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A magnesium enamide derived from N-2-(N',N'-diethylamino)ethyl imine reacts with a primary and secondary alkyl chloride or a primary alkyl fluoride to give an alpha-alkylated ketone in good to excellent yield after hydrolysis. The reaction takes place with a high level of inversion of stereochemistry at the electrophilic carbon center and will be useful for production of optically active compounds.
3-Ethyl-3-(4-pyridyl)piperidine-2,6-dione (1) is a strong competitive inhibitor of human placental aromatase (Ki = 1.1 microM; testosterone as substrate) that, unlike the structurally related aromatase inhibitor aminoglutethimide (2), is not also an inhibitor of the cholesterol side-chain cleavage enzyme desmolase. An improved synthesis of 1 is described, which was readily adapted to the preparation of homologues in a series of 3-alkyl-3-(4-pyridyl)-piperidine-2,6-diones (6-13). Alkylation of 1 afforded a second series, comprising 1-alkyl-3-ethyl-3-(4-pyridyl)-piperidine-2,6-diones (14-23). Inhibitory activity toward aromatase was maximal in both series for the octyl derivatives. Respective Ki values for the competitive inhibition exerted by the 3-octyl (12) and the 1-octyl (21) analogues with testosterone as substrate were 0.09 and 0.12 microM. The compounds 1, 2, 12, and 21 differed in their relative potencies as inhibitors of the aromatization of testosterone and androstenedione. Respective Ki values were as follows: for 1, 1.1 and 14 microM (ratio 12.7); for 2, 0.6 and 1.8 microM (3); for 12, 0.09 and 0.20 microM (2.2); and for 21, 0.12 and 0.48 microM (4).
New N-aryl-N'-2-chloroethylureas (CEUs) with enhanced cytotoxicity were developed as antimitotic agents potentially useful in cancer chemotherapy. Highly potent CEUs were obtained by introduction of a branched alkylating chain, the N'-(1-methyl-2-chloro)ethyl group. Their cytotoxic activity was enantio-dependent and induced through specific alkylation of beta-tubulin, leading to microtubule disruption and mitotic arrest. Overall, the structural modifications of the CEUs described here significantly improved their kinetics of beta-tubulin alkylation. In this new series, CEUs 16a and 18a displayed particularly enhanced antiproliferative activity related to a faster reaction with beta-tubulin and merit further investigation as potential antitumor agents.
[reaction: see text] The diastereoselective alkylation of glycolate oxazolidinones has been demonstrated as a method for the enantioselective preparation of alpha-alkoxy carboxylic acid derivatives and selectively protected 1,2-diols. Various protecting groups on the glycolate hydroxyl and multiple substitution patterns on allylic iodides are tolerated in the alkylation. Yields for the alkylations are typically 70-85% with diastereoselectivities of >98:2.
The reaction in ether-methanol between 2'-deoxyguanosine and diazomethane or its ethyl or n-butyl homologue gives 1-, O(6)- and 7-alkyl-2'-deoxyguanosine. N(2),O(6)-Dimethyl-2'-deoxyguanosine was also detected. The hydrolysis of the methyl and the ethyl derivatives gives the corresponding alkylguanines: the O(6)-alkyl-2'-deoxyguanosines were sequentially hydrolysed, first to 2-amino-6-alkoxypurines, subsequently to guanine. The mass spectra of O(6)-alkyl-2'-deoxyguanosines (methyl and ethyl) and of the corresponding 2-amino-6-alkoxypurines were determined. The reaction of diazomethane with thymidine afforded O(4)-methylthymidine, in addition to the previously detected 3-methylthymidine.
We have determined that hepsulfam, in common with its structural homologue busulfan, alkylates both free guanosine and GMP in DNA at the 7 nitrogen. Mass spectral analysis of the products of the reaction of hepsulfam with guanosine has identified the mono- and bis-alkylated guanosine adducts. UV spectrophotometry and mass spectrometry were used to confirm that alkylation occurred at the 7 nitrogen by following the formation of the formamidopyrimidyl form of the hepsulfam-guanosine adduct at high pH. We have also isolated and identified 1-guanyl,7-hydroxyheptane, 1-guanyl,7-sulfamylheptane, and 1,7-bis(guanyl)heptane from in vitro reaction mixtures of hepsulfam and calf thymus DNA. We have isolated bis-(7-formamidopyrimidyldeoxyguanosinyl)-heptane from an enzymatic digest of DNA treated with hepsulfam. Finally, we have found that hepsulfam forms interstrand cross-links at 5'-GXC-3' sites in model oligonucleotides.
A series of new glycosides with extended alkyl side-chains (C(13-16)) linked to maltose or sucrose were synthesized and tested for their efficacy in enhancing nasal insulin absorption in anesthetized rats. The new reagents were compared to previously tested alkylglycosides with shorter alkyl side chains (C(8-12)). Dose-response studies revealed that within the family of alkylmaltoside derivatives, (C(8-16)), maximal increases in insulin absorption took place when tetradecylmaltoside (C(14)) was added to the formulation. Pentadecylmaltoside (C(15)) and hexadecylmaltoside (C(16)) were less potent at increasing insulin absorption, although both reagents achieved maximal effects when used at higher concentrations. Within the family of alkanoylsucrose derivatives, tridecanoylsucrose (C(13)) and tetradecanoylsucrose (C(14)) were most potent at increasing insulin absorption. Cross-comparisons between alkylmaltoses and alkanoylsucroses showed that the alkyl chain length had a greater impact than the glycoside moiety in determining the potency of a potential insulin-absorption enhancing agent. When tetradecylmaltoside was applied to the nasal mucosa 15 min before insulin was applied, the enhanced insulin absorption was still observed.
Various alkyl ethyleneglycophospholipids, i.e., alkyl phospholipids, with ethyleneglycol or its congener in place of glycerol as a molecular backcone, were synthesized and their effects on cell proliferation and differentiation of cultured human (HL-60) and mosue (Ml) myeloid leukemia cells were studied. On incubation with alkyl ethyleneglycophospholipids, proliferation of both cell lines was inhibited and the cells were induced to differentiate into morphologically and functionally mature granulocytes and macrophages. Among the compounds tested, dodecyl ethyleneglycophospholipid with a pyridinioethyl group was the most effective in induction of differentiation of both cell lines.
Various concentrations of commercially available alkyl ether sulphate surfactants with alkyl chains consisting of even or odd numbers of carbon atoms have been tested for their primary irritancy to rabbit skin in vivo. All six surfactants (2 with even and 4 with odd carbon number) produced skin irritation. The level of irritation showed dose-dependent increases in the concentration range 4-12% (w/w), with a plateauing of responses of moderate to severe irritation occurring between 12 and 24% (w/w). Recovery generally took 10-14 days to occur. There were no significant differences in the intensity or duration of response between surfactants with alkyl chains consisting of even and odd numbers of carbon atoms.
The characteristics of host-guest complexation between beta-cyclodextrin (beta-CD) and phenanthrene derivatives (phenanthrene, n-propyl, n-butyl and n-hexyl-phenanthrene) were investigated by fluorescence spectrometry. Linear and non-linear regression methods were used to estimate the formation constants (K1). A 1:1 stoichiometric ratio and an effect of n-alkyl chain length on the formation constant were observed for the binary inclusion complex between guest and beta-CD. The formation constant dramatically increases with the length of n-alkyl, it starts from the value of 140 l mol(-1) for the phenanthrene to reach the value of 580 l mol(-1) for hexyl-phenanthrene. The effect of the temperature on the fluorescence intensity of each complex (guest-host) was also studied; and then the thermodynamic parameters were calculated. The main inclusion site seems to be aromatic moiety for short chain molecules, and it moves toward the alkyl chain part, as the chain becomes longer.
Alkyl sulfates (AS), alkyl ethoxysulfates (AES) and linear alkyl benzene sulfonates (LAS) are all High Production Volume (HPV) and 'down-the-drain' chemicals used globally in detergent and personal care products, resulting in low levels ultimately released to the environment via wastewater effluent. Due to their surfactant properties, they preferentially sorb to sediments. Hence, assessment of their levels and potential perturbations on benthos are of interest. The relative levels of AS/AES decreased with distance from the wastewater treatment plant outfall. However, this was not evident for LAS. Short chained AES and especially AS dominated the homologue distribution for AES. There were no evident patterns in LAS homologue distribution. The overall mean margin of exposure (MoE) for AS/AES and LAS is approximately 40 (range: 3 to 100) suggesting no noteworthy perturbation on biota. The findings in this study are in concordance with previous preliminary hazard screening. Comparative sediment contamination analyses principally based on Chapman and Anderson [Chapman PM, Anderson, J. A decision-making framework for sediment contamination. Integr Environ Assess Mana. 2005; 1: 163-173.] and the U.S. Environmental Protection Agency RAPID assessment methods [USEPA. Rapid bioassessment protocols for use in wadeable streams and rivers: Periphyton, benthic, macroinvertebrates, and fish. 1999. Second Edition. U.S. Environmental Protection Agency Office of Water, Washington, D.C. EPA 841-B-99-002.] did not reveal significant correlations between the surfactant concentrations and ecological status of the sampling locations. Several Lines of Evidence (LoE) of the Weight-of-Evidence (WoE) lead to the conclusion of low aquatic risk associated to the monitored compounds.
Sarcina ventriculi, an anaerobic Gram-positive bacterium, adapts to increasing temperature, the presence of organic solvents, or the lowering of the pH of its growth medium by joining the tails of membrane lipids from opposite sides of the bilayer, forming transmembrane, bifunctional fatty acid species. Since this is done to offset the increase in membrane mobility caused by these perturbations, it is of interest to determine whether the motional (dynamic) properties of membrane lipid alkyl chains are conserved. In this study, conservation of the motional time scales of the alkyl chains of total membrane lipids from Sarcina ventriculi cells grown at different pH values was demonstrated using proton nuclear magnetic resonance (NMR) spectroscopy. The NMR longitudinal relaxation times (T1) of the protons in the bulk methylene groups were measured for lipids from cells grown at pH 3.0 and 7.0. These measurements indicated that the temperature profile of the T1 relaxation behavior for the methylene protons from these two different preparations was the same. Analysis of the data from T1 measurements indicated that the thermal barrier for relaxation is the same in both lipid systems. This is only true if the pH of the sample on which the measurement is being made is adjusted to the same value as that at which the corresponding cells were cultured. It is clear from this latter observation that the state of protonation of the lipid head groups is a contributor to the overall motional freedom of the membrane lipid components. The correlation times (tau c) of characteristic lipid alkyl chain motion were estimated to be approximately 10(-10) s.(ABSTRACT TRUNCATED AT 250 WORDS)
The aqueous Barbier-Grignard-type alkylation of aldehydes with unactivated alkyl iodides and bromides was developed. By using a combination of zinc and cuprous iodide, catalyzed by indium(I) chloride, we successfully added tertiary, secondary, and primary alkyl halides to various aromatic aldehydes in 0.07 M aqueous Na2C2O4. A mechanistic rationale for the success of the reaction has been proposed.
At atmospheric pressure and at 130-160 degrees C, primary aromatic amines (p-XC6H4NH2, X = H, Cl, NO2) are mono-N-alkylated in a single step, with symmetrical and asymmetrical dialkyl carbonates [ROCOOR', R = Me, R' = MeO(CH2)2O(CH2)2; R = R' = Et; R = R' = benzyl; R = R' = allyl; R = Et, R' = MeO(CH2)2O(CH2)2], in the presence of a commercially available NaY faujasite. No solvents are required. Mono-N-alkyl anilines are obtained with a very high selectivity (90-97%), in good to excellent yields (68-94%), on a preparative scale. In the presence of triglyme as a solvent, the mono-N-alkyl selectivity is independent of concentration and polarity factors. The reaction probably takes place within the polar zeolite cavities, and through the combined effect of the dual acid-base properties of the catalyst.
Systematic investigations to develop an efficient enantioselective synthetic method for alpha-alkyl-alanine by catalytic phase-transfer alkylation were performed. The alkylation of 2-naphthyl aldimine tert-butyl ester, 1E, with RbOH and O(9)-allyl-N-2',3',4'-trifluorobenzylhydrocinchonidinium bromide, 6, at -35 degrees C showed the highest enantioselectivities, up to 96% ee.
[reaction: see text] We report a new phosgene-free method for the synthesis of symmetrical organic carbonates via alkylation of metal carbonate with various alkyl halides and sulfonates in 1-n-butyl-3-methylimidazolium hexafluorophosphate, [bmim][PF6], as an ecofriendly reaction media. Alkylation of metal carbonate in various ionic liquids with 1-bromo-3-phenylpropane (1a) as a model reactant has thoroughly been investigated. Potassium and cesium carbonates appeared to be the most suitable metal carbonate due to their high solubility in ionic liquids. Besides good to excellent yields, this simple and convenient methodology is devoid of highly toxic and harmful chemicals such as phosgene and carbon monoxide, which is an additional advantage.
Reaction of azaenolates of 2-alkyl-oxa(thia)zolines 6 with imidoyl chlorides 7 as electrophiles to furnish masked N-substituted beta-enamino acid derivatives 1-2 in 70-90% yield is described. Alternative routes are discussed. Compounds 1-2 generally appear in one tautomeric form, imino or enamino, depending on the nature of the imidoyl chloride. The configuration of the enamino moiety (Z) and the conformation (s-cis) of compounds 1-2 obtained were established by an NMR study and unequivocally set by nuclear Overhauser effect difference experiments. An X-ray structure of compound 1e is also reported, showing a strong intramolecular NH.N hydrogen bond. Ab initio calculations (HF/3-21G and HF/3-21+G) have been carried out on several representative examples (1e, 1p, and 1l) in an attempt to support and provide the correct geometry of these derivatives. Structural considerations among the possible isomers of compounds 1 are discussed. From these studies it was concluded that the theoretical calculations agree with the experimental results. In addition, a very simple one-pot procedure for the preparation of masked N-substituted alpha-alkylated beta-enamino acid derivatives 2 from 6, 7, and different alkyl halides (R(3)Y) is described.
In a nonaqueous solvent, alkyl nitrites can be easily achieved through the reaction of alkyl alcohols and gaseous NO. In the presence of air, the nitric oxide can in fact be oxidized to nitrous anhydride, which acts as a nitrosating agent. A quantitative study conducted on cycloalkyl alcohols has shown conversion yields to nitrites within the range 65-90%. This result has been validated by ESR spectroscopy experiments on several alkyl alcohols/NO mixtures, which lead to the detection of the same radical species detectable when a solution of the corresponding nitrites is photolyzed.