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PubMed1979

Metabolic and mutagenicity studies on DDT and 15 derivatives. Detection of 1,1-bis(p-chlorophenyl)-2,2-dichloroethane and 1,1-bis(p-chlorophenyl)-2,2,2-trichloroethyl acetate (kelthane acetate) as mutagens in Salmonella typhimurium and of 1,1-bis(p-chlorophenyl) ethylene oxide, a likely metabolite, as an alkylating agent.

Using a novel in vitro technique, whereby microsomal enzymes were embedded in an agar layer to prolong their viability, 1,1-bis(p-chlorophenyl) ethylene(DDNU), a mammalian metabolite of 1,1-bis(p-chlorophenyl)-2,2,2-trichloroethane (DDT), was converted by microsomal mono-oxygenases of mouse liver into 1,1-bis(p-chlorophenyl)-1,2-ethanediol (DDNU-diol). The putative epoxide intermediate, 1,1-bis(p-chlorophenyl)ethylene oxide (DDNU-oxide), a new compound, was synthesized; it showed weak alkylating activity with 4-(4-nitrobenzyl)pyridine but was not mutagenic in Salmonella typhimurium strains TA100 and TA98. DDT and 13 of its metabolites or putative synthetic derivatives, including 1,1-bis(p-chlorophenyl)-2,2-dichloroethylene (DDE), 1 1,1-bis(p-chlorophenyl)-2-chloroethylene (DDMU), 1,1-bis(p-chlorophenyl)-2-chloroethane (DDMS)-DDNU, 2,2-bis(p-chlorophenyl)ethanol (DDOH), bis(p-chlorophenyl)acetic acid (DDA) and 1,1-bis(p-chlorophenyl)-2,2,2-trichloroethanol (Kethane), caused no mutagenic effects in S. typhimurium strains TA100 or TA98, either in the presence or absence of a mouse-liver microsomal fraction. 1,1-Bis(p-chlorophenyl)-2,2,2-trichloroethyl acetate (Kelthane acetate) was a direct-acting mutagen in strain TA100, whereas 1,1-bis(p-chlorophenyl)-2,2-dichloroethane (DDD) was mutagenic in TA98, only in the presence of a mouse-liver microsomal system. The results are discussed in relation to possible pathways whereby DDT is activated to mutagenic and/or carcinogenic metabolites.

Alkylation↗
PubMedDate not supplied

[Identification of beta, beta-caroten-2-ol and beta, beta-carotene-2,2'-diol in the stick insect, Carausius morosus Br.; a reinvestigation study].

Two major carotenoids of the stick insect were reinvestigated and shown to be beta,beta-caroten-2-ol and beta,beta-carotene-2,2'-diol and not isocryptoxanthin (beta,beta-carotin-4-ol) and isozeaxaanthin (beta,beta-carotene-4,4'-diol). Both pigments are esterified with fatty acids. The identification is based on cochromatography with authentic 2-, 3- and 4-isomers of the mono- and dihydroxy pigment, mass spectra, and chemical behaviour. In acid solution beta-beta-carotene-2,2'-diol is specifically dehydrogenated and rearranged to ketones with retro structures in analogy to the reactionof beta,beta-caroten-2-ol as recently reported. The final product of the diol is 4,5-dihydro-4,5'-retro-beta,beta-carotene-2,2'-dione. This is the first demonstration of beta,beta-carotene-2,2'-diol in an animal.

Animals↗
PubMed1977

Nucleoside 3'-phosphotriesters as key intermediates for the oligoribonucleotide synthesis. IV. New method for removal of 2,2,2-trichloroethyl group and 31P NMR as a new tool for analysis of deblocking of internucleotide phosphate protecting groups.

Zinc/acetylacetone/pyridine treatment has been designed as a very efficient method for removal of 2,2,2,-trichloroethyl group from phosphoesters. Internucleotide and terminal 2,2,2-trichloroethylphosphotriesters were transformed to corresponding diesters quantitatively. Much less reactive 2,2,2-trichloroethylphosphodiesters produced monoesters with ca. 90% yield. 31P NMR spectroscopy has been proposed as a new tool for analysis of removal of internucleotide phosphate protecting groups-a crucial step in oligonucleotides synthesis via phosphotriester approach.

Chromatography, Thin Layer↗
PubMed1979

Inhibition of T cell-mediated cytolysis by 2-deoxy-D-glucose (2-DG): differential effect of 2-DG on effector cells isolated early or late after alloantigenic stimulation in vitro.

The effect of the hexose analogue 2-deoxy-D-glucose (2-DG) on the functional activity of various populations of cytolytic T lymphocytes (CTL) has been compared. Under aerobic conditions, CTL harvested at the peak of the response (day 4) in primary or secondary mixed leukocyte cultures (MLC) were much more readily inhibited by 2-DG that CTL obtained from MLC at later times (day 11 to 18) or from the peritoneal cavity of alloimmune mice. Quantitatively, 0.4 mM 2-DG was sufficpient to inhibit cytolysis by 50% in day 4 CTL populatons, whereas 25 mM had little or no effect on day 11 to 18 CTL. Evidence was obtained that inhibition of cytolysis by 2-DG under these conditions was accompanied by a parallel inhibition of effector:target cell binding. In contradistinction to these findings, the cytolytic activity of both day 4 and day 11 MLC cells was readily inhibited by 2-DG under conditions where cell respiration was blocked by sodium azide. Furthermore, uptake of radiolabeled 2-DG was observed under aerobic conditions in both day 4 and day 11 MLC cells. These results strongly suggest that inhibition of cytolysis by 2-DG under aerobic conditions is mediated via a direct effect on CTL which is independent of the consequences of energy depletion. An indirect method by which CTL may be inhibited by 2-DG is suggested.

Animals↗
PubMed1975

Hydrolysis of nucleoside phosphates: IV. The metal ion-nucleic base interaction in the Cu2+-promoted dephosphorylation of the 5'-di- and 5'-triphosphates of cytidine, inosine and guanosine, and their protection toward hydrolysis by coordination to Cu(2,2'-bipyridyl)2+.

The dephosphorylation of CTP, GTP, ITP, ATP, CDP, GDP, IDP and ADP was characterized by measuring the first-order rate constant (50 degrees; I = 0.1, NaClO4) in dependence on pH (2 to 10). Except with CTP and CDP, the reactions are significantly accelerated by Cu2+ and pass through pH optima. By computing the pH dependence of the distribution of the several species present in the nucleotide (NP) systems, it is shown that the most reactive species is Cu(NP). Cu(NP-H), where N(1) is deprotonated, is somewhat less reactive. In both types of complexes, a metal ion-nucleic base interaction, which is responsible for the increased reactivity, occurs, i.e., macrochelates involving the phosphate chains and the base moieties are formed. In accord herewith, CTP and CDP are rather stable as the coordination tendency of the cytosine moiety is small. Furthermore, in the ternary complexes Cu(2,2'-bipyridyl)(NP) and Cu-(2,2'-bipyridyl)(NP-H), where the formation of a macrochelate is inhibited, the nucleotides are protected. The structure-reactivity relationship is also evident with Cu(ITP)2- and Cu(IDP)- which exist only in part as macrochelates; hence, they are less reactive than for example Cu(ATP)2- or Cu(ADP)-. With the aid of the initial rate, vo = d[PO4(3-)]/dt, the rate laws of the ascending side of the pH optima were determined: vo = k[Cu(NP)]/[H+]. A reaction mechanism that includes an intermolecular attack of OH- at the terminal phosphate group is proposed. The descending side of the pH optimum is attributed to the formation of CU(NP)(OH) or Cu(NP-H)(OH), where the Cu2+-base interaction is insignificant. However, these hydroxy complexes are still somewhat faster dephosphorylated than the free nucleotides. This is attributed to an intramolecular attack of the bound OH- at the terminal phosphate group.

2,2'-Dipyridyl↗
PubMed1978

Transfer of 2,4,5,2',4',5'-hexachlorobiphenyl and 2,2-bis-(p-chlorophenyl),1,1,1-trichloroethane (p,p'-DDT) from maternal to newborn and suckling rats.

Pregnant rats were given a small dose of 14C-2,4,5,2',4',5'-hexachlorobiphenyl (HCB) and 3H-DDT intraperitoneally. The transfer of HCB and DDT through the placenta and milk was then investigated. Transfer through the placenta was 2.7 and 1.5% (respectively) of the initial doses; transfer through milk was 39.2 and 21.5%. HCB is obviously more transferable than DDT through the placenta and milk, the ratio of the amount of HCB transferred through milk to the amount transferred through the placenta agrees with that for DDT. Concentrations of HCB and DDT in the whole suckling rat increases rapidly and is similar to the sigmoidal growth curve and change in lipid concentration. Therefore, the concentrations of the chemicals in the maternal tissue generally decrease in comparison with those of nonpregnant rats.

Animal Population Groups↗
PubMed1979

High-performance liquid chromatography of 2,6- and 2,4-diaminotoluene, and its application to the determination of 2,4-diaminotoluene in urine and plasma.

2,4-Diaminotoluene is used for the production of industrial dyes, and along with the 2,6-isomer, as an intermediate in the production of polyurethane foams. 2,6- and 2,4-diaminotoluene were resolved as sharp peaks by normal-phase high-performance liquid chromatography in 3 min by an acetonitrile-water-saturated chloroform elution solvent (8:2, v/v) with detection by ultraviolet absorbance at 250 nm. The relationship between peak height and amount injected was linear over a range of 0.025-2 microgram for both compounds. Retention times and peak heights were highly reproducible. Detection was very sensitive, allowing quantitation of 1-2 ng of either compound. Quantitative recovery of 2,4-diaminotoluene from spiked urine and plasma samples was obtained by extraction with methylene chloride.

Animals↗
PubMed1979

Absolute configuration of glycerol derivatives. 7. Enantiomers of 2-[[[2-(2,6-dimethoxyphenoxy)ethyl]amino]methyl]-1,4-benzodioxane (WB-4101), a potent competitive alpha-adrenergic antagonist.

The enantiomers of 2-[[[2-(2,6-dimethoxyphenoxy)ethyl]amino]methyl]-1,4-benzodioxane (4) were prepared from the chiral 2-[(tosyloxy)methyl]-1,4-benzodioxanes [(2S)- and (2R)-5]. The corresponding (2R)- and (2S)-2-(aminoethyl)-1,4-benzodioxanes [2R)- and (2S)-7] were prepared by a modified Gabriel synthesis and converted to the enantiomers of 4 by condensation with 2,6-dimethoxyphenoxyacetaldehyde (8) and reduction of the intermediate imine with NaBH4. The enantiomer (2S)-4 was 40--50 times as potent as the enantiomer (2R)-4 in antagonizing the alpha-adrenergic response of methoxamine-induced contraction of rabbit aortic strips, showing a pA2 = 9.0. This result is consistent with the previous observation that S enantiomers of 2-[(alkylamino)methyl]benzodioxanes are more potent antagonists at a alpha-adrenergic receptors than the R enantiomers.

Adrenergic alpha-Antagonists↗
PubMed1977

Experimental antiulcer drugs. 2. 2-Substituted 2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carboxamides.

Condensation of a 1-substituted 2,5-dimethylpyrrole 6 with 2 mol of 2-amino-2-methylpropionitrile in hot acetic acid yielded a 2-substituted 2,4,5,6-tetrahydro-1,3,4,5,6,6-pentamethylcyclopenta[c]pyrrole-4-carbonitrile (4). Hydrolysis of the nitriles to the amides gave a group of compounds which were active as antisecretory agents in the pyloric-ligated rat. Outstanding in this respect was the 2-phenyl derivative 5b, the most active compound in the series. It did not possess anticholinergic properties. In contrast to the indoles and pyrroles reported earlier, 5b demonstrated marked activity in blocking gastric acid secretion in the histamine-stimulated dog.

Animals↗
PubMed1978

Effects of pure chlorobiphenyls (2,4',5-trichlorobiphenyl and 2,2',4,4',5,5'-hexachlorobiphenyl) on the post-natal growth in mice.

The post-natal growth rate of young mice, pre- and post-natally exposed to either 2,4',5-trichlorobiphenyl or 2,2',4,4',5,5',-hexachlorobiphenyl has been studied. The results show that both the chlorobiphenyls have the ability toincrease the post-natal growth rate in mice and they indicate that this ability of 2,4',5-trichlorobiphenyl is most pronounced in females whereas that of 2,2',4,4',5,5',-hexachlorobiphenyl is most pronounced in males.

Age Factors↗
PubMed1978

Effects of pure chlorobiphenyls (2,4',5-trichlorobiphenyl and 2,2',4,4',5,5'-hexachlorobiphenyl) on the reproductive capacity in female mice.

The effects of two pure chlorobiphenyls (2,4',5-trichlorobiphenyl and 2,2',4,4',5,5'-hexachlorobiphenyl) on the reproductive capacity in female mice have been studied. The results obtained show that females given 0.5 mg 2,5',5-trichlorobiphenyl (TCB)/day or 0.5 mg 2,2',4,4',5,5'-hexachlorobiphenyl (HCB)/day for six consecutive days, starting on the first day of pregnancy, have significantly lower frequencies of implanted ova than the control females, whereas the frequency of implanted ova does not differ either between females given 0.05 mg/day of TCB or HCB and the control females, or between females given TCT 0.05 mg/day or 0.5 mg/day and those given the corresponding dose of HCB. Females given 0.5 mg/day of TCB or HCB, respectively, also have significantly higher contents in the livers of cytochrome P-450, on Day four of pregnancy, than the control females. The results also show that, under the experimental conditions used, neither the frequency of pregnancies nor the number of implanted ova per pregnant female differ significantly between the different groups.

Animals↗
PubMed1979

[Determination of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in 2,4,5-trichlorophenoxyacetic acid, 2,4,5-trichlorophenoxyacetic acid-alkylesters and in the corresponding herbicide formulations (author's transl)].

A method is described for the determination of 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) in 2,4,5-Trichlorophenoxyacetic Acid (2,4,5-T), 2,4,5-T-Akylesters and commercial herbicide formulations containing these substances. TCDD is extracted from alkaline solution with n-hexane and purified by column chromatography on silica gel and Florisil. TCDD is determined by gas-liquid chromatography with EC-detection. For TCDD-additions of 20 micron/kg to herbicide formulations recoveries of dioxin are 96--104%. The detection limit is about 5 microgram/kg 2,4,5-T.

2,4,5-Trichlorophenoxyacetic Acid↗
PubMed1977

(Acylaryloxy)acetic acid diuretics. 1. (2-Alkyl- and 2,2-dialkyl-1-oxo-5-indanyloxy)acetic acids.

The discovery of the (acryloylaryloxy)acetic acids as a new class of potent diuretics prompted the investigation of related bicyclic compounds. Annelated analogues of the parent series, the (2-alkyl- and 2,2-dialkyl-1-oxo-5-indanyloxy)acetic acids, were the subjects of this study. Those compounds, unlike the monocyclic parent compound, lacked the double bond adjacent to the carbonyl group. More importantly, they possessed both saluretic and uricosuric properties. The optimal single 2-substituents for maximal saluretic and uricosuric activity were determined. In general, better activity was observed when a second 2-alkyl substituent (especially methyl) was present in the molecule. Replacement of the carboxy substituent by 5-tetrazolyl generally resulted in a reduction in activity.

Acetates↗
PubMed1977

Effects of pure chlorobiphenyls (2,4',5-trichlorobiphenyl or 2,2',4,4',5,5'-hexachlorobiphenyl) on the disappearance of 14C from the blood plasma after intravenous injection of 4-14C-progesterone and on the hepatic drug metabolizing system in the female rat.

Effects of two pure chlorobiphenyls (2,4',5-trichlorobiphenyl or 2,2',4,4',5,5'-hexachlorobiphenyl) on the hepatic drug metabolizing system and on the elimination rate of 14C from the blood after intravenous injection of 4(-14)C- progesterone have been studied in the female rat. The results obtained show that females pre-treated with small amounts of 2,2',4,4'5,5'-hexachlorobiphenyl (o.5 mg/day for 14 consecutive days) have significantly higher elimination rates of 14C (originating from intravenous injection of 4(-14C-progesterone) from the blood plasma, significantly higher content of hepatic cytochrome P-450 and significantly heavier livers than control females. On the other hand, trichlorobiphenyl (0.5 mg/day for 14 consecutive days) do not differ significantly from the results obtained from control females.

Administration, Oral↗
PubMed1979

Effects of 2-[4-(2-imidazo[1,2-a]pyridyl)phenyl] propionic acid (Y-9213) on in vivo release of lysosomal enzymes from rat polymorphonuclear leukocytes during phagocytosis of particles.

Intraperitoneal administration of carrageenin-zymosan suspension into rats induced an increment of the free activity and its ratio of aryl sulfatase in the exudate and such was accompanied by protein exudation and polymorphonuclear leukocyte emigration. Each test solution was orally administered twice, 1 hr before and 2 hr after, or once 2 hr after injection of the irritant. The peritoneal fluid was withdrawn 5 hr after the injection. 2-[4-(2-imidazo[1,2-a]pyridyl)phenyl] propionic acid (Y-9213) and other anti-inflammatory drugs tested inhibited the increment of the ratio of the free activity (aryl sulfatase) in the peritoneal fluid at the same dose which showed anti-inflammatory activities such as prevention of protein exudation. These results suggest that Y-9213 inhibits the phagocytic secretion in vivo of lysosomal constituents from leukocytes.

Animals↗
PubMed1978

A new cephalosporin. SCE-963: 7-[2-(2-aminothiazol-4-yl)-acetamido]-3-[[[1-(2-dimethylaminoethyl)-1h-tetrazol-5-yl]-thio]methyl]ceph-3-em-4-carboxylic acid. Chemistry and structure-activity relationships.

The synthesis and the in vitro and in vivo antimicrobial activities of a series of 7-[2-(2-aminothiazol-4-yl)acetamido]cephalosporins (1) having varied 3-substituents, such as methyl, hydroxymethyl, acetoxymethyl, pyridiniomethyl and heterocyclicthiomethyls, are described. The derivatives having five membered heterocyclicthiomethyls exhibited strong inhibitory activities against Gram-negative organisms including some strains of Escherichia coli and Proteus morganii which are insensitive to cefazolin and cephaloridine. Pronounced activities were noted with 7-[2-(2-aminothiazol-4-yl)-acetamido]-3-[[[1-(2-dimethylaminoethyl)-1H-tetrazol-5-yl]thio]methyl]ceph-3-em-4-carboxylic acid (1y; SCE-963).

Animals↗
PubMed1979

Studies on the derivatives of thiazole acetic acid. II. Syntheses and pharmacological analysis of 2-N-aralkylidene and 2-N-aralkyl derivatives of 2-amino-4-p-chlorophenylthiazole-5-acetic acid.

A number of 2-N-aralkylidene, 2-N-aralkyl and 2-N-aralkyl-alpha-sulphoderivatives of 2-amino-4-p-chlorophenylthiazole-5-acetic acid (I, R = H) and its methyl ester (I, R = CH3) were synthesized. As a result of condensation of methyl ester I with various aromatic aldehydes in boiling benzene solution, the Schiff-bases (anils) II--VIII were obtained. After reduction with NaBH4 compounds II--VIII were transformed into adequate amino esters IX--XV. Esters IX--XV heated with diluted aqueous solution of sodium hydroxide underwent selective hydrolysis giving the respective amino acids XVI--XXII. Some of Schiff bases (II, III, V, VII, VIII) reacted with aqueous alcoholic solution of sodium bisulphite after its several (XXIII--XXVII). alpha-sulphoderivatives had been obtained. Several tests were performed in order to detect the anti-inflammatory and immunosuppressive activity of the compounds. The pharmacological analysis allowed us to draw conclusions concerning the relationship between chemical structure and biological activity in this group of compounds. The most efficacious immunosuppressive and anti-inflammatory activity exhibited 2-aralkyl-alpha-sulphoderivatives.

Adjuvants, Immunologic↗
PubMed1977

Reaction of dichloroketene and sulfene with N,N-disubstituted 6-aminomethylene-5,6,8,9-tetrahydro-7H-benzocyclohepten-7-ones. Synthesis of 5H-benzo(5,6)cyclohepta(2,1-b)pyran and 5H-benzo(5,6)cyclohepta(1,2-e)-1,2-oxathiin derivatives.

The 1,4-cycloaddition of dichloroketene to N,N-disubstituted 6-aminomethylene-5,6,8,9-tetrahydro-7H-benzocyclohepten-7-ones afforded N,N-disubstituted 4-amino-3,3-dichloro-3,4,10,11-tetrahydro-5H-benzo[5,6]cyclohepta[2,1-b]pyran-2-ones only in the case of full or partial aromatic N-substitution. The relative adducts gave N,N-disubstituted 4-amino-3-chloro-10,11-dihydro-5H-benzo[5,6]cyclohepta[2,1-b]pyran-2-ones by dehydrochlorination. The 1,4-cycloaddition with sulfene occurred readily in the case of both aliphatic and aromatic N-substitution to give N,N-disubstituted 4-amino-3,4,10,11-tetrahydro-5H-benzo[5,6]cyclohepta[1,2-e]-1,2-oxathiin-2,2-dioxides. These compounds, as well as the pyran derivatives, can be considered as linear heterocyclic analogues of the Amitriptyline ring system.

Cycloheptanes↗