Chloroethyl Groups Research Articles

Cationic poly(ester‐phosphoester)s: Facile synthesis and antibacterial properties

ABSTRACTBiodegradable poly(ester‐phosphoester)s bearing multiple chloroethyl groups were synthesized facilely by the ring‐opening copolymerization of 2‐(2‐chloroethoxy)‐2‐oxo‐1,3,2‐dioxaphospholane (CEP) and ε‐caprolactone (CL) in the presence of lanthanum tris(2,6‐di‐tert‐butyl‐4‐methylphenolate)s (La(DBMP)3) as single‐component catalyst under mild conditions. Then the quaternization reaction was carried out between the halide copolymers and a series of N,N‐dimethyl alkylamines to give poly(ester‐phosphoester)s containing ammonium groups with various charge density and alkyl chain length. The antibacterial properties of these cationic poly(esterphosphoester)s were evaluated by OD600 and zone of inhibition methods against gram‐negative (Escherichia coli) and gram‐positive (Staphylococcus aureus) bacteria. Cationic poly(esterphosphoester)s with long alkyl chain on the ammonium groups show excellent antibacterial activity for both gram‐negative and gram‐positive bacteria even with low charge density. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2013, 51, 3667–3673

Dichlorophosphinic bis(2-chloroethyl)amide

In the title compound, C4H8Cl4NOP, the two chloro­ethyl groups are not related by crystallographic symmetry. The difference in the conformation of the two groups is shown by their N—C—C—Cl torsion angles of 64.57 (15) and 175.62 (10)°.

A novel technique to monitor carboxypeptidase G2 expression in suicide gene therapy using 19F magnetic resonance spectroscopy

Development and evaluation of new anticancer drugs are expedited when minimally invasive biomarkers of pharmacokinetic and pharmacodynamic behaviour are available. Gene-directed enzyme prodrug therapy (GDEPT) is a suicide gene therapy in which the anticancer drug is activated in the tumor by an exogenous enzyme previously targeted by a vector carrying the gene. GDEPT has been evaluated in various clinical trials using several enzyme/prodrug combinations. The key processes to be monitored in GDEPT are gene delivery and expression, as well as prodrug delivery and activation. {4-[bis(2-chloroethyl)amino]-3,5-difluorobenzoyl}-L-glutamic acid, a prodrug for the GDEPT enzyme carboxypeptidase-G2 (CPG2; K(m) = 1.71 microM; k(cat) = 732 s(-1)), was measured with (19)F magnetic resonance spectroscopy (MRS). The 1 ppm chemical shift separation found between the signals of prodrug and activated drug (4-[bis(2-chloroethyl)amino]-3,5-difluorobenzoic acid) is sufficient for the detection of prodrug activation in vivo. However, these compounds hydrolyze rapidly, and protein binding broadens the MR signals. A new CPG2 substrate was designed with hydroxyethyl instead of chloroethyl groups (K(m) = 3.5 microM, k(cat) = 747 s(-1)). This substrate is nontoxic and stable in solution, has a narrow MRS resonance in the presence of bovine and foetal bovine albumin, and exhibits a 1.1 ppm change in chemical shift upon cleavage by CPG2. In cells transfected to express CPG2 in the cytoplasm (MDA MB 361 breast carcinoma cells and WiDr colon cancer cells), well-resolved (19)F MRS signals were observed from clinically relevant concentrations of the new substrate and its nontoxic product. The MRS conversion half-life (470 min) agreed with that measured by HPLC (500 min). This substrate is, therefore, suitable for evaluating gene delivery and expression prior to administration of the therapeutic agent.

Effect of nitrogen mustard, a vesicant agent, on lymphocyte energy metabolism

The vesicant agents sulfur and nitrogen mustards, which contain chloroethyl groups, are potent inhibitors of DNA synthesis and cell growth, likely changing the utilization of anaerobic glycolysis for energy generation. To investigate the effect of nitrogen mustard on cellular energy metabolism, lymphocytes treated with increasing doses of mechlorethamine (HN2), a nitrogen mustard and an analogue of sulfur mustard, were incubated with radiolabeled glucose. The rates of aerobic and anaerobic glycolysis were then determined. Glycogen consumption was significantly higher in cells treated with HN2 in a dose-dependent manner compared to untreated cells. Similarly, the amount of end-product lactate was increased, but CO2 was reduced in HN2-treated cells. Lymphocytes normally use aerobic glycolysis under aerobic conditions, but energy metabolism predominantly involved anaerobic glycolysis after severe intoxication with mustard agent.

The Protective and Therapeutic Effects of Zinc Chloride and Desferrioxamine on Skin Exposed to Nitrogen Mustard

The nitrogen mustard (HN2), which contains chloroethyl groups, is a potent inhibitor of DNA synthesis and cell growth. It also has vesicant properties. Due to these damaging effects of HN2 on the skin, zinc chloride (ZnCl2) and desferrioxamine were used in the form of ointment for treatment and prevention of the histopathological destruction of skin of guinea pigs. According to results of the histopathological study, both ZnCl2 and desferrioxamine had therapeutic and protective effects for HN2-induced skin damage at moderate levels. Taking into consideration the alkylating effect of HN2 on the skin, our results suggest that ZnCl2 and desferrioxamine may be used in the prevention of nuclear damage and for handling the burns caused by the HN2.

Gas chromatographic determination of 2- and 3-dechloroethylifosfamide in plasma and urine

The metabolic oxidation of one of the chloroethyl groups of the antitumour drug ifosfamide leads to the formation of the inactive metabolites 2- and 3-dechloroethylifosfamide together with the neurotoxic metabolite chloroacetaldehyde. A very sensitive capillary gas chromatographic method, requiring only 50 μl of plasma or urine, has been developed to measure the amounts of the drug and the two inactive metabolites in a single run. Calibration curves were linear ( r > 0.999) in the concentration ranges from 50 ng/ml to 100 μg/ml in plasma and from 100 ng/ml to 1 mg/ml in urine.

EPR study on the interaction of spin-labelled hydrazine mustard derivatives with DNA

The interaction of three spin-labelled compounds, derivatives of bis-(2-chloroethyl)-hydrazine (HMSL), N-methyl, N-chloroethyl-hydrazine (MCEHSL) and bis-(2-bromoethyl)-hydrazine (BEHSL) with DNA was studied by the method of electron paramagnetic resonance (EPR). It was found that HMSL (containing two chloroethyl groups) and MCEHSL (containing one chloroethyl group) gave spin-labelled dsDNA with identical strongly immobilized EPR spectra. The conclusion was drawn that only one of the alkylating groups of HMSL reacted with DNA. In contrast, the EPR spectrum of DNA spin-labelled with BEHSL was non-immobilized due to the strong destabilizing effect of this compound on the double helix. The extent of alkylation of DNA with the three hydrazine mustard derivatives was one and the same. It was found, however, that chloroethyl-containing derivatives (HMSL and MCEHSL) had an expressed base specificity and alkylated preferably the guanilic residues, and their bromoanalogue (BEHSL) did not show any base specificity and alkylated the bases of DNA at random.

Use of models of template synthesis of RNA to study the mechanism of the antineoplastic action of N-nitrosoureasin vivo

The antineoplastic activity of a number of N-alkyl-Nnitrosoureas (ANU) has been established in various types of experimental tumors in animals [i]. Some of these compounds, such as 2-deoxy-2-{[(3-methyl-3-nitrosoamino)-carbonyl]amino}-D-glucopyranose (I), 1-methyl-1nitrosourea (II), and 1,3-bis(2-chloroethyl)-l-nitrosourea (III), are widely used for the treatment of patients with various forms of cancer. A number of ANU, including II and III, are characterized by substantial myelotoxicity. In recent years, new derivatives have been synthesized, containing not only chloroethyl groups, but also various substituents: 1-(2chloroethyl)-3-(2,6-dihydroxy-3-piperidyl)-l-nitrosourea (IV), 2-[3-(2-chloroethyl)-3-nitrosoureido]-D-glucopyranose (V), and certain others.

Possibilities of obtaining polymers with supposed antitumor activity

AbstractIt is known that dichloroethylamines in which the two chloroethyl groups are bound to different N atoms at a given distance from each other retain their activity and considerably lower their toxicity. It was assumed that by controlling the distance between the two chloroethyl substituents to the polymer chain a product of analogous action could be obtained. Two possibilities of binding monochloroethylamine (MCA) to a polymer were investigated: (1) Copolymerization of N‐vinyl pyrrolidone (VP) with monochloroethylamide of methacrylic acid (MCAMA). The constants of copolymerization of this pair: r1 = 3.88 ± 0.31 and r2 = 0.089 ± 0.017 were determined, as well as the mean length of the elementary link of the copolymer chain. It was found that at a ratio of VP:MCAMA = 1:3 a copolymer of statistically probable structure could be obtained in which the distance between two monochloroethylamine groups is the most appropriate: about 6 atoms. (2) A polymer‐analogous reaction of the copolymer of VP with maleic anhydride (MA) permitting the binding of MCA to the polymer chain by severing the MA ring. It was established that the reaction proceeded best in a medium of dimethylformamide at 80°C for 1 hr. Water‐soluble products characterized by their C1 content and ir spectra were obtained. These products showed a physiological activity.

Studies on surface wettability of stereospecific poly(methacrylic acid esters)

The wettability of stereospecific poly(methacrylates) was studied. In the wettability of poly(methacrylates) having bulky substituents such as phenyl and chloroethyl groups, it was found that the critical surface tensions for isotactic polymers were low compared to those for attactic polymers. The steric effect of the bulky substituent on wetting was also discussed.

Decomposition of BCNU (1,3-Bis(2-chloroethyl)-1-nitrosourea) in aqueous solution

BCNU, labelled with 14C in the chloroethyl groups, decomposes in neutral aqueous solution to release half of its radioactivity as volatile products. These have been identified by a combination of gas chromatography and mass spectrometry as vinyl chloride, acetaldehyde, dichloroethane, and chloroethanol. This set of products is consistent with the existence of chloroethylcarbonium ions as reactive intermediates which would produce the previously described substituted nucleotides.

Organische Phosphorverbindungen 39. Methoden zur Herstellung von Chloräthylphosphonsäuredichlorid, ClCH2CH2P(O)Cl2 und CH3CHClP(O)Cl2 [1

AbstractIt is shown that the KINNEAR‐PERREN reaction with ClCH2CH2Cl, PCl3, and AlCl3 produces the two possible isomers ClCH2CH2P(O)Cl2 and CH3CHClP(O)Cl2. Methods for the preparation of pure ClCH2CH2P(O)Cl2 and pure CH3CHClP(O)Cl2 are described. The physical properties of a number of chloroethyl groups containing phosphorus compounds are listed.

Nitrogen mustard therapy in the reticuloses.

Parenteral administration of the nitrogen mustards leads to changes in the tissues where there are many actively proliferating cells, particularly in the gastrointestinal tract, the lymphatic glands, and the bone marrow. Detailed observations of tissue cultures and mammalian cornea reveal a disturbance of mitosis—an inhibition of the prophase—similar to that produced by X rays. This may be followed by nuclear fragmentation and death of the cell. These drugs also resemble X rays in their ability to produce mutations and in their carcinogenic activity in certain species (Karnofsky 1950). The mechanisms of these actions of the nitrogen mustards have been studied intensively. They have been shown to interfere with the action of many of the enzymes vital to body activities and they alter the physical and chemical properties of the nucleoproteins. When nitrogen mustard is dissolved in water, the chloroethyl groups undergo rearrangement with the formation of imonium rings. These are chemically very active and co...

ACQUIRED HYPERSENSITIVITY TO THE CHLORINATED ETHYLAMINE VESICANTS

In 1935 Ward 1 reported briefly on the vesicant qualities of β, β′, β″ -trichlorotriethylamine, either as the base or as the hydrochloride. He suggested that with nitrogen compounds three chloroethyl groups are necessary before vesicant action may be noted. REPORT OF CASE To test a person known to be very sensitive to bis- β -dichlorodiethylsulfide (mustard agent), β, β′, β″ -trichlorotriethylamine hydrochloride was prepared in the manner described by Ward and isolated in the form of clear white crystals. The free amine ( β, β′, β″ -trichlorotriethylamine) was obtained from the hydrochloride by treating an aqueous solution of the latter with a sodium carbonate solution. The free amine separated as an oil, colored slightly brown but darkened slowly on standing. The crystals of the hydrochloride were suspended in alcohol (95 per cent) and applied on the flexor surface of the forearm. A drop was applied with a metal