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PubMed1980

Determination of reaction rate constants for alkylation of 4-(p-nitrobenzyl) pyridine by different alkylating agents.

The rate constants have been determined for the reaction between some different alkylating agents and 4-(p-nitrobenzyl) pyridine (NBP) in methanol. These constants have been compared with those for alkylation of aniline in water. All the constants were lower in methanol than in water but in different degrees. The rate constants of the different alkylating agents have been calculated at a nucleophilic strength n=2. The genetic risk defined as the degree of alkylation of a nucleophile (n=2) is equivalent to the rate constant kn=2 and the target dose. The dependence of the genetic risk on the rate constant (kn=2) is discussed.

Alkylating Agents↗
PubMedDate not supplied

Alkylation of guanine and cytosine in DNA by bizelesin. Evidence for a covalent immobilization leading to a proximity-driven alkylation of normally unreactive bases by a (+)-CC-1065 cross-linking compound.

Bizelesin, an intrahelical DNA-DNA interstrand cross-linker related to (+)-CC-1065, has been shown to alkylate DNA through guanine in restriction enzyme sequences in which there is a suitably positioned adenine contained in a highly reactive monoalkylation sequence on the opposite strand. Oligomers containing the sequence 5'-TTTTTN*, in which "N" was either G, C, or T, were synthesized to evaluate the cross-linking potential of bizelesin at nonadenine bases. Kinetic analysis of monoalkylation and cross-linking events demonstrates that it is the reaction at "N" (guanine or cytosine) that results in the cross-link which is the slow step. On the basis of this analysis and the normal unreactivity of guanine and cytosine to alkylation by the cyclopropapyrroloindole alkylating moiety of (+)-CC-1065, we propose that the molecular mechanism for this type of cross-linking reaction most likely involves a covalent immobilization of the second alkylating arm, resulting in a "proximity-driven" reaction.

Alkylating Agents↗
PubMed1988

Albumin adsorption on alkyl chain derivatized polyurethanes: I. The effect of C-18 alkylation.

The initial adsorption rate of delipidized Human Serum Albumin (HSA) is increased by addition of C-18 alkyl chains to a polyurethane. The presence of alkyl chains does not appear to influence the total amount of HSA adsorbed after one hour exposure to a 5.0 mg/mL HSA solution. Neither does the desorption following one hour of adsorption appear to be influenced by the presence of alkyl chains. A study of the effects of solution concentration and temperature showed that the initial adsorption rates on both polymers are proportional to the protein concentration raised to the 0.36 power, and that alkylation of the polymer increases the activation energy of the initial adsorption rate above the 14 kJ/mol observed for the underivatized polyurethane. A new technique is presented to quantify the mass of adsorbed protein using Fourier transform infrared spectroscopy and attenuated total reflection optics. This technique uses the absorbance of bulk protein as an internal calibration reference, and appears to be as accurate and perhaps more precise than radiolabeling techniques.

Adsorption↗
PubMed2001

Microbial desulfurization of alkylated dibenzothiophene and alkylated benzothiophene by recombinant Rhodococcus sp. strain T09.

The dibenzothiophene (DBT) desulfurizing operon, dsz, was introduced into various benzothiophene (BT)-desulfurizing bacteria using a Rhodococcus-E. coli shuttle vector. Of the tested recombinant bacteria, only those from Rhodococcus sp. strain T09 grew with both DBT and BT as the sole sulfur source. These recombinant cells desulfurized not only alkylated BTs, but also various alkylated DBTs, producing alkylated hydroxybiphenyls as the desulfurized products. Recombinant strain T09 also desulfurized alkylated DBT in an oil-water, two-phase resting-cell reaction. The dsz operon had the same desulfurizing activity when inserted into the vector in either orientation, indicating that the promoter region of the operon was functional in strain T09.

Alkylation↗
PubMed1990

Alkylation of DNA by melphalan in relation to immunoassay of melphalan-DNA adducts: characterization of mono-alkylated and cross-linked products from reaction of melphalan with dGMP and GMP.

A product expected to result from cross-linking of guanine bases in DNA by melphalan (4-(2-(di-guanin-7-yl))ethylamino-L-phenylalanine) was obtained from hydrolysis of melphalan-treated sodium deoxyguanylate at pH7 and characterized by U.V. and mass spectra. When tested in a competitive immunoassay using an antibody specific for melphalan-alkylated DNA it showed an affinity intermediate between that of melphalan-alkylated DNA and melphalan. From this and other assays it seemed possible that the cross-linked moiety in DNA was recognised by the antibody, but that its conformation differed from that of the free base tested, sufficiently to account for the discrepancy. It seemed possible that cross-linked guanine nucleotides would provide a better model, and these were therefore isolated, characterised and tested. Products derived from cross-linking of guanylic acid moieties through N-7 and N-7, and through N-7 and phosphate, had higher affinity than the cross-linked base, approximately the same as for alkylated native DNA, but less than for alkylated denatured DNA or RNA.

Alkylation↗
PubMedDate not supplied

Quantitative estimation of the extent of alkylation of DNA following treatment of mammalian cells with non-radioactive alkylating agents.

Alkaline sucrose sedimentation has been used to quantitate phosphotriester formation following treatment of human cells with the monofunctional alkylating agents methyl and ethyl methanesulfonate. These persistent alkaline-labile lesions are not repaired during short-term culture conditions and thus serve as a useful and precise index of the total alkylation of the DNA. Estimates of alkylation by this procedure compare favorably with direct estimates by use of labeled alkylating agents.

Alkylating Agents↗
PubMed2002

Transformation of mutagenic aromatic amines into non-mutagenic species by alkyl substituents. Part II: alkylation far away from the amino function.

Alkyl and trifluoromethyl derivatives of 4-aminobiphenyl (1) (4ABP) and 2-aminofluorene (7) (2AF) were synthesised and assayed for mutagenicity using Salmonella typhimurium tester strains TA98 and TA100 with and without the addition of S9 mix. Modification of 1 was achieved by attachment of alkyl groups (methyl, ethyl, iso-propyl, n-butyl, tert-butyl) and a trifluoromethyl group (CF(3)) in the 4'-position, the 3'-position (Me, CF(3)) and the 3'-, 5'-positions (DiMe, DiCF(3)). Compound 7 was modified by introduction of alkyl groups (methyl, tert-butyl, adamantyl) and a trifluoromethyl group (CF(3)) in the 7-position. The derivatives of 1 and 7 show for groups with growing steric demand decreased mutagenic activity. The bulkiest groups (CF(3), tert-butyl and adamantyl) induce the strongest effects on the mutagenicity. It was even possible to eliminate the mutagenicity of 1 and 7 by introduction of such substituents. In the last part of the work, we compared the experimental mutagenicities with calculated values derived from QSAR correlations. Our findings show that the predictions for aromatic amines with bulky substituents were generally too high. The strongest deviations were observed in the case of the CF(3)-, tert-butyl- and the adamantyl-group. Only the parent compounds and derivatives with small alkyl groups were predicted well. These investigations show that "large" substituents have an influence on the mutagenicity caused by their steric demand. To predict the correct mutagenicities of such compounds, it is necessary to introduce steric parameters in the respective QSAR equations which will be done in a forthcoming paper.

2-Naphthylamine↗
PubMedDate not supplied

Efficient DNA alkylation by a pyrrole-imidazole CBI conjugate with an indole linker: sequence-specific alkylation with nine-base-pair recognition.

Conjugates 7, 8, and 10 of N-methylpyrrole (Py)-N-methylimidazole (Im) polyamides and 1,2,9,9a-tetrahydrocyclopropa[1,2-c]benz[1,2-e]indol-4-one (CBI) with a 5-amino-1H-indole-2-carbonyl linker were synthesized by Fmoc solid-phase synthesis and a subsequent liquid-phase coupling procedure. The DNA alkylating abilities of conjugates 7, 8, 6b, and 10 were examined using Texas Red-labeled PCR fragments and high-resolution denaturing gel electrophoresis. CBI conjugates 7 and 8 exhibited highly efficient sequence-specific DNA alkylation comparable with previous CBI conjugates with a vinyl linker. In particular, conjugate 10, with a 10-ringed hairpin Py-Im polyamide, alkylated at the adenine of 5'-ACAAATCCA-3'. Introduction of an indole linker greatly facilitated the synthesis of sequence-specific alkylating Py-Im polyamides.

Alkylation↗
PubMed1981

Interaction of tubulin with drugs and alkylating agents. 2. Effects of colchicine, podophyllotoxin, and vinblastine on the alkylation of tubulin.

The antimitotic drugs colchicine, podophyllotoxin, and vinblastine are known to be potent inhibitors of microtubule polymerization, but little is known about how they affect the chemical properties of the tubulin molecule. In the preceding paper [Ludueña, R. F., & Roach, M. C. (1981) Bio-chemistry (preceding paper in this issue)], we have shown that the alkylating agent iodo[14C]acetamide reacts specifically with the sulfhydryl groups of tubulin and that its bifunctional analogue, N,N'-ethylenebis(iodoacetamide) (EBI), reacts with native tubulin to convert beta-tubulin into a form, designated beta*, which appears to represent an intrachain cross-linked form of beta. In this paper, we have incubated tubulin with the drugs prior to alkylation and measured their effects on the alkylation reactions. We have found that at 100 microM concentrations, podophyllotoxin, colchicine, and vinblastine inhibited the reaction of tubulin with iodo[14C]acetamide by 19-32%, 33-47%, and 62-72%, respectively; each drug was half-maximally effective at 3-5 microM, indicating that the suppressive effects of the drugs were mediated by their high-affinity binding sites. Similarly, beta* formation induced by EBI was suppressed by 92-94% in the presence of either colchicine or podophyllotoxin In contrast, vinblastine enhanced beta* formation by 40%. Alkylation with longer chain analogues of EBI revealed no evidence that the reactive sulfhydryls were being pushed apart by the drugs. These results indicate that each of the drugs has potent effects on the accessibility of the sulfhydryl groups of tubulin and that the effects of vinblastine are very different from those of either colchicine or podophyllotoxin.

Alkylating Agents↗
PubMed1996

Preparation and characterization of alkylated poly(vinyl alcohol) hydrogels using alkyl halides.

A poly(vinyl alcohol) hydrogel coated onto polyethylene was partially alkylated by reaction with an alkylhalide (C4, C8, or C18) in the presence of a deprotonating agent (sodium ethoxide or potassium tert-butoxiDATE Surface coverage determined by X-ray photoelectron spectroscopy (XPS) was respectively approximately 34, 25, and approximately 8% for the C4, C8, and C18 modified surfaces. Statistically significant differences were observed in the fraction of C8 and C18 grafted alkyl groups as a function of depth (i.e. take-off angle) indicating the presence of a verticle composition gradient. All three surfaces showed maximal surface coverage of alkyl groups after 1 h reaction. At this reaction time, no further coverage was observed beyond a base/PVA ratio twenty times greater than the stoichiometric ratio. The advancing contact angle data exhibited an increase in hydrophobicity that correlated with the degree of coverage obtained by XPS: 90 +/- 1, 83 +/- 0.5, and 71 +/- 1 deg for C4, C8 and C18 alkylated PVA, and 55 +/- 2 deg for PVA respectively. Large contact angle hysteresis was observed on all three surfaces consistent with surface heterogeneity.

Alkylation↗
PubMed1982

Mutagenicity of N-alkyl-N-(alpha-hydroperoxyalkyl) nitrosamines in V79 Chinese hamster cells in relation to alkylating activity.

Mutagenicity and cytotoxicity of a series of N-alkyl-N-(alpha-hydroperoxyalkyl)-nitrosamines (alkyl = methyl, ethyl, propyl, butyl and tert-butyl) were tested in V79 Chinese hamster cells to examine the effects of alkyl chain length and the mode of substitution at the alpha-carbon bearing the hydroperoxy group on the biological activities. Among a series of hydroperoxymethyl compounds whose carbon bearing the hydroperoxy group is primary, the N-methyl compound was the most mutagenic and cytotoxic, and the biological activities of the compounds decreased in the following order: methyl much greater than ethyl greater than propyl greater than or equal to butyl greater than tert-butyl, the last one being nonmutagenic at the concentration tested. In a series of alpha-hydroperoxyalkyl compounds whose alpha-carbon bearing the hydroperoxy group is secondary, the N-methyl compound was also found to be the most mutagenic and cytotoxic, and the biological activities of the compounds decreased in the following order: methyl greater than ethyl much greater than propyl greater than butyl. A comparison of the biological activities of the corresponding compounds having the hydroperoxy group at primary or secondary alpha-carbon showed that the latter compounds were far more active than the former. A plot of the alkylating activity of the compounds toward 4-(rho-nitrobenzyl) pyridine after deoxygenation with NaHSO3 versus their mutagenic potency in V79 cells was linear, indicating that the chemical reactivity of the compounds plays an important role in inducing mutation in V79 cells.

Alkylation↗
PubMed2004

Low-melting, low-viscous, hydrophobic ionic liquids: 1-alkyl(alkyl ether)-3-methylimidazolium perfluoroalkyltrifluoroborate.

A series of twenty two hydrophobic ionic liquids, 1-alkyl(alkyl ether)-3-methylimidazolium ([C(m)mim]+ or [C(m)O(n)mim]+; where Cm is 1-alkyl, Cm = nCmH(2m+1), m = 1-4 and 6; C(m)O(n) is 1-alkyl ether, C2O1 = CH3OCH2, C3O1 = CH3OCH2CH2, and C5O2 = CH3(OCH2CH2)2) perfluoroalkyltrifluoroborate ([RFBF3]-, RF = CF3, C2F5, nC3F7, nC4F9), have been prepared and characterized. Some of the important physicochemical properties of these salts including melting point, glass transition, viscosity, density, ionic conductivity, thermal and electrochemical stability, have been determined and were compared with those of the reported [BF4](-)-based ones. The influence of the structure variation in the imidazolium cation and the perfluoroalkyltrifluoroborate ([RFBF3]-) anion on the above physicochemical properties was discussed. The key features of these new salts are their low melting points (-42 to 35 degrees C) or extremely low glass transition (between -87 and -117 degrees C) without melting, and considerably low viscosities (26-77 cP at 25 degrees C).

Journal Article↗
PubMed1999

Influence of Alkyl Chain Length and Structure on the Extraction of Copper(II) from Aqueous Acid by 5-Alkyl-2-hydroxybenzaldoximes in Hydrocarbon Solvents: Diffusion Coefficients of Extractants and Their Complexes.

Measurement of the kinetics of extraction of copper(II) by 19 different 5-alkyl-2-hydroxybenzaldoximes (alkyl is C7H15 and C9H19) from acidic (hydrogen sulfate buffer) aqueous solution in the range pH 3.4-2.0, into 20% v/v toluene in n-hexane is reported. The lowering of the interfacial tension has been measured in some cases. The solubility of the extractants in water has been measured spectrophotometrically. A modified Taylor-Aris dispersion technique has been used to measure the diffusion coefficients in n-hexane and Orfom SX7 of some of the extractants and of the copper(II) complexes which they form. At low initial bulk concentrations (<10 mol m-3) of the extractants, the rate of extraction is controlled by the rate of diffusion of the extractant from the bulk to the organic-aqueous interface. The diffusion coefficient is related to the steric bulk of the alkyl substituent. At higher initial bulk concentrations (200 mol m-3) of the extractants, when the interface is saturated, the rate of extraction is inversely related to the apparent steric bulk of the alkyl substituent. Copyright 1999 Academic Press.

Journal Article↗
PubMed2001

Synthesis and Surface Properties of N-Alkyl-N-methylgluconamides and N-Alkyl-N-methyllactobionamides.

Three series of nonionic N-alkylaldonamides, N-alkyl-N-methylgluconamides (Cn-MGA, Cn: n-C(10)H(21), n-C(12)H(25), n-C(14)H(29), n-C(16)H(33), and n-C(18)H(37)), N-alkyl-N-methyllactobionamides (Cn-MLA, alkyl as above-mentioned), and N-oleyl-N-methylglucon/lactobionamide, were synthesized in the reaction of an appropriate N-alkyl-N-methylamine with delta-D-glucolactone and lactobionic acid, respectively. Krafft temperatures of aqueous solutions and surface properties of these surfactants at 20 degrees C, i.e., surface excess concentration, Gamma(cmc), surface area demand per molecule, A(min), efficiency in surface tension reduction, pC(20), effectiveness in surface tension reduction, Pi(cmc), critical micelle concentration, CMC, and CMC/C(20) parameter as well as standard free energies of adsorption, DeltaG degrees (ads), and of micellization, DeltaG degrees (mic), were determined. It was shown that introduction of the methyl group to the amide nitrogen increased the solubility of the surfactants, which was confirmed by their Krafft temperatures. Lactobionamides are more water soluble than gluconamides. On the other hand, the Cn-MGA surfactants are more surface active than the respective Cn-MLA ones. This observation is based on the determined adsorption and micellization parameters. The presence of one double bond in a hydrocarbon chain as in oleyl-amides increases their hydrophilic character compared with that of saturated C18 derivatives. No distinct differences were observed between the A(min) values obtained for both series studied, although they differ markedly in the size of the hydrophilic groups. Copyright 2001 Academic Press.

Journal Article↗
PubMed2002

Synthesis and biological activity of 5-alkyl-6-(alkylsulfanyl)- or 5-alkyl-6-(arylsulfanyl)pyrazine-2-carboxamides and corresponding thioamides.

Nucleophilic substitution of chlorine in 5-alkyl-6-chloropyrazine-2-carboxamides with various alkyl and arylthiolates afforded 20 5-alkyl-6-(alkylsulfanyl)- and 5-alkyl-6-(arylsulfanyl)pyrazine-2-carboxamides. The reaction of the amides with Lawesson's reagent yielded the corresponding thioamides. The assessment of in vitro antimycobacterial and antifungal activity of the compounds was carried out. In both series, the antimycobacterial activity increases with increasing molecular weight of the alkylsulfanyl group in position 6 of the pyrazine ring. Thioamides exhibited higher activity than the corresponding amides. 5-Butyl-6-(phenylsulfanyl)pyrazine-2-carbothioamide (2j) possessed the highest activity (91% inhibition) against Mycobacterium tuberculosis and also the highest lipophilicity (log P = 4.95). Only a poor in vitro antifungal effect was noted in 5-butyl-6-(butylsulfanyl)pyrazine-2-carboxamide (1i) and 6-(ethylsulfanyl)-5-isobutylpyrazine-2-carbothioamide (2q) against Trichophyton mentagrophytes and Absidia corymbifera.

Anti-Infective Agents↗
PubMed1988

4-alkyl radical extrusion in the cytochrome P-450-catalyzed oxidation of 4-alkyl-1,4-dihydropyridines.

Rat liver microsomal cytochrome P-450 oxidizes the 4-methyl, 4-ethyl (DDEP), and 4-isopropyl derivatives of 3,5-bis(carbethoxy)-2,6-dimethyl-1,4-dihydropyridine to mixtures of the corresponding 4-alkyl and 4-dealkyl pyridines. A fraction of the total microsomal enzyme is destroyed in the process. The 4-dealkyl to 4-alkyl pyridine metabolite ratio, the extent of cytochrome P-450 destruction, and the rate of spin-trapped radical accumulation are correlated in a linear inverse manner with the homolytic or heterolytic bond energies of the 4-alkyl groups of the 4-alkyl-1,4-dihydropyridines. No isotope effects are observed on the pyridine metabolite ratio, the destruction of cytochrome P-450, or the formation of ethyl radicals when [4-2H]DDEP is used instead of DDEP. N-Methyl- and N-ethyl-DDEP undergo N-dealkylation rather than aromatization but N-phenyl-DDEP is oxidized to a mixture of the 4-ethyl and 4-deethyl N-phenylpyridinium metabolites. In contrast to the absence of an isotope effect in the oxidation of DDEP, the 4-deethyl to 4-ethyl N-phenylpyridinium metabolite ratio increases 6-fold when N-phenyl[4-2H]DDEP is used. The results support the hypothesis that cytochrome P-450 catalyzes the oxidation of dihydropyridines to radical cations and show that the radical cations decay to nonradical products by multiple, substituent-dependent, mechanisms.

Animals↗
PubMed2005

Synthesis and antifungal activities of alkyl N-(1,2,3-thiadiazole-4-carbonyl) carbamates and S-alkyl N-(1,2,3-thiadiazole-4-carbonyl) carbamothioates.

A series of alkyl N-(1,2,3-thiadiazole-4-carbonyl) carbamates and S-alkyl N-(1,2,3-thiadiazole-4-carbonyl) carbamothioates with unsubstituted or monobrominated straight chain alkyl groups were synthesized and evaluated as fungistatic agents against Gibberella zeae and Alternaria kikuchiana. These compounds showed variable antifungal activities at concentrations of 5 and 50 microg/mL. The results showed that antifungal activities depended on the length of the alkyl chain with the optimal chain length of 6-11 carbons. Carbamic acid, (1,2,3-thiadiazole-4-ylcarbonyl)-, hexyl ester (4) showed a strong fungistatic activity against A. kikuchiana at both concentrations, with 90.7 and 54% growth inhibition at 50 and 5 microg/mL, respectively. Carbamic acid, (1,2,3-thiadiazole-4-ylcarbonyl)-, heptyl ester (5); Carbamic acid, (1,2,3-thiadiazole-4-ylcarbonyl)-, octyl ester (6); and Carbamic acid, (1,2,3-thiadiazole-4-ylcarbonyl)-, undecyl ester (9) showed strong fungistatic activity against G. zeae at both concentrations. Their growth inhibitions against G. zeae at the concentration of 5 microg/mL were 78, 63, and 59%, respectively.

Alternaria↗
PubMed1975

Synthesis and absolute stereochemistry of 5-alkyl-5-(3'-hydroxy-1'-methylbutyl)barbituric acid and 5-alkyl-5-(3'-hydroxy-1'-methylbutyl)-2-thiobarbituric acids.

5-Alkyl-5-(3-hydroxy-1-methylbutyl) barbituric acid (2) and 5-alkyl-5-(3-hydroxy-1-methylbutyl)-2-thiobarbituric acids (3) are matabolites of 5-alkyl-5-(2-pentyl) barbituric acid and 5-alkyl-5-(2-pantyl)-2-thiobarbituric acid, respectively. We have synthesized the four possible optical isomers of 2 and 3 by a procedure which established the absolute stereochemistry of each isomer. The two racemic pairs in each case were also prepared. The properties of these synthetic samples of 2 and 3 of known stereochemistry are compared to the properties of 2 and 3 which have been isolated from metabolism studies.

Barbiturates↗