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PubMed1987

Biochemistry of protein-isocyanate interactions: a comparison of the effects of aryl vs. alkyl isocyanates.

In addition to their use in the polyurethane and pesticide industries, isocyanates have proven to be useful probes for the exploration of protein structure. This paper focuses on three aspects of isocyanates: their broad reactivity, their reversible interaction with cholinesterases, and the relative hydrolysis rates of alkyl and aryl isocyanates. The broad reactivity of isocyanates as well as the demonstrated affinity labeling of serine and sulfhydryl esterases are discussed. Extension of the affinity labeling studies to include the analysis of the inhibition of cholinesterases by methyl isocyanate shows that methyl isocyanate is not an effective inhibitor of any of the cholinesterases. The inhibition of cholinesterases by alkyl isocyanates shows a pattern of decreased specificity with decreased alkyl chain length. The inhibition of cholinesterases by isocyanates is shown to be reversible, with a maximum rate of reversal seen at physiological pH. This reversal is characteristic of the reaction of an isocyanate with a sulfhydryl group. Finally, the affinity labeling of proteins must compete successfully with the hydrolysis of isocyanates in aqueous solution. The hydrolysis of alkyl isocyanates is shown to be significantly slower than that of the aryl isocyanates.

Affinity Labels↗

PubMed2005

1H and 13C nuclear magnetic resonance studies of the hindered phencyclone adducts of some smaller branched N-alkyl maleimides: rigorous aryl proton assignments with high-resolution two-dimensional (COSY45) spectroscopy, and anisotropic shielding effects and ab initio geometry optimizations.

Phencyclone, 1, a potent Diels-Alder diene, reacts with a series of N-alkylmaleimides, 2, to form hindered adducts, 3. The 300 MHz 1H and 75 MHz 13C NMR studies of these adducts at ambient temperatures have demonstrated slow rotations on the nuclear magnetic resonance (NMR) timescales for the unsubstituted bridgehead phenyl groups, and have revealed substantial magnetic anisotropic shielding effects in the 1H spectra of the N-alkyl groups of the adducts. The selected N-alkyl groups for the target compounds emphasized smaller branched alkyls, including C3 (isopropyl, a); C4 (isobutyl, b; and t-butyl, c); C5 (n-pentyl, d; isopentyl [isoamyl], e; 1-ethylpropyl, f; t-amyl, g;) and a related C8 isomer (1,1,3,3-tetramethylbutyl ["t-octyl"], h). The straight-chain n-pentyl analog was included as a reference. This present work on the branched N-alkylmaleimide adducts appreciably extends our earlier compilation on the N-n-alkylmaleimide adducts. Key methods for proton assignments included "high-resolution" 1H-1H chemical shift correlation spectroscopy, COSY45. 13C NMR of the adducts, 3, verified the expected number of aryl carbons for slow exchange limit (SEL) spectra of the bridgehead phenyl groups. The synthetic routes involved reaction of the corresponding amines, 4, with maleic anhydride to give the N-alkylmaleamic acids, 5, which underwent cyclodehydration to form the maleimides, 2. Magnetic anisotropic shielding magnitudes for alkyl group protons in the adducts were calculated relative to corresponding proton chemical shifts in the maleimides. Geometry optimizations for the above adducts (and for the N-n-butylmaleimide adduct) were performed at the Hartree-Fock level with the 6-31G* basis set. The existence of different contributing conformers for the adducts is discussed with respect to their calculated energies and implications regarding experimentally observed anisotropic shielding magnitudes.

Anisotropy↗

PubMed2004

Interaction of an intermediate structure of Bacillus subtilis alpha-amylase with alkyl-substituted sepharose 4B: a model of membrane translocation.

An intermediate form of alpha-amylase from Bacillus subtilis was prepared following a previously reported procedure. Stabilization of this protein structure by various additives and its interaction with alkyl-substituted Sepharose 4B (Sepharose-lipid), used to mimic the role of the alkyl chains of the phospholipid bilayer, were investigated. Exposure of hydrophobic clusters in the protein structure on denaturation was indicated by a greater affinity of the intermediate form for interaction with the alkyl chains on the matrix, as compared with the original native structure. Near- and far-ultraviolet circular dichroism studies supported loss of tertiary structure with retention of secondary structure, as expected from molten globular intermediate forms. Based on the results presented, we suggest that interaction of a protein in its native and nonnative forms with an alkyl-substituted matrix may provide useful information regarding its capacity for insertion into and translocation across the biologic membrane.

Animals↗

PubMed2005

Determination and distribution of alkyl ethoxysulfates and linear alkylbenzene sulfonates in coastal marine sediments from the Bay of Cadiz (southwest of Spain).

The distribution of the two main anionic surfactants manufactured and used in the world, alkyl ethoxysulfates (AES) and linear alkylbenzene sulfonates (LAS), has been studied in sediments from a salt marsh and an estuary of the Bay of Cadiz (southwest of Spain). The identification and quantification of AES and LAS was carried out after automated Soxhlet extraction with methanol, followed by solid-phase extraction and liquid chromatography coupled to electrospray mass spectrometry. The latter procedure permitted the unequivocal identification of every LAS homologue as well as the AES homologues of up to 16 carbon atoms in their alkyl chain and of up to 12 ethylene oxide groups. Recoveries were in the range of 51% to 84% and limits of detection from 1 to 5 microg/kg. We have focused our attention particularly on AES because, in spite of their great use, these compounds have received less attention than LAS and their occurrence has not been described in marine environmental samples. Alkyl ethoxysulfates concentration values range between 100 and 400 microg/kg in the topmost layer of sediments at the sampling areas. The relative distribution of AES homologues shows higher percentages for the longer alkyl chain homologues in sediments as well as for the shorter ethoxymers. A decrease in LAS concentrations has been found relative to past studies in one of the sampling areas as a consequence of the reduction of urban wastewater discharges.

Alkanesulfonic Acids↗

PubMed2005

DNA repair proteins as molecular therapeutics for oxidative and alkylating lung injury.

Endogenous and environmental oxidation is increasingly becoming an important factor associated with numerous disorders in both children and adults. The lung is particularly prone to oxidation, as the gas exchange organ is continuously exposed to a great deal of airborne oxidants. Lung oxidation-induced toxicity is a critical clinical problem that is currently lacking cure. For example, treatment for acute respiratory distress syndrome (ARDS), a common type of acute diffuse lung injury, is strictly supportive. Alkylating chemotherapeutics and many methyl chemicals can cause acute or chronic lung injury, which is also difficult to treat. Many new approaches are being tried to improve the treatment of lung oxidation and alkylation; one of these is the use of DNA repair proteins, such as base excision repair proteins that are largely involved in repairing DNA damage caused by oxidation and alkylation. Recent advances have revealed their promising potential for treating oxidation toxicity. Here we discuss discoveries that have led to this possibility, including pioneering research into the cellular signaling transduction and molecular mechanisms of DNA repair proteins. In conclusion, when combined with other therapeutic measures such as anti-oxidant chemicals and enzymes, DNA repair proteins may have great potential for treating acute and chronic lung toxicity induced by oxidation and alkylation.

Animals↗

PubMed1995

Modelling the relative metabolic occurrence of alkyl-nitrogen bond cleavage using structure-reactivity maps.

Over a broad range of tertiary N-methyl amines, whenever alkyl-nitrogen bond cleavage was observed, N-demethylation was also observed. Alkyl-nitrogen bond cleavage in rings, alkyl-nitrogen bond cleavage if the carbon of the N-dealkylation reaction-site is in a ring and the nitrogen atom of the reaction-site is not in a ring, and dedimethylamination are not likely to occur relative to N-demethylation. Structure-reactivity relationships for other N-dealkylations, such as N-debenzylation, N-dethiophenation, and N-dedimethylaminoethylation of tertiary amines were evident from a visual inspection of the structure-reactivity map. Structure-reactivity maps proved to be a useful tool for ascertaining structural environments influencing the relative occurrence of alkyl-nitrogen bond cleavage in tertiary N-methyl amines.

Biotransformation↗

PubMed1987

Orally active 1-(cyclohexyloxycarbonyloxy)alkyl ester prodrugs of cefotiam.

Orally active 1-(alkyl substituted cyclohexyloxycarbonyloxy)alkyl ester prodrugs (9b-h) of 7 beta-[2-(2-aminothiazol-4-yl)acetamido]-3- [[[1-(2-dimethylaminoethyl)-1H-tetrazol-5-yl]thio]-methyl]ceph+ ++-3- em-4-carboxylic acid (cefotiam, CTM) have been studied as well as the thia (9i) and aza (9j) analogs. These represent derivatives of the 1-(cyclohexylacetoxy)ethyl ester (2) of CTM. The syntheses and oral bioavailability (BA) in mice are described. Among them, the 1-(cyclohexyloxycarbonyloxy)butyl ester (9h) gave the highest BA, 93.5%; the esters having a cyclohexyloxy group in the ester moiety gave BAs of more than 75%, although the BA of the 1-(ethoxycarbonyloxy)ethyl ester (9a) was only 23.9%. The thia analog showed a moderate BA, 46%, but the aza analog, 9j, did not show a BA of CTM. These results indicate that the 1-(substituted cyclohexyloxycarbonyloxy)alkyl group was the suitable promoiety to improve the oral BA of CTM. Chiral 1-(alkoxycarbonyloxy)alkyl groups used as the ester moiety, gave an almost 1: 1 mixture of diastereoisomeric esters. These were tested as such. However, an experiment in which the separated isomers of the 1-(cyclohexyloxycarbonyloxy)ethyl ester (9d) were administered orally confirmed that both diastereoisomers gave identical BAs.

Administration, Oral↗

PubMed1989

Synthesis and antibacterial evaluation of N-alkyl vancomycins.

Over eighty N-alkyl vancomycins were synthesized by reductive alkylation of vancomycin with the appropriate aldehydes. The N-alkyl vancomycins exhibit greater antibacterial activity than the corresponding N-acyl vancomycins and the parent antibiotic. Some of these semisynthetic vancomycins are five times more active than vancomycin. The N-alkyl vancomycins also show longer elimination half-lives in rats than vancomycin.

Animals↗

PubMed1998

Syntheses of antifungal aureobasidin A analogs with alkyl chains for structure-activity relationship.

The syntheses of aureobasidin A (AbA) derivatives with alkyl chains and their in vitro structure-biological activity relationships are discussed. The analogs replaced at positions 6, 7, or 8 of AbA with either L-glutamic acid, delta-hydroxy-L-norvaline, or delta-hydroxy-N-methyl-L-norvaline are prepared. The gamma-carboxyl or delta-hydroxyl group of these new amino acids was coupled with acids, alcohols, or amines with alkyl chains. While the analogs having L-glutamic acid residue at positions 6 or 8 showed weak activity, esterification of the gamma-carboxyl group with benzyl or shorter alkyl (C4 or C6) alcohols, significantly enhanced the activities. Introduction of longer alkyl (C14) chain to the same amino acids residues at positions 6, 7, or 8 resulted in total loss of antifungal activity. Among the lipophilic analogs in [L-Glu6] derivatives, the C6 alcohol ester showed the strongest antifungal activity against Candida spp. so far tested. None of the derivatives showed activity against Cryptococcus neoformans.

Antifungal Agents↗

PubMed1976

[Condensation of N-alkyl-o-phenylendiamine with ethyl benzoylacetate].

By reaction in hot xylene of ethyl benzoylacetate with N-methyl-o-phenylenediamine (I a) and N-benzyl-o-phenylenediamine (I b) three five-membered ring compounds and one seven-membered ring compound were obtained. Compounds isolated were: 1-alkyl-2-phenacylbenzimidazoles (III), 1-alkyl-2-phenylbenzimidazoles (V), 1-alkyl-2-methylbenzimidazoles (VI) and 1-alkyl-4-phenyl-1,3-dihydro-2H-1,5-benzodiazepine-2-ones (IV). In the reaction with N-benzyl-o-phenylenediamine we isolated also the N-benzyl-2-benzoylacetamidoaniline (II b), which by further heating in xylene gave (IV b). The structures of compounds were elucidated from their chemical reactivity and their N.M.R. and I.R. spectra.

Aniline Compounds↗

PubMed1992

Further examination of 9-alkyl- and sugar-modified anthracyclines in the circumvention of multidrug resistance.

Anthracyclines possessing either a 9-alkyl modification in the A-ring of the tetracyclic aglycone and/or specific changes to the amino sugar moiety retain effective cytotoxic activity against multidrug resistant (MDR) cell lines. To obtain a better understanding of the structural features responsible for this potentially valuable behaviour, we used the MTT tetrazolium dye reduction assay to calculate resistance factors (RF = the ratio of ID50 for the drug-resistant line to that for the parental line) for the EMT6/P mouse mammary tumour and its MDR variant EMT6/AR1.0, and the H69/P human small cell lung cancer line and its MDR counterpart H69/LX4. Both MDR lines exhibit marked resistance to doxorubicin, MDR 1 gene amplification, hyperexpression of the membrane P-glycoprotein and reduced drug accumulation. RF values for doxorubicin were 34 and 131 in the EMT6 and H69 cell line pairs, respectively. The 9-alkyl-substituted anthracyclines were confirmed as having RF values 9- to 15-fold lower than those for doxorubicin. The 9-ethyl analogues Ro 31-1966 (RF for EMT6 2.2, RF for H69 4.7) and Ro 31-1749 (RF for EMT6 3.9, RF for H69 9.5) were superior to the previously studied 9-methyl analogue Ro 31-1215 (RF for EMT6 8.1 RF for H69 12.4). A clear trend for RF values to decrease with increasing 9-alkyl chain length was also noted in the structurally more complex aclacinomycin series. For example, 13-methyl-aclacinomycin (RF for EMT6 1.0, RF for H69 2.2) featuring a 9-isopropyl moiety was superior to the 9-alkyl-containing aclacinomycin A (RF for EMT6 4.7, RF for H69 5.8), and this was in turn more effective than the 9-methyl analogue sulfurmycin A (RF for EMT6 6.4, RF for H69 14.2). The trisaccharide moiety was not an essential feature for activity against MDR lines in the aclacinomycins, as shown by the low RF value with aklavine (RF for EMT6 2.1, RF for H69 2.5). However, a small change in one of the sugar moieties of aclacinomycin A, as in marcellomycin, resulted in a considerable increase in RF values (RF for EMT6 18.5, RF for H69 25.3). The complex anthracyclines AD 32 (RF for EMT6 6.5, RF for H69 11.7) and particularly tetrahydropyranyl-doxorubicin (RF for EMT6 1.4, RF for H69 3.2) were effective against MDR lines.(ABSTRACT TRUNCATED AT 400 WORDS)

Aclarubicin↗

PubMed2005

Effects of N-alkyl-N,N-dimethylamine-N-oxides on the activity of purified sarcoplasmic reticulum Ca(2+)-transporting ATPase.

N-alkyl-N,N-dimethylamine-N-oxides (CnNO, n = 10-20 is the number of alkyl carbon atoms) stimulate the skeletal sarcoplasmic reticulum (SR) Ca(2+)-transporting ATPase activity at low concentrations and inhibit it at high concentrations. The minimum concentration (cmin), at which CnNO inhibits the ATPase, continuously decreases up to n = 16-18 and then increases. The values of Cmin are smaller than the CnNO critical micelle concentration (cmc) for C10NO-C14NO homologs, but larger than cmc for C18NO-C20NO homologs. The ATPase inhibition is caused by the CnNO-induced lipid bilayer structural perturbation in the ATPase annular region, modulated by the partition equilibria of the CnNO molecules between the bilayer and aqueous phase for short alkyl chain (n = 10-16) CnNO homologs, and between the bilayer, micelles and aqueous phase for long alkyl chain (n = 18-20) CnNO homologs.

Animals↗

PubMedDate not supplied

[The properties of [omega(3-acetylpyridinio)-n-alkyl]adenosine pyrophosphates, structural analogs of the coenzyme NAD (author's transl)].

[omega-(3-Acetylpyridinio)-n-alkyl]adenosine pyrophosphates are coenzyme analogs of NAD. The adenosine pyrophosphate moiety and the 3-acetylpyridine ring of the analogs are connected by n-alkyl chains of different lengths (ethyl--hexyl). The analogs form strong dissociating complexes with lactate dehydrogenase. The complex formation is predominantly achieved by interaction of the ADP moiety with its respective binding domain at the active site. The redox potentials of the analogs and NAD are of similar magnitude. The coenzyme function of the analogs depends upon the length of the hydrocarbon chain. Lactate dehydrogenase and alcohol dehydrogenases from yeast and horse liver do not catalize hydrogen transfer from their substrates to any other alkyl analog but [4-(3-acetylpyridinio)-n-butyl]adenosine pyrophosphate, aldehyde dehydrogenase from horse liver catalizes hydrogen transfer from acetaldehyde to the pentyl derivative and glyceraldehyde-3-phosphate dehydrogenase catalizes hydrogen transfer to both analogs. In no case, hydrogen transfer from or to one of the 3-acetylpyridine-n-alkyl analogs proceeded with a velocity comparable to NAD or its 3-acetylpyridine analog. The results show that the nicotinamide bound ribose in NAD is involved in the binding and the activation of the coenzyme.

Mathematics↗

PubMed1990

Lipolysis of menhaden oil triacylglycerols and the corresponding fatty acid alkyl esters by pancreatic lipase in vitro: a reexamination.

In order to distinguish between possible fatty acid differences during lumenal lipolysis and cellular absorption, we have reinvestigated the in vitro hydrolysis of menhaden oil and its alkyl esters by pancreatic lipase. For this purpose we incubated menhaden oil or its fatty acid methyl and ethyl esters with porcine pancreatic lipase in the presence of bile salts and determined the composition of the released free fatty acids, monoacylglycerols, diacylglycerols, and residual triacylglycerols, or the free fatty acids and residual alkyl esters, respectively, by thin-layer and gas-liquid chromatography. There was significant discrimination against the delta 4- to delta 7-unsaturated fatty acids of both medium and long chain lengths during the hydrolysis of menhaden oil and its fatty acid ethyl esters. In general, the ethyl esters were hydrolyzed 10-50 times more slowly than the corresponding glyceryl esters, depending on the exact ratio of the two substrate types. None of the triacylglycerols or ethyl esters, however, was completely resistant to hydrolysis resulting in an eventual cleavage of all the alkyl esters and presumably all the primary ester bonds in the triacylglycerol molecules. Since the rate of release of the least resistant fatty acid exceeded that of the most resistant acid by only a factor of 6, it is concluded that in the presence of a large excess of lipase the liberated fatty acids would approach the composition of the dietary alkyl or glyceryl esters, as observed during lumenal lipolysis (Yang, L.-Y., A. Kuksis, and J. J. Myher. 1989. Biochem. Cell Biol. 67: 192-204).

Animals↗

PubMed1990

Metabolism of 7 beta-alkyl chenodeoxycholic acid analogs and their effect on cholesterol metabolism in hamsters.

The metabolism of 7-ethyl- and 7-propyl-chenodeoxycholic acids was studied in hamsters. Both bile acid analogs were absorbed efficiently by the intestine and secreted into the bile at rates similar to those of chenodeoxycholic acid. After intraduodenal administration into bile fistula hamsters, the 7-alkyl analogs were present in bile as the glycine and taurine conjugates. The glycine/taurine ratios were: chenodeoxycholic acid, 1.9; 7-ethyl analog, 0.3; and 7-propyl analog, 0.2. After oral administration, during a 21-day feeding experiment, the 14C-labeled analogs were recovered quantitatively in the feces. Chenodeoxycholic acid was largely 7-dehydroxylated to lithocholic acid in the intestinal tract. In contrast, the 7 alpha-hydroxy group of the 7-alkyl bile acids was completely resistant to bacterial action. 7-Ethyl-chenodeoxycholic acid was transformed in part to a compound tentatively identified as 7 alpha-hydroxy-3-oxo- 7 beta-ethyl-5 beta-cholanoic acid while 7-propyl-chenodeoxycholic acid was excreted unchanged. In the hamsters used, the 7-alkyl bile acid analogs did not inhibit the bacterial dehydroxylation of chenodeoxycholic acid. At the end of the 21-day feeding period, analysis of the gallbladder bile showed that 7-methyl-, 7-ethyl-, and 7-propyl-chenodeoxycholic acids accounted for 38, 31, and 12% of total bile acids, respectively. The 7-alkyl bile acids decreased cholesterol absorption; the 7-propyl analog caused significant decrease in serum and liver cholesterol concentration. These experiments demonstrate that the 7-ethyl- and 7-propyl chenodeoxycholic acids, just like the 7-methyl-analog, are absorbed by the intestine and participate in the enterohepatic circulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1975

Alkyl isocyanates as active site-directed inactivators of guinea pig liver transglutaminase.

Alkyl isocyanates are effective inactivators of guinea pig liver transglutaminase. Based on the specificity of the reaction the protection against inactivation by glutamine substrate, and the essential nature of calcium for the inactivation reaction, it is concluded that these reagents act as amide substrate analogs and, thus function in an active site-specific manner. Support for the contention that inactivation results from alkyl thiocarbamate ester formation through the single active site sulfhydryl group of the enzyme is (a) the loss of one free--SH group and the incorporation of 1 mol of reagent/mol of enzyme in the reaction, (b) similarity in chemical properties of the inactive enzyme derivative formed to those previously reported for another alkyl thiocarbamoylenzyme and an alkyl thiocarbamoylcysteine derivative, and (c) the finding that labeled peptides from digests of [methyl-14C]thiocarbamoyltransglutaminase and those from digests of iodoacetamide-inactivated enzyme occupy similar positions on peptide maps. Transglutaminase was found to be inactivated neither by urethan anlogs of its active ester substrates nor by urea analogs of its amide substrates. It is concluded on the basis of these findings that inactive carbamoylenzyme derivatives are formed only by direct addition of the transglutaminase active--SH group to the isocyanate C--N double bond, and not, like several serine active site enzymes, by nucleophilic displacement with urethan analogs of substrate, or by nucleophilic displacement with urea analogs of substrate.

Alcohols↗

PubMed1988

The lateral order of dipalmitoylphosphatidylcholine model membranes in the presence of N-alkyl-N,N,N-trimethylammonium ions as studied by Raman spectroscopy.

Effects of N-alkyl-N,N,N-trimethylammonium ions with different alkyl substituents (hexyl, nonyl, dodecyl, and octadecyl) on the lateral packing of lipids in dipalmitoylphosphatidylcholine (DPPC) dispersions in H2O was investigated by Raman spectroscopy in a spectral region of 2800--3100 cm-1 at temperatures between 22--70 degrees C. The lateral order parameter Slat calculated by empirical equation reveals that the addition of the ions decreases the lateral ordering of lipid hydrocarbon chains in the gel phase, while in the liquid crystalline state the lateral ordering is increased. In addition, this observation is supported by decomposition of the spectra into component bands using a computer fitting program. This enabled to follow changes in individual band parameters (position, amplitude, and height) in dependence on temperature and/or additives. The results suggest that N-alkyl-N,N,N-trimethylammonium ions have a condensing effect on DPPC bilayer in the liquid crystalline state, the effect increasing with the increasing length of the alkyl substituent.

1,2-Dipalmitoylphosphatidylcholine↗

PubMed1977

[Lysis of yeast protoplasts under sodium alkyl sulfates treatment].

The lytic action of homologous series of sodium alkyl sulfates on yeast protoplasts was studied. The concentration dependences study allowed to estimate the lytic concentrations C50 of the agents required for the 50% lysis of protoplasts in the suspension. The data concerning the agents micelle formation in the lytic medium allowed to make some suggestions and to produce a model of the lytic action of alkyl sulfates on the plasma membrane of the protoplasts. The amounts of the agents absorbed on the membrane and involved in the interaction followed by the membrane breakdown in the model are evaluated. On the basis of the data obtained it is concluded that sodium dodecyl sulfate displays the highest lytic activity to the yeast protoplast plasma membrane as compared to the other alkyl sulfates used in the study. The results obtained are discussed in terms of the effect of yeast cell wall on the extraction of intracellular proteins from intact yeast cell under sodium alkyl sulfates action.

Kinetics↗