Uncoupling effect of anacardic acids from cashew nut shell oil on oxidative phosphorylation of rat liver mitochondria

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     

Crystal structures and thermal analyses of alkyl 2-deoxy-α-d-arabino-hexopyranosides

The crystal structures of alkyl 2-deoxy-α-d-arabino-hexopyranosides, with the alkyl chain lengths from C₈ to C₁₈, are established by the single crystal X-ray structural determination. The even-alkyl chain length derivatives crystallized orthorhombic, with space group P2₁2₁2₁, whereas the odd-alkyl chain length derivatives crystallized monoclinic, with space group P2₁. The sugar moieties retained a ⁴C₁ chair conformation and the conformation of the alkyl chains was all-trans. The molecules formed a bilayer structure, in which alkyl chains were interdigitated. The hydrogen bonds, originating from the sugar moieties, were observed in adjacent layers and also within the same layer, resulting in the formation of infinite chains. The alkyl chains arranged parallel to each other and formed planar structures. The thermal properties of the alkyl 2-deoxy glucosides were analyzed further. It was observed that none of the derivatives exhibited mesomorphism. This study establishes that the absence of the hydroxyl group at C-2 of the sugar moiety results in a non-mesogenic nature of the alkyl 2-deoxy-α-d-glycosides, as opposed to the profound mesogenic nature of the normal alkyl glycosides.     

6-Hydroxyquinolinium salts differing in the length of alkyl side-chain: Synthesis and antimicrobial activity

Quaternary ammonium salts substituted with a long alkyl chain exemplify a trustworthy group of medicinal compounds frequently employed as antifungal and antibacterial agents. A great asset of these surfactants underlying their widespread use is low local and system toxicity in humans. In this Letter, a series of novel quaternary 6-hydroxyquinolinium salts with varying length of N-alkyl chain (from C₁₀ to C₁₈) was synthesized and tested for in vitro activity against pathogenic bacterial and fungal strains. 6-Hydroxyquinolinium salt with C12 alkyl chain seems to be very interesting candidate due to a high antimicrobial efficacy and cytotoxic safety.     

Effects of alkyl chain length of gallates on their antifungal property and potency as an environmentally benign preservative against wood-decay fungi

This study investigated effects of alkyl chain length of eight aliphatic gallates from C₁ to C₁₈ on their antifungal activity and free radical scavenging activity, which are two important indicators in developing wood preservatives. Results from the agar plate test showed that the antifungal activity against wood-rot fungi of gallates was related to alkyl chain length. It increased with increasing alkyl chain length, reaching a maximum at octyl gallate (C₈), and then decreased as chain length increased. Octyl gallate also exhibited potential antifungal activity against soft-rot Chaetomium globosum and copper-tolerant fungi Wolfiporia extensa and Poria placenta, which are difficult to combat with current copper-based wood preservatives. Octyl gallate is a potent antifungal agent with excellent antifungal activity over a broad antifungal spectrum. All of the gallates tested, regardless of their alkyl chain length, showed strong scavenging activity on the DPPH radical with EC₅₀ values around 1–5 μg ml^?1, indicating that the alkyl chain length was not directly related to this activity. Results from the soil block test showed that excellent antioxidants such as propyl gallate (C₃) and octyl gallate impart wood with good resistance against wood-decay fungi. This suggests that antioxidants have potential as environmentally benign wood preservatives.     

Trifluoromethylated carboline compounds targeting DNA: Synthesis,binding and anti-proliferative effects on human cancer cell lines

Three sets of carboline derived compounds were prepared by Pictet-Spengler cyclization. These tetrahydro β- and γ-carbolines have CF₃ group with an additional amino alkyl chains (α- or δ-position) and guanidine alkyl chains (α-position), of varying length. Structure–activity relationship of these molecules with calf thymus DNA was emphasized by fluorescence, ITC, FTIR and viscosity. Binding with DNA resulted in dramatic enhancement and quenching in the fluorescence emission. Gamma-carboline analogs showed maximum DNA binding followed by beta-carboline compounds with amino alkyl chain and least with guanidine alkyl chain compounds. It decreased with increasing chain length. The bindings were entropically driven being more with guanidine alkyl chain analogs. Site preference and mode of binding with partial intercalation and external binding was supported by FTIR and viscosity. Cytotoxic potencies of the compounds were tested on seven different cancer cell lines. The smallest alkyl chain analog attached to gamma position, Comp3, showed maximum cytotoxicity with GI₅₀ 6.2 µM, against HCT-116 causing apoptosis, followed by the guanidine alkyl chain compounds, but amino alkyl chain compounds to beta position showed poor cytotoxicity.These results may be of prospective use in a framework to design novel carboline derivatives as antitumor drugs for improved therapeutic applications in future.     

Molecular basis of the protonophoric and uncoupling activities of the potent uncoupler SF-6847 ((3,5-di-tert-butyl-4-hydroxybenzylidene)malononitrile) and derivatives. Regulation of their electronic structures by restricted intramolecular rotation

We reported recently (Yoshikawa, K. and Terada, H. (1982) J. Am. Chem. Soc. 104, 7644–7646) that the potent uncoupler of oxidative phosphorylation SF-6847 ((3,5-di-tert-butyl-4-hydroxybenzylidene)malononitrile) shows unique intramolecular restricted rotation of the malononitrile moiety. In this study, values for the activation energy E_a of the restricted rotation of SF-6847 derivatives with the same alkyl chain R in both ortho positions of the phenolic hydroxyl group were determined from the temperature-dependent change in the¹H-NMR signals of their aromatic protons. The E_a values of the neutral forms of these derivatives were found to be the same irrespective of R, but those of the anionic forms increased with increase in the alkyl chain length of R. It was found that the restricted rotation of the malononitrile moiety regulates its electron-withdrawing ability in such a way as to keep the acid dissociability of these derivatives similar, overcoming the effect of steric hindrance by R. The protonophoric activity of these derivatives, in a phospholipid bilayer membrane and their uncoupling activity in rat-liver mitochondria were both found to depend on E_a of their anionic forms. The stability of the uncoupler anions regulated by the restricted rotation of the malononitrile group in a nonpolar membrane environment was found to be important for exhibition of these activities. The hydrophobicity of the anionic forms of these derivatives was suggested also to be affected by the intramolecular rotation.     

Lack of activation of UCP1 in isolated brown adipose tissue mitochondria by glucose-O-ω-modified saturated fatty acids of various chain lengths

We previously demonstrated that uncoupling protein 1 activity, as measured in isolated brown adipose tissue mitochondria (and as a native protein reconstituted into liposome membranes), was not activated by the non-flippable modified saturated fatty acid, glucose-O-ω-palmitate, whereas activity was stimulated by palmitate alone (40 nM free final concentration). In this study, we investigated whether fatty acid chain length had any bearing on the ability of glucose-O-ω-fatty acids to activate uncoupling protein 1. Glucose-O-ω-saturated fatty acids of various chain lengths were synthesized and tested for their potential to activate GDP-inhibited uncoupling protein 1-dependent oxygen consumption in brown adipose tissue mitochondria, and the results were compared with equivalent non-modified fatty acid controls. Here we demonstrate that laurate (12C), palmitate (16C) and stearate (18C) could activate GDP-inhibited uncoupling protein 1-dependent oxygen consumption in brown adipose tissue mitochondria, whereas there was no activation with glucose-O-ω-laurate (12C), glucose-O-ω-palmitate (16C), glucose-O-ω-stearate (18C), glucose-O-ω-arachidate (20C) or arachidate alone. We conclude that non-flippable fatty acids cannot activate uncoupling protein 1 irrespective of chain length. Our data further undermine the cofactor activation model of uncoupling protein 1 function but are compatible with the model that uncoupling protein 1 functions by flipping long-chain fatty acid anions.     

The modes of action of long chain alkyl compounds on the respiratory chain-linked energy transducing system in submitochondrial particles

The interactions of long chain (greater than C7), alkyl compounds with tightly coupled, beef heart submitochondrial particles (SMP) have been investigated with respect to their effects upon respiratory chain-linked electron transfer and energy coupling capacity. Long chain alkyl alcohols, amines, free fatty acids, and methyl esters exhibit a general uncoupling effect, with stimulation of the succinate oxidase activity but inhibition of the NADH oxidase, in SMP. The degree of effectiveness is dependent on the nature of the functional group and the length of the alkyl chain. Submitochondrial particles depleted of F1 and the F1-inhibitor protein are similarly affected. Subsequent treatment with bovine serum albumin reverses the effects of free fatty acids and results in partial recovery of activity with alkyl amines, alcohols, and methyl esters. Differences between the effects of these alkyl compounds and those of sodium dodecyl sulfate, deoxycholate, palmitoyl carnitine, and palmitoyl CoA rule out detergent-like action as the explanation for these observations. These data suggest that specific lipophilic interactions with the membrane, modulated by the nature of the functional group, are responsible for the effects of these compounds on the energy transducing system of SMP. Analyses of the reduction kinetics of the cytochromes indicate that the sites of interaction of these compounds with the inner mitochondrial membrane are associated with the primary dehydrogenase of complex I and energy coupling site 2; alkyl amines possess an additional site of interaction in the region of complex III.     

Role of hydroxyl group on the mesomorphism of alkyl glycosides: synthesis and thermal behavior of alkyl 6-deoxy-β-d-glucopyranosides

A homologous series of alkyl 6-deoxy-β-d-glucopyranoside amphiphiles was prepared, in an effort to identify the role of hydroxyl group in the mesomorphic behavior of alkyl glycosides. Synthesis was performed by a chlorination of the sugar moiety in alkyl β-d-glucopyranosides with methylsulfonyl chloride in DMF, followed by a metal mediated dehalogenation to secure alkyl 6-deoxy-β-d-glucopyranosides, wherein the alkyl chain length varied from C₉ to C₁₆. The mesomorphic behavior of these 6-deoxy alkyl glycosides was assessed using polarizing optical microscopy, differential scanning calorimetry and X-ray diffraction method. Whereas the lower homologues exhibited a monotropic SmA phase till sub-ambient temperatures, the higher homologues formed a plastic phase. A partial interdigitized bilayer structure of SmA phase is inferred from experimental d-spacing and computationally derived lengths of the molecules. The results were compared with those of normal alkyl glucopyranosides, retained with hydroxyl groups at C-2–C-6 carbons, and alkyl 2-deoxy-glucopyranosides, devoid of a hydroxyl group at C-2 and the comparison showed important differences in the mesomorphic behavior.     

Gentisides C–K: Nine new neuritogenic compounds from the traditional Chinese medicine Gentiana rigescens Franch

Nine new alkyl 2,3-dihydroxybenzoates, gentisides C–K, were isolated from the traditional Chinese medicine Gentiana rigescens Franch. Their structures and stereochemistry were elucidated by spectroscopic methods, and comparison of the specific rotation with that of the gentiside B. These metabolites are additional members of the gentisides which belong to a novel class of neuritogenic compounds. They are structurally different from one another because they possess varying alkyl chain lengths, with or without an isobutyl or isopropyl group at the end of the alkyl chain. These compounds are potent inducers of neurite outgrowth on PC12 cells. The gentiside C possessing the shortest alkyl chain length exhibited the highest neuritogenic activity among all of the gentisides. Gentiside C showed a significant neuritogenic activity at 1 μM against PC12 cells comparable to that seen for the best nerve growth factor (NGF) concentration of 40 ng/mL. In addition, evident neuritogenic activity was observed in the cells when treated with gentiside C at a concentration as low as 0.03 μM. The structure–activity relationships within the gentisides A–K revealed that alkyl chain length is important for the activity, but structure diversity at the end of the alkyl chain is not.     

Fatty Acid Spectra of Pediococcus urinae-Equi,P. homari Comparing with Other Pediococci

A new biological activity of 6-(methylsulfinyl)hexyl isothiocyanate derived from Wasabia japonica was discovered as an inhibitor of glycogen synthase kinase-3β. The most potent isothiocyanate, 9-(methylsulfinyl)hexyl isothiocyanate, inhibited glycogen synthase kinase-3β at a K_i value of 10.5 μM and showed ATP competitive inhibition. The structure-activity relationship revealed an inhibitory potency of methylsulfinyl isothiocyanate dependent on the alkyl chain length and the sulfoxide, sulfone, and/or the isothiocyanate moiety.     

Anti-Salmonella activity of (2E)-alkenals

AIMS: This study investigated the effect of a series of naturally occurring aliphatic (2E)-alkenals against Salmonella choleraesuis subsp. choleraesuis ATCC 35640 and evaluated their antibacterial action. METHOD AND RESULTS: A homologous series of aliphatic (2E)-alkenals from C5-C13 were tested for their antibacterial activity against Salm. Choleraesuis. The antibacterial action of (2E)-alkenals against Salm. choleraesuis increases with increasing carbon chain length. (2E)-Dodecenal (C12) was the most effective against this food-borne bacterium with minimum bactericidal concentration (MBC) of 6.25 microg ml-1 (34 micromol l-1), followed by (2E)-undecenal (C11) with an MBC of 12.5 microg ml-1 (77 micromol l-1). The activity was found to correlate with the hydrophobic alkyl chain length from the hydrophilic aldehyde group. The time-kill curve study showed that (2E)-dodecenal was bactericidal against Salm. choleraesuis at any growth stage. CONCLUSIONS: The antibacterial activity of (2E)-alkenals against Salm. choleraesuis was found to correlate with the hydrophobic alkyl chain length. The conjugated double bond is not essential in eliciting the activity but is associated with increasing it. SIGNIFICANCE AND IMPACT OF THE STUDY: Because of their easy availability and wide distribution in many edible plants, (2E)-alkenals can be used as anti-Salmonella agents.     

The relationship between the structure of plastoquinone derivatives and their biological activity in Photosystem II of spinach chloroplasts

The relationship between the structure of reconstituted plastoquinone derivatives and their ability to recover the Hill reaction was investigated by extraction and reconstitution of lyophilized chloroplasts from spinach, followed by monitoring DCIP photoreduction at 600 nm. The results show that: It is not essential that the plastoquinone side chain be an isoprenoid or a phytol; the activity increases with increasing length of the side chain up to 13–15 carbon atoms; for chains longer than 15 carbon atoms, the activity is practically constant. Lipophilic groups (such as -Br) in the side chain increased the activity, hydrophilic groups (such as -OH) decreased the activity. Conjugated double bonds in the side chain decreased the activity greatly, but non-conjugated double bonds had almost no effect on the activity, indicating a requirement of flexibility of the side chain. The activity is decreased in the order of PQ, UbiQ and MQ, showing a large effect of the ring structure.Abbreviations DCIP 2,6-dichlorophenolindophenol - DCMU 3-(3,4-dichlorophenyl)-1,1-dimethylurea - Q_A primary electron acceptor in PS II reaction centers - Q_B secondary electron acceptor in PS II reaction centers - PQ _n plastoquinones with an isoprenoid side chain (n, number of the isoprenoid units in the side chain) - PQ-n synthetic plastoquinones with alkyl side chain (n, number of the carbon atoms in the alkyl side chain) - PQ-n synthetic plastoquinones with a double bond in the alkyl side chain - UQ _n ubiquinones with an isoprenoid side chain (n, number of the isoprenoid units in the side chain) - UQ-n synthetic ubiquinones with alkyl side chain (n, number of the carbon atoms in the akyl side chain) - MQ-n 2-alkyl-1,4-naphthoquinone (n, number of the carbon atoms in the alkyl side chain)     

Alamethicin and synthetic peptide fragments as uncouplers of mitochondrial oxidative phosphorylation. Effect of chain length and change

Alamethicin, its derivatives and some synthetic fragments have been shown to be uncouplers of oxidative phosphorylation in rat liver mitochondria. A minimum peptide chain length of 13 residues is necessary for this activity. Peptide esters are more efficient uncouplers than the corresponding peptide acids. Esterification of the Glu(18) γ-COOH group in alamethicin does not diminish uncoupling activity. The structural requirements for uncoupling activity parallel those determined for ionophoretic action in small, unilamellar liposomes.     

Use of sodium dodecyl sulphate for stimulation of biodegradation of n-alkanes without residual contamination by the surfactant

The capacity of a range of aliphatic alkanes (C₆–C₁₆), intermediates of n-decane oxidation and sodium dodecyl sulphate (SDS) to induce decane-mineralization activity in the cells of Pseudomonas C12B was compared with that for n-decane. The comparison on quantitative basis had two serious limitations: low solubility of tested inducers in aqueous solutions and their toxicity to bacterial cells. Carbon chain length and the presence of hydroxyl group were the important factors for induction activity. However, presence of hydroxyl groups at both ends of alkyl chain prevented the induction of decane-mineralization activity. Good induction activity by SDS was caused either by the presence of free end of alkyl chain, or by bacterial hydrolysis of sulphate group to yield alcohol, which in turn served as true inducer. The presence of SDS in the culture medium with n-decane as main source of carbon and energy accelerated the growth of Pseudomonas C12B. SDS disappeared from the culture medium in early stages of cultivation suggesting preferential degradation by the bacterium, while the consumption of n-decane was accelerated. This may be associated with the capacity of SDS to induce decane-mineralization system in Pseudomonas C12B and/or with the ability of SDS to stimulate the surface attachment of competent bacteria resulting in the close proximity of the cells with alkane droplets, and thus, enhanced breakdown of the hydrocarbon pollutant.     

Effect of 4-Thiouridine on Chloroplast Development

The methoxymethyl group of the 6-methoxy-2-methoxymethyl-3-(3,4-methylenedioxyphenyl)-1,4-benzodioxan-7-yl moiety of insecticidallignans of Phryma was modified with sereral alkyl groups to evaluate the effect on activity of the substituents. The assay results make it evident that this activity was significantly modified by the chain length or bulkiness of the alkyl groups and that the oxygen atom of the methoxymethyl group was fairly important for enhancing the activity.     

Dielectric properties of yeast cells: Effect of some ionic detergents on the plasma membranes

Summary Dielectric measurements were made on suspensions of yeast cells treated with two homologous series of sodium alkyl (C₈, C₁₀, C₁₂, C₁₄) sulfonates and alkyl (C₈, C₁₀, C₁₂, C₁₄, C₁₆, C₁₈) benzyl dimethyl ammonium chlorides over a frequency range of 10 kHz to 100 MHz. Dielectric dispersions observed for the suspensions of intact yeast cells are found to be reduced by treatment with these detergents, the reduction being accompanied by a decrease in packed volume of the cells and by a leakage of intracellular compounds. The reduction of dielectric dispersions is considered to be caused by a decrease in volume of the cells in suspensions and an increase in conductivity of the cell membranes. An effect of the alkyl chain length of the detergents on the reduction of dielectric dispersions is also examined for these ionic detergents. The reducing effect shows the maximum at the alkyl chain, C₁₄ for sodium alkyl sulfonates and at C₁₆ for alkyl benzyl dimethyl ammonium chlorides. These results are consistent with hemolysis and bactericidal activity.     

Photosynthesis-Inhibiting efficiency of 4-chloro-2-(chlorophenylcarbamoyl)phenyl alkylcarbamates

A series of photosynthetic electron transport (PET) inhibitors from the group of salicylanilide alkylcarbamates was investigated. The compounds were analyzed using RP-HPLC to determine lipophilicity, and their PET inhibition was determined in spinach (Spinacia oleracea L.) chloroplasts. The site of action of the studied compounds is situated at the donor site of photosystem 2 (PS 2). Compounds substituted by chlorine in C′-3 and C′-4 of the aniline ring and the optimal length of the alkyl chain pentyl-heptyl in the carbamate moiety provided the most active PET inhibitors (IC₅₀ inhibition <10 μmol/L). Disubstitution in C′-3,4 by chlorine caused significant PET inhibiting activity decrease. Nevertheless, for all three series of C′-3, C′-4, C′-3,4 compounds, the dependence of PET activity on lipophilicity showed to be quasi-parabolic.     

Design,synthesis, and anti-HCV activity of thiourea compounds

A series of thiourea derivatives were synthesized and their antiviral activity was evaluated in a cell-based HCV subgenomic replicon assay. SAR studies revealed that the chain length and the position of the alkyl linker largely influenced the in vitro anti-HCV activity of this class of potent antiviral agents. Among this series of compounds synthesized, the thiourea derivative with a six-carbon alkyl linker at the meta-position of the central phenyl ring (10) was identified as the most potent anti-HCV inhibitor (EC₅₀ = 0.047 μM) with a selectivity index of 596.     

Stereoselective synthesis of β-arabino glycosyl sulfones as potential inhibitors of mycobacterial cell wall biosynthesis

A series of β-arabino glycosyl sulfones with varying alkyl chain lengths were synthesised in a stereoselective fashion as putative mimics of decaprenolphosphoarabinose (DPA), and as potential inhibitors of mycobacterial cell wall biosynthesis. Biological testing against Mycobacterium bovis BCG revealed low to moderate anti-mycobacterial activity with marked dependence on alkyl chain length, which was maximal for a C-12 chain.