the titres 3–&gt;5 log units depending on the multiplicity of infection. In our model system (African swine fever virus in Vero cells), the addition of the drug 1 h before virus adsorption completely abolished virus productivity in a one-step growth virus cycle. Interestingly, no inhibitory effect was observed when lauryl gallate was added after 5–8 h post-infection. Both cellular and viral DNA synthesis and late viral transcription were inhibited by the drug; however, the early viral protein synthesis and the virus-mediated increase of p53 remained unaffected. Activation of the apoptotic effector caspase-3 was not detected after lauryl gallate treatment of Vero cells. Furthermore, the presence of the drug abrogated the activation of this protease induced by the virus infection. Conclusions Lauryl gallate is a powerful antiviral agent against several pathogens of clinical and veterinary importance. The overall results indicate that a cellular factor or function might be the target of the antiviral action of alkyl gallates.

Antiproliferative and apoptosis-inducing activities of alkyl gallate and gallamide derivatives related to (−)-epigallocatechin gallate

Green tea and (−)-epigallocatechin gallate (EGCG: one of the main components of green tea) are reported to have cancer-preventive activity in humans. A previous SAR study of EGCG and derivatives indicated that a galloyl group is essential for the activity. To test this hypothesis, we synthesized various alkyl gallate and gallamide derivatives and evaluated their antiproliferative effects on human leukemia HL-60 cells. Dodecyl 3,4,5-trihydroxybenzoate ( 6c) showed the most potent activity, being more potent than EGCG. To clarify the molecular mechanism of the antiproliferative action, we investigated the effects of 6c on various factors. Compound 6c was found to induce apoptosis mediated by endoplasmic reticulum (ER)-stress-related caspase-12. Upregulation of gadd-153, an ER-stress marker protein, was also observed. These results indicate that 6c induced apoptosis via the ER-stress-related pathway.

알킬갈레이트 유도체의 어병세균 Edwardsiella tarda와 Vibrio anguillarum에 대한 항균활성 및 항생제와의 병용효과

Methyl gallate isolated from bark of the tree Rhus verniciflua Stokes has significant antimicrobial activity against the fish pathogenic bacteria Edwardsiella tarda and Vibrio anguillarum. To evaluate the antimicrobial activity of gallate derivatives, eight alkyl gallates were tested. Ethyl gallate and propyl gallate had the highest activities, with MICs of against E. tarda. For V. anguillarum, propyl gallate and butyl gallate were highly effective, with MICs of . When used in combination with antibiotics, methyl gallate exhibited synergistic effects with oxytetracycline against E. tarda and with norfloxacin against V. anguillarum. These results suggest that short-chain alkyl gallates can be used as alternatives to antibiotics against the fish pathogenic bacteria.

Antibacterial Effects of Guava Tannins and Related Polyphenols on Vibrio and Aeromonas Species

An extract obtained from a bottled tea drink of Psidium guajava L. (Myrtaceae) showed antibacterial effects on Vibrio vulnificus, V. mimicus, V. parahaemolyticus, and Aeromonas sobria. HPLC-diode array detector (DAD) analysis of an effective fraction obtained from the extract revealed the presence of several tannins and related polyphenols. To verify these results and to estimate the antibacterial effects of the polyphenols, we isolated the polyphenols from the leaves of P. guajava. Among the polyphenols isolated, pedunculagin, castalagin, casuarinin, and stenophyllanin A were effective against Vibrio and Aeromonas species. Studies of structurally related compounds revealed that penta- O-galloyl-β-D-glucose (PGG), (-)-epigallocatechin gallate (EGCG), and alkyl gallates such as isoamyl gallate (IG) and n-octyl gallate exhibited potent antibacterial activities. The minimum bactericidal concentrations (MBCs) of three polyphenols (i.e., PGG, EGCG, and IG) that exhibited low minimum inhibitory concentrations (MICs) were then determined. Comparisons of the MBCs and MICs indicated that PGG was not bactericidal at the MIC, whereas EGCG and IG were. The effect of combinations of the three polyphenols with several antibiotics was also examined. The combination of IG and kanamycin (KM) effectively reduced the MIC of KM against V. vulnificus and V. mimicus; the combination of EGCG and tetracycline (TC) also reduced the MIC of TC against V. parahaemolyticus. Thus, polyphenols may be useful in the development of antibacterial agents against Vibrio bacteria.

Antiviral activity of lauryl gallate against animal viruses.

Antiviral compounds are needed in the control of many animal and human diseases. We analysed the effect of the antitumoural drug lauryl gallate on the infectivity of the African swine fever virus among other DNA (herpes simplex and vaccinia) and RNA (influenza, porcine transmissible gastroenteritis and Sindbis) viruses, paying attention to its effect on the viability of the corresponding host cells. Viral production was strongly inhibited in different cell lines at non-toxic concentrations of the drug (1-10 microM), reducing the titres 3->5 log units depending on the multiplicity of infection. In our model system (African swine fever virus in Vero cells), the addition of the drug 1 h before virus adsorption completely abolished virus productivity in a one-step growth virus cycle. Interestingly, no inhibitory effect was observed when lauryl gallate was added after 5-8 h post-infection. Both cellular and viral DNA synthesis and late viral transcription were inhibited by the drug; however, the early viral protein synthesis and the virus-mediated increase of p53 remained unaffected. Activation of the apoptotic effector caspase-3 was not detected after lauryl gallate treatment of Vero cells. Furthermore, the presence of the drug abrogated the activation of this protease induced by the virus infection. Lauryl gallate is a powerful antiviral agent against several pathogens of clinical and veterinary importance. The overall results indicate that a cellular factor or function might be the target of the antiviral action of alkyl gallates.

Stabilization of Foams with Inorganic Colloidal Particles

Wet foams are used in many important technologies either as end or intermediate products. However, the thermodynamic instability of wet foams leads to undesired bubble coarsening over time. Foam stability can be drastically improved by using particles instead of surfactants as foam stabilizers, since particles tend to adsorb irreversibly at the air-water interface. Recently, we presented a novel method for the preparation of high-volume particle-stabilized foams which show neither bubble growth nor drainage over more than 4 days. The method is based on the in-situ hydrophobization of initially hydrophilic particles to enable their adsorption on the surface of air bubbles. In-situ hydrophobization is accomplished through the adsorption of short-chain amphiphiles on the particle surface. In this work, we illustrate how this novel method can be applied to particles with various surface chemistries. For that purpose, the functional group of the amphiphilic molecule was tailored according to the surface chemistry of the particles to be used as foam stabilizers. Short-chain carboxylic acids, alkyl gallates, and alkylamines were shown to be appropriate amphiphiles to in-situ hydrophobize the surface of different inorganic particles. Ultrastable wet foams of various chemical compositions were prepared using these amphiphiles. The simplicity and versatility of this approach is expected to aid the formulation of stable wet foams for a variety of applications in materials manufacturing, food, cosmetics, and oil recovery, among others.

Xanthine oxidase inhibitory activity of alkyl gallates

A series (C1-C12) of alkyl gallates was examined for their effects on the activity of xanthine oxidase. Octyl (C8), decyl (C10), and dodecyl (C12) gallates competitively inhibited uric acid formation generated by xanthine oxidase, and the inhibition increased upon increasing the alkyl chain length. Interestingly, neither menthyl nor bornyl gallates inhibited uric acid formation. These data indicate that the hydrophobic alkyl portion is associated with the xanthine-binding site in the Mo-binding domain. It is likely that the linear alkyl portion interacts with the hydrophobic domain close to the binding site, and the hydrophobic interaction is crucial to inhibit the xanthine oxidase reaction. On the other hand, all of gallic acid and its esters equally suppress superoxide anion generation catalyzed by xanthine oxidase at low concentration. The suppression is not due to scavenging activity of these gallates but due to reduction of xanthine oxidase by these gallates. The reduced enzyme catalyzes the reaction to generate hydrogen peroxide and uric acid.

Comparative cytotoxicity of alkyl gallates on mouse tumor cell lines and isolated rat hepatocytes

Alkyl esters of gallic acid inhibited the respiration rate of mouse sarcoma 786A and mouse mammary adenocarcinoma TA3 cell lines and its multiresistant variant TA3-MTX-R more effectively than gallic acid, both in the absence and in the presence of the uncoupler CCCP. The order of inhibition of the respiration rate by gallates in intact cells was n-octyl- approximately iso-amyl- approximately n-amyl- approximately iso-butyl->n-butyl->iso-propyl->n-propyl-gallate>>gallic acid. Sarcoma 786A was significantly more susceptible to all seven esters than the TA3 cell line. Respiration rates of the TA3-MTX-R cell line showed almost the same sensitivity to these esters as the TA3 cell line. However, hepatocytes were significantly less sensitive than all tumor cells tested. These alkyl gallates blocked mitochondrial electron flow, mainly at the NADH-CoQ segment, preventing ATP synthesis, which would lead to cellular death. These esters also inhibited, in the same order of potencies as respiration, the growth of 786A, TA3 and TA3-MTX-R cells in culture. In mice carrying TA3 or TA3-MTX-R tumor cells, an important decrease of the tumor growth rate and an increase of survival were observed when mice were treated with iso-butyl gallate alone or in combination with doxorubicin. These results indicate that alkyl gallates are selectively cytotoxic to tumor cells, which may be due to the mitochondrial dysfunctions of these cells.

In vivo treatment of acute Chlamydia pneumoniae infection with the flavonoids quercetin and luteolin and an alkyl gallate, octyl gallate, in a mouse model

Increasing evidence suggests that plant polyphenolic compounds may protect from cardiovascular diseases, which have been addressed to their antioxidative properties. In addition, these compounds have been shown to possess anti-inflammatory and anti-microbial potential. In the present study we tested the effects of two flavonoid compounds, quercetin and luteolin, and one alkyl gallate, octyl gallate, on the course of acute Chlamydia pneumoniae infection in vivo. C57BL/6J mice were treated with quercetin, luteolin or octyl gallate for 3 days prior to and 10 days after C. pneumoniae inoculation. Lung tissue was analysed for the presence of chlamydia by culture and quantitative PCR, and inflammatory responses were assessed. Luteolin was found histologically to suppress inflammation in lung tissue, the development of C. pneumoniae-specific antibodies and the presence of chlamydia in lung tissue. Octyl gallate had no significant effect on the course of infection, but quercetin increased both the inflammatory responses and the chlamydial load in the lungs. The infection and inflammation-enhancing effects of quercetin treatment may be attributable to the dose and the route of administration and should be reassessed in further studies with lower doses or with different metabolites of the compound. Contrariwise, the effects of luteolin treatment suggest this compound to have potential in decreasing the infection load and inflammatory reactions in vivo.

Effects of alkyl gallates on P-glycoprotein function

In this study, we examined the effects of the food antioxidants, alkyl gallates, on the function of P-glycoprotein (P-gp) and elucidated the importance of alkyl chains and gallic acid moieties on the activity of P-gp. We examined the effects of three alkyl ( n-butyl, n-octyl and n-dodecyl) gallates and their related compounds on the cellular accumulation and efflux of rhodamine 123 and daunorubicin in P-gp overexpressing KB-C2 cells. Alkyl gallates increased the cellular accumulation of these P-gp substrates dependent on their alkyl chain lengths by inhibiting the efflux of the substrates. n-Dodecylresorcinol also increased the accumulation, but its effect was less than that of n-dodecyl gallate. However, either lauric acid or n-dodecyl-β- d-maltoside, which does not have a phenol group, did not increase the accumulation. The results indicated that both the gallic acid moiety and a long alkyl chain play important roles in the modification of P-gp function. The cytotoxicity of daunorubicin was recovered in the presence of alkyl gallates possibly due to their inhibition of P-gp function.

Alkyl gallates, intensifiers of beta-lactam susceptibility in methicillin-resistant Staphylococcus aureus.

We found that ethyl gallate purified from a dried pod of tara (Caesalpinia spinosa) intensified beta-lactam susceptibility in methicillin-resistant and methicillin-sensitive strains of Staphylococcus aureus (MRSA and MSSA strains, respectively). This compound and several known alkyl gallates were tested with MRSA and MSSA strains to gain new insights into their structural functions in relation to antimicrobial and beta-lactam susceptibility-intensifying activities. The maximum activity of alkyl gallates against MRSA and MSSA strains occurred at 1-nonyl and 1-decyl gallate, with an MIC at which 90% of the isolates tested were inhibited of 15.6 microg/ml. At concentrations lower than the MIC, alkyl gallates synergistically elevated the susceptibility of MRSA and MSSA strains to beta-lactam antibiotics. Such a synergistic activity of the alkyl gallates appears to be specific for beta-lactam antibiotics, because no significant changes were observed in the MICs of other classes of antibiotics examined in this study. The length of the alkyl chain was also associated with the modifying activity of the alkyl gallates, and the optimum length was C5 to C6. The present work clearly demonstrates that the length of the alkyl chain has a key role in the elevation of susceptibility to beta-lactam antibiotics.