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PubMed1981

Interaction of tubulin with drugs and alkylating agents. 1. Alkylation of tubulin by iodo[14C]acetamide and N,N'-ethylenebis(iodoacetamide).

The sulfhydryl groups of tubulin are reported to play a role in regulating microtubule assembly and colchicine binding to tubulin. The alkylating agents iodo[14C]acetamide and its bifunctional analogue N,N'-ethylenebis(iodoacetamide) are used as probes for the sulfhydryl groups of tubulin. In the presence of 8 M urea, alpha- and beta-tubulin have 10-11 and 8 alkylatable sulfhydryls, respectively, and one of the high molecular weight proteins (HMW 2) has 5 sulfhydryls/Mr 271 000. In the absence of urea, the rates of alkylation of alpha- and beta-tubulin are significantly lower but that of HMW 2 is unaffected. The sulfhydryls of tubulin are masked in intact microtubules. N,N'-Ethylenebis(iodoacetamide) reacts with free tubulin to generate a band, designated beta, which migrates ahead of beta on polyacrylamide gels. beta appears to represent a form of beta-tubulin containing at least one intrachain cross-link between sulfhydryl groups. Formation of beta* is inhibited in intact microtubules and is abolished if tubulin is denatured by 8 M urea, 1% sodium dodecyl sulfate, or boiling. N,N'-Ethylenebis(iodoacetamide) may thus be used as a probe for the native conformation of free tubulin.

Alkylating Agents↗
PubMed1981

Comparative carcinogenicity of alkylating agents: comparisons of a series of alkyl and aralkyl bromides of differing chemical reactivities as inducers of sarcoma at the site of a single injection in the rat.

A series of alkylating and aralkylating bromides was used in a comparative study of chemical reactivity (using 4-(p-nitrobenzyl) pyridine as standard nucleophile), and carcinogenic activity (using single injections by the subcutaneous route in 6-week old female CB-hooded rats). Benzyl, ethyl, isopropyl, and trityl bromides were inactive as carcinogens at doses up to 0.83, 12.5, 8.3 and 0.25 mmol/kg, respectively. 7-Bromomethylbenz[a]anthracene and 7-bromomethyl-12-methylbenz[a]anthracene gave high yields of sarcomas at the injection site (in the right flank); at the highest doses used, 35% yield of tumors was obtained using 0.25 mmol/kg 7-bromomethylbenz[a]anthracene, and 75% yield with 0.056 mmol/kg of the 12-methyl homologue. The order of chemical reactivity was trityl greater than 7-bromomethyl-12-methylbenz[a]anthracenyl greater than 7-bromomethyl-benz[a]anthracenyl greater than benzyl greater than ethyl greater than isopropyl. The relationship suggested between carcinogenicity and reactivity is that the highest reactivity permitted little in vivo penetration to essential cellular receptor sites because of immediate solvolysis, whereas the lower reactivities did not ensure sufficient alkylation of such receptors. The bromomethylbenz[a]anthracenes (of intermediate chemical reactivity) are known to react with DNA in vivo, but so far no differences in reactivity between them can account for their quantitatively different carcinogenic potencies.

Alkylating Agents↗
PubMed2003

Synthesis and properties of 2'-O-alkylated 2-thiouridine derivatives and oligonucleotides containing 2'-O-alkylated 2-thiouridine derivatives.

Oligonucleotides containing 2-thiouridine form stable RNA duplexes with complementary RNAs and show high selectivity in the base pair recognition. Moreover, alkylation of the 2'-hydroxyl group provides new insight into developments of new antisense RNAs capable of formation of more stable duplexes with target RNAs. Oligonucleotides having such properties are desirable as agents for the antisense strategy and SNPs analysis. In this study, we report a new method for the synthesis of 2-thiouridine and its 2'-O-alkylated derivatives. The hybridization and structural properties of these modified nucleosides were also studied in detail by the 1H NMR analysis and melting temperature (Tm) measurement of RNA duplexes.

Alkylation↗
PubMed1990

[Alkylation of nucleic acid components by ethyleneimine derivatives. I. Alkylation of bases].

In the course of investigating the reaction conditions of the nucleic acid components alcylation, the interaction of thioTEPA (N,N',N''-triethylenethiophosphoamide) with hydrochloric and perchloric acids was studied, perchloric acid increasing the alkylation products yield. HPLC and UV spectroscopy were used to isolate and identify products of nucleic bases alkylation by ethylenimine and its derivatives (thioTEPA and monoaziridinediethylphosphate). It is shown that under neutral conditions phosphoaminoethylation takes place, whereas under slightly acidic conditions products of aminoethylation are formed.

Adenine↗
PubMed1986

Inactivation of purified human O6-alkylguanine-DNA alkyltransferase by alkylating agents or alkylated DNA.

O6-Alkylguanine-DNA alkyltransferase partially purified from cultured human lymphoblasts (CEM-CCRF line) was inactivated with DNA substrates that had been treated separately with five methylating agents or with five chloroethylnitrosoureas. The extent of depletion of the transferase by alkylated DNA was compared with its inactivation by direct reaction with these ten agents. As expected, DNA substrates treated with methylating agents that efficiently produce O6-methylguanine were most effective in depleting the transferase, as was DNA pretreated with 1-(2-chloroethyl)-1-nitrosourea, 1,3-bis(2-chloroethyl)-1-nitrosourea, and chlorozotocin, agents presumed to form O6-chloroethylguanine as well as O6-hydroxyethylguanine in DNA. Unexpectedly, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea and 1-trans-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea were relatively ineffective in producing a DNA substrate that would inactivate the transferase, suggesting that both agents produce low steady-state levels of O6-alkylguanine. All of the agents tested were capable of inactivating the transferase by direct alkylation, although the efficiency of this activity ranges widely. We conclude that simple methylating agents and the cross-linking chloroethylnitrosoureas can inactivate O6-alkylguanine-DNA alkyltransferase both directly and indirectly, affording two mechanisms by which such agents could modulate their own cytotoxicity.

Alkylating Agents↗
PubMed2005

Regioselective formation of beta-alkyl-alpha-phenyliridabenzenes via unsymmetrical 3-vinylcyclopropenes: probing steric and electronic influences by varying the alkyl ring substituent.

The synthesis of unsymmetrical (Z)-1-alkyl-3-(2-iodovinyl)-2-phenyl-1-cyclopropenes (R=Me (8 a), Et (8 b), iPr (8 c), and tBu (8 d)) and their reactions with Vaska's complex [Ir(CO)Cl(PPh3)2] and its trimethylphosphine analogue [Ir(CO)Cl(PMe3)2] were investigated. Iridabenzvalene (13/20), iridabenzene (14/21), and/or eta(5)-cyclopentadienyliridium complexes (15/22) were obtained in modest yields and were fully characterized by spectroscopic means. X-ray structural data was secured for iridabenzvalene 13 d and iridabenzenes 14 a,b,d. Whereas iridabenzenes 14 a-c were stable at 75 degrees C for 48 h, 14 d, which possesses a bulky tBu group, rearranged cleanly to cyclopentadienyliridium 15 d at 50 degrees C over 15 h and displayed first-order kinetics. The influence of the alkyl substituent on the mechanisms of iridacycle generation, isomerization, and iridabenzene regioselectivity is discussed.

Journal Article↗
PubMed2001

Antimicrobial and diffusional correlation of N-alkyl betaines and N-alkyl-N,N-dimethylamine oxides from semisolids.

Previous studies have shown that two classes of amphoteric surfactants, N-alkyl betaines and N-alkyl-N,N-dimethylamine oxides, exhibit pronounced antimicrobial activity in combination and have potential for use in a semisolid formulation for topical or vaginal delivery. In this work, several potential delivery systems were prepared and evaluated for antimicrobial activity and diffusional properties. A novel antimicrobial test for semisolids was proposed that determined the contact time needed to kill microorganisms. The unformulated agents in solution exhibited the faster kill within 60 min, followed by the hydroxyethylcellulose gel formulation in 90 min, and the poloxamer gel and a cream that required several hours. Diffusion from the dosage form utilized a Slide-A-Lyzer diffusion cassette with a 10,000 MWCO membrane with (14)C-labeled active species added to the aforementioned antimicrobial formulations. Diffusion of the individual betaine and amine oxide derivatives were tracked over time to determine the diffusion rates and profiles of the components in each formulation and in solution. The betaine derivative diffused up to three times faster than the amine oxide derivative within the first 2 h, but the amount diffused was approximately equivalent at 24 h. The formulations delayed release in the same rank order as the contact time kill analysis: hydroxyethylcellulose gel > poloxamer gel > cream.

Anti-Bacterial Agents↗
PubMed1976

The effect of N-alkyl groups of substituted phenyl-N-alkyl carbamates on the inhibition of human plasma cholinesterase.

The inhibition constants for human plasma cholinesterase (dissociation, carbamylation, decarbamylation, overall bimolecular rate constants) were determined for two series of substituted phenyl-N-alkyl carbamates. N-propyl carbamates were found to be better inhibitors than the corresponding compounds carrying smaller N-alkyl groups. In both series the carbamylation constants of N-ethyl carbamates were lower than those of the N-methyl and N-propyl analogues, whereas the decarbamylation constants of the former were found to be higher than those of the latter carbamates. The experimental results obtained with human plasma cholinesterase are compared with published inhibition constants determined for several types of acetylcholinesterases.

Carbamates↗
PubMed1980

Induction of prophage and mutagenic effects by alkyl alkylaminosulfonates, ethyl aminosulfonate and alkyl methanesulfonates.

Prophage induction and mutation by alkylaminosulfonates, ethyl aminosulfonate and alkyl methanesulfonates were examined comparatively. Prophage induction was carried out with a lysozyme lysis technique on the lysogenic strain Micrococcus lysodeikticus 53-40 (N5). The sulfonic ester derivatives show a slight lysogenic induction. At higher concentrations their toxicity seems to mask phage detection. Only methyl isopropylaminosulfonate and ethyl aminosulfonate exhibit no or negligible toxic effects, and with these compounds at higher concentrations a strong prophage induction is found. Alkyl sulfonate derivatives induce mutations in the tester strain of Salmonella typhimurium TA1535. Methyl methylaminosulfonate and ethyl N-methyl-N-2-chloroethyl aminosulfonate show a mutagenicity comparable to that of the well-known methyl methanesulfonate or ethyl methanesulfonate. With ethyl aminosulfonate, however, which does not show inactivation, no significant mutagenic effect was observed. DNA alterations were found in the polymerase-deficient strain E. coli P3478. The results of prophage induction and mutagenicity are compared and discussed.

Alkanesulfonates↗
PubMed2005

Identification of alkyl carbazoles and alkyl benzocarbazoles in Brazilian petroleum derivatives.

Carbozoles are important compounds in crude oils, as they may be used as geochemical tracers, being the major type of nitrogen compounds in petroleum. At the same time, they are regarded as undesirable due to the problems they may cause in the refining process, such as catalyst poisoning, corrosion, gum or color formation in final products. As separation and identification of carbazoles are challenging goals, this work presents a chromatographic method, made of a pre-fractionation on neutral alumina followed by the separation and identification of two classes of carbazoles using FeCl(3)/Chromossorb W and gas chromatograph with mass spectrometer (GC/MS) (SIM-single ion monitoring mode) analysis. For the first time, a series of alkyl carbazoles and alkyl benzocarbazoles were identified in heavy gas oil (HGO) and atmospheric residue of distillation (ARD) obtained from Brazilian petroleum.

Aluminum Oxide↗
PubMed2005

Structures of micelles formed by synthetic alkyl glycosides with unsaturated alkyl chains.

Three new alkyl glycosides with similar molecular structures (oleyl and oleoyl alkyl chains and various head groups: disaccharide, trisaccharide and disaccharide with an additional amidoethoxy spacer) were synthesized and their supramolecular structure in aqueous solution was investigated. Small angle neutron scattering, surface tension measurement and the contact preparation method were applied to get molecular structure-property relationships. Although the chemical structures differ only in small details, their CMC values, lyotropic phase behaviour, surface area per surfactant molecule in the micelle and at the liquid-air interface, and the size and shape of the micelles are very different. We have found three different types of aggregates: spherical, cylindrical and polymer-like micelles in dilute solutions.

Journal Article↗
PubMed2005

Occurrence and hazard screening of alkyl sulfates and alkyl ethoxysulfates in river sediments.

Alkyl sulfates (AS) and alkyl ethoxysulfates (AES) are High Production Volume (HPV) 'down-the-drain' chemicals widely used globally in detergent and personal care products, resulting in low levels (ng to microg L(-1) range) ultimately released to the environment via wastewater. These surfactants have a strong affinity for sorption to sediments. However, data regarding the fate and effects following release into the environment has not been reported. Sediment samples from both normal exposed and presumably low exposed locations (background) were analyzed to determine the levels of AS/AES. The method used in this study shows broad applicability across various sediment types and the most common congeners of AS/AES. The combined levels of AS/AES detected in the two presumed lower exposed sites ranged from 0.025 and 0.034 microg g(-1) on a dry weight (dw) basis while the presumed higher exposed site had combined levels of AS/AES of 0.117 microg g(-1) (dw) based on triplicate analyses. Results indicate that detectable levels of AS/AES can be found in sediments in the environment at these three sites that are below the concentrations expected to produce significant adverse ecological effects for individual homologues and the whole mixture, the hazard screening for these three sites had PEC(porewater)/PNEC(total mixture) ratios of 0.007-0.024. However, further investigation of potential effects and risk assessment is warranted.

Environmental Monitoring↗
PubMed1980

Binding of n-alkyl beta-D-xylopyranosides and n-alkyl 1-thio-beta-D-xylopyranosides to beta-D-xylosidase from Bacillus pumilus PRL B12.

The binding of D-xylose and of a series of n-alkyl beta-D-xylopyranosides and their 1-thio analogues to beta-D-xylosidase from B. pumilus PRL B12 has been investigated. The binding constants and thermodynamic equilibrium parameters delta H0 and delta S0 have been determined. The enzyme does not distinguish between alpha- and beta-D-xylopyranose. Although the enthalpy of binding of D-xylose is very favourable, the overall free-energy is small, due to a large decrease in entropy. Furthermore, all of the evidence available suggests that the aglycon group is bound by unspecific, hydrophobic forces. However, simple correlations between the binding parameters and the relative hydrophobicity of the compounds could not be found. Unexpectedly, no parallelism between binding of n-alkyl beta-D-xylopyranosides and the corresponding 1-thio derivatives was found.

Bacillus↗
PubMed2002

Synthesis of an ether-linked alkyl 5a-carba-beta-D-glucoside, a 5a-carba-beta-D-galactoside, a 2-acetamido-2-deoxy-5a-carba-beta-D-glucoside, and an alkyl 5a'-carba-beta-lactoside.

For the purpose of providing biologically stable building blocks for the biocombinatorial synthesis using a living cell, some ether-linked alkyl 5a-carba-beta-D-glycoside primers were prepared. The key step of the synthesis was coupling of 1-bromo-n-alkanes with the 1-OH unprotected derivatives of 5a-carba-sugar analogues of D-glucose, D-galactose, and 2-acetamido-2-deoxy-D-glucose (N-acetyl-D-glucosamine), in DMF in the presence of sodium hydride. Alternatively, alkyl carba-lactoside was synthesized by incorporation of a 5a-carba-beta-D-galactose residue into the 4-position of dodecyl beta-D-glucopyranoside. A strong and specific inhibition of beta-galactosidase (K(i) 0.67 microM, bovine liver) was found for dodecyl 5a-carba-beta-D-galactopyranoside.

Animals↗
PubMedDate not supplied

Two-generation reproduction toxicity studies of di-(C(7)-C(9) alkyl) phthalate and di-(C(9)-C(11) alkyl) phthalate in the rat.

Di-(C(7)-C(9) alkyl) phthalate (D79P) and di-(C(9)-C(11) alkyl) phthalate (D911P), based on high-normality linear oxo-alcohols, have been assessed for their impact upon reproductive performance in Sprague-Dawley rats. Rats were continuously exposed to either D79P or D911P at dietary levels of 0%, 0.1%, 0.5%, or 1.0% over two generations. Selected F(0) offspring (F(1) generation) were exposed to the same dietary concentration of D79P or D911P as the respective F(0) animals, and were mated to produce F(1) offspring. Both D79P and D911P markedly reduced body weight gain in F(0) and F(1) adult males at the highest dose, but females were affected to a lesser extent. There was no impairment of fertility, fecundity, or development in either generation, but body weights of offspring in the 1.0% D79P and 1.0% D911P groups were slightly and transiently reduced over the weaning period. Although decreases in the weight of several organs were accounted for by depressed body weight, ovary weights were reduced in both generations exposed to 1.0% D79P, and epididymidal weights were slightly reduced in adults of both generations exposed to 1.0% D911P. However, ovarian function-assessed by the oestrus cycle and mating behaviour-and epididymidal sperm concentration, motility, and morphology were unaffected by either substance. Treatment resulted in liver changes, particularly in males, characterised by increased liver weight in young animals, histopathologic changes and reduced organ weight in mature animals, and an increase in palmitoyl CoA oxidase activity. In conclusion, neither D79P nor D911P impaired reproductive function in rats when administered in the diet at levels that induce systemic toxicity, and the NOAEL for effects on reproduction in the rat is 0.5% for both D79P and D911P.

Animals↗
PubMedDate not supplied

Developmental toxicity of di-(C(7)-C(9) alkyl) phthalate and di-(C(9)-C(11) alkyl) phthalate in the rat.

Two phthalate esters, di-(C(7)-C(9) alkyl) phthalate (D79P) and di-(C(9)-C(11) alkyl) phthalate (D911P), have been assessed for their potential to cause developmental toxicity in the rat. Groups of 22 timed-mated Sprague-Dawley rats were administered 250, 500, or 1000 mg/kg D79P or D911P daily by oral gavage (5 ml/kg) between gestation days (GD) 1 and 19. Control animals received the vehicle (olive oil) alone. On GD20, the animals were sacrificed and the fetuses examined. Treatment resulted in no signs of maternal toxicity, as assessed by adjusted maternal bodyweight gain throughout gestation and clinical examinations, and no effects upon litter size, fetal survival or bodyweight. Pups of the high dose D79P and intermediate and high dose D911P groups showed increased incidences of supernumerary lumbar ribs. There was a significant increase in dilated renal pelves in pups of the low dose D79P and high dose D911P groups, but only for D911P was there a significant trend. Consequently, the no observed adverse effect level (NOAEL) for maternal toxicity for both D79P and D911P is 1000 mg/kg/day. The NOAEL values for developmental toxicity are 500 mg/kg/day D79P and 250 mg/kg/day D911P.

Abnormalities, Drug-Induced↗
PubMed2003

The first applications of carbene ligands in cross-couplings of alkyl electrophiles: sonogashira reactions of unactivated alkyl bromides and iodides.

A Pd/N-heterocyclic carbene-based catalyst achieves the Sonogashira coupling of an array of functionalized, beta-hydrogen-containing alkyl bromides and iodides under mild conditions. By furnishing the first example of a nonphosphine-based palladium catalyst for cross-coupling unactivated alkyl electrophiles, this study provides an impetus for future efforts at catalyst development that extend beyond phosphine ligands.

Alkynes↗