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PubMed1976

Mutagenicity of K-region epoxides of polycyclic aromatic compounds: structure-activity relationship.

The mutagenicity of several K-region arene oxides was tested in histidine-dependent mutants of Salmonella typhimurium. Benzo(a)pyrene-4,5-oxide and pyrene-4,5-oxide as well as some substituted phenanthrene oxides were mutagenic in strains TA 1538 and TA 98 which detect frame-shift mutagens. Structure-activity relationships are discussed from the standpoint of chemical reactivity. The absence of direct correlation between electrophilic reactivity and mutagenicity may suggest that primilarily physical properties, such as relative position of the epoxide group and molecular shape of arene oxides, are important for the emergence of mutagenicity of arene oxides.

Benzopyrenes↗
PubMed1977

Bis-basic-substituted polycyclic aromatic compounds. A new class of antiviral agents. 8. Bis-basic derivatives of carbazole, dibenzofuran, and dibenzothiophene.

A series of bisalkamine esters, bis-basic ethers, and bis-basic ketones of carbazole, N-ethylcarbazole, dibenzofuran, and dibenzothiophene was synthesized and evaluated for antiviral activity. The series also included two bis-basic alkanes of N-ethylcarbazole and one bis-basic carboxamide of dibenzofuran. Structure-activity relationships indicated that within the carbazole and N-ethylcarbazole series the bisalkamine esters gave the most active derivatives while the bis-basic ketone derivatives of dibenzofuran and dibenzothiophene afforded the more potent compounds within the respective series. The [6,5,6]heterocyclic nuclei were compared with the [6,5,6] aromatic nuclei (fluroene and fluoren-9-one) including tilorone with respect to antiviral activity against encephalomyocarditis (EMC) virus. Maximum activity was associated with the bis-basic ketone side chain and fluoren-9-one nucleus.

Animals↗
PubMed1976

Bis-basic-substituted polycyclic aromatic compounds. A new class of antiviral agents. 7. Bisalkamine esters of 9-oxoxanthene-2,7-dicarboxylic acid, 3,6-bis-basic ethers of xanthen-9-one, and 2,7-bis(aminoacyl)xanthen-9-ones-xanthenes, and -thioxanthenes.

3,6-Bis[2-(dimethylamino)ethoxy]-9H-xanthen-9-one dihydrochloride (4, RMI 10874DA) and 1,1'-(9H-xanthene 2,7-diyl)bis[2-(dimethylamino)ethanone] dihydrochloride (16, RMI 11513DA) were found to prolong survival of mice infected with lethal challenges of encephalomyocarditis (EMC) virus. They were effective by oral as well as subcutaneous administration and showed broad-spectrum antiviral activity. They were selected for preclinical evaluation from the five series of compounds named in the title that were synthesized in analogy to tilorone and related fluorenone derivatives, described earlier. In addition to 4 and 16, compounds 11, 12, 17, and 18 showed high antiviral activity on oral as well as subcutaneous administration. High antiviral activity on subcutaneous admistration was found in the bisalkamine esters 1,2, and 14, the bis(aminoacyl)xanthenes 23 and 26, the bis(aminoalkylene)xanthene 31, the bis(aminoacyl)thioxanthenes 34-40, and the bis-basic ethers of 9-benzylide-nexanthenes 41 and 42. Structure-activity relationships showed a decrease of oral activity with increased length of side chains and increased molecular weight of dialkylamino substituents of 3,6-bis-basic ethers of xanthen-9-one and of 2,7-bis(aminoacyl)xanthenes and-xanthen-9-ones. At least one carbonyl or alkenyl function in conjugation to the xanthene nucleus either at the 9 position of the nucleus or in the side chains is required for high antiviral activity.

Administration, Oral↗
PubMed1975

Polycyclic aromatic isothiocyanate compounds as fluorescent labeling reagents.

Polycyclic aromatic isothiocyanates were synthesized in an attempt to produce new fluorescent agents for protein labeling and for use in microanalytical techniques. The relative fluorescence of these reagents, the required intermediates, and the derivatives were established. Of the compounds evaluated, the 9-acridine derivatives were the most promising.

Acridines↗
PubMed1992

Structure-activity relationship of genotoxic polycyclic aromatic nitro compounds: further evidence for the importance of hydrophobicity and molecular orbital energies in genetic toxicity.

A quantitative structure-activity relationship (QSAR) has been formulated for 15 polycyclic aromatic nitro compounds acting on E. coli PQ37. Upon damage of DNA by these substances beta-galactosidase is induced and can be easily assayed colorimetrically, hence, this is a short-term test for mutagenicity. The QSAR (log SOSIP = 1.07 log P - 1.57 epsilon LUMO - 6.41) is strikingly similar to that found earlier with nitroaromatics acting in the Ames test (TA100) and differs significantly for that found using TA98 organisms. The QSAR brings out in a unique manner the underlying similarity in the two test systems.

Mutagenicity Tests↗
PubMed1978

The mutagenicity of airborne particulate pollutants.

The mutagenic effect of extracts derived from airborne particulate matter was investigated with the Ames-test. The whole extract proved to be distinctly mutagenic. To find out whether the content of polycyclic aromatic hydrocarbons may be responsible for the mutagenic effect, the extract was split into several fractions. The fraction containing the polycyclic compounds showed the lowest mutagenic rate that was enzymatically mediated. The other fractions required metabolic activation for some of their components, but some components were active without metabolic activation.

Air Pollutants↗
PubMed1976

Evaluation of the mutagenicity of compounds of known carcinogenicity, belonging to the benz[a]anthracene, chrysene, and cyclopenta[a]phenanthrene series, using Ames's test.

Fifty-four polycyclic compounds, 29 of the cyclopenta[a]phenanthrene series, 11 chrysenes, and 14 benz[a]anthracenes, have been tested for mutagenicity by Ames's method, using Salmonella typhimurium TA100. Without exception all 37 carcinogens and a known initiator were mutagens. Of the 16 noncarcinogens 7 were mutagenic, but none of these has yet been tested for initiating, as opposed to carcinogenic, activity. There appeared to be little quantitative correspondence between carcinogenic and mutagenic potency, however, and possible reasons for this are discussed. The aryl hydrocarbon hydroxylase inhibitor 7,8-benzoflavone strongly inhibited the mutagenicity of certain compounds when it was added to the incubations.

Animals↗
PubMed1991

Biodegradation of halogenated organic compounds.

In this review we discuss the degradation of chlorinated hydrocarbons by microorganisms, emphasizing the physiological, biochemical, and genetic basis of the biodegradation of aliphatic, aromatic, and polycyclic compounds. Many environmentally important xenobiotics are halogenated, especially chlorinated. These compounds are manufactured and used as pesticides, plasticizers, paint and printing-ink components, adhesives, flame retardants, hydraulic and heat transfer fluids, refrigerants, solvents, additives for cutting oils, and textile auxiliaries. The hazardous chemicals enter the environment through production, commercial application, and waste. As a result of bioaccumulation in the food chain and groundwater contamination, they pose public health problems because many of them are toxic, mutagenic, or carcinogenic. Although synthetic chemicals are usually recalcitrant to biodegradation, microorganisms have evolved an extensive range of enzymes, pathways, and control mechanisms that are responsible for catabolism of a wide variety of such compounds. Thus, such biological degradation can be exploited to alleviate environmental pollution problems. The pathways by which a given compound is degraded are determined by the physical, chemical, and microbiological aspects of a particular environment. By understanding the genetic basis of catabolism of xenobiotics, it is possible to improve the efficacy of naturally occurring microorganisms or construct new microorganisms capable of degrading pollutants in soil and aquatic environments more efficiently. Recently a number of genes whose enzyme products have a broader substrate specificity for the degradation of aromatic compounds have been cloned and attempts have been made to construct gene cassettes or synthetic operons comprising these degradative genes. Such gene cassettes or operons can be transferred into suitable microbial hosts for extending and custom designing the pathways for rapid degradation of recalcitrant compounds. Recent developments in designing recombinant microorganisms and hybrid metabolic pathways are discussed.

Bacteria↗
PubMed1979

[Measurement of fluorescence decay of substances absorbed by an isolated living cell: an experimental device and early results].

A microfluorometric system allowing the mesurements of fluorescence decay (i.e. fluorescence lifetime) has been built. It will complete the microspectrofluorometric studies of absorbed compounds-polycyclic aromatic hydrocarbons, metabolites of benzo (a) pyrene-by single living cells and allows a better understanding of the intake and metabolisation of these compounds. The preliminary results with benzo (a) pyrene, dibenzocarbazole, pyrene are shown.

Benzopyrenes↗
PubMed1986

Carbonyl reductase provides the enzymatic basis of quinone detoxication in man.

Enzymes catalyzing the two-electron reduction of quinones to hydroquinones are thought to protect the cell against quinone-induced oxidative stress. Using menadione as a substrate, carbonyl reductase, a cytosolic, monomeric oxidoreductase of broad specificity for carbonyl compounds, was found to be the main NADPH-dependent quinone reductase in human liver, whereas DT-diaphorase, the principal two-electron transferring quinone reductase in rat liver, contributed a very minor part to the quinone reductase activity of human liver. Carbonyl reductase from liver was indistinguishable from carbonyl reductase previously isolated from brain (B. Wermuth, J. biol. Chem. 256, 1206 (1981] on the basis of molecular weight, isoelectric point, immunogenicity, substrate specificity and inhibitor sensitivity. The purified enzyme from liver catalyzed the reduction of a great variety of quinones. The best substrates were benzo- and naphthoquinones with short substituents, and the K-region orthoquinones of phenanthrene, benz(a)anthracene, pyrene and benzo(a)pyrene. A long hydrophobic side chain in the 3-position of the benzo- and naphthoquinones and the vicinity of a bay area or aliphatic substituent (pseudo bay area) to the oxo groups of the polycyclic compounds decreased or abolished the ability of the quinone to serve as a substrate. Non-k-region orthoquinones of polycyclic aromatic hydrocarbons were more slowly reduced than the corresponding K-region derivatives. The broad specificity of carbonyl reductase for quinones is in keeping with a role of the enzyme as a general quinone reductase in the catabolism of these compounds.

Alcohol Oxidoreductases↗
PubMed1978

Carcinogenicity and polarographic behavior of dibenz[a,h]anthracene, dibenz[a,h]acridine and dibenz[a,h]phenazine.

In a simultaneous test of carcinogenicity the authors have studied the activities of dibenz-[a,h]anthracene, dibenz[a,h]acridine and dibenz-[a,h]phenazine. These compounds were dispersed in paraffin disks and subcutaneously implanted in rats. Each experimental group consisted of 30 animals. The number of sarcomas induced by the above-mentioned compounds was 20, 5 and 3 respectively. Tumorigenicity of the aza analogues of dibenz[a,h]anthracene was proportional to their electron donation and inversely proportional to their electron acceptance in the performed polarographic test. The authors discuss the possibilities of using polarography as a screening test for the exclusion of carcinogenic polycyclic compounds.

Acridines↗
PubMed1991

Comparison of three forward mutation systems in Saccharomyces cerevisiae for sensitivity to polycyclic and heterocyclic compounds.

Forward mutation to cycloheximide resistance, L-canavanine resistance and DL-alpha-aminoadipic acid resistance in Saccharomyces cerevisiae wild-type strain S7a was tested for sensitivity to nine mutagens in treat-and-plate assays. Eight of these agents, 2-aminofluorene, 2-acetylaminofluorene, benzo[a]pyrene, benzidine, cyclophosphamide, acriflavine, 7,12-dimethylbenz[a]anthracene and 2-aminoanthracene were known or suspected to be difficult to detect whilst one, methyl methanesulphonate, was known to be very active in yeast. Forward mutation to cycloheximide resistance was, overall, the most sensitive system, detecting all nine agents under optimal conditions, although neither benzidine nor benzo[a]pyrene were consistently positive. Mutation to adipic acid resistance occasionally gave responses superior to those at the cycloheximide loci, but mutation to canavanine resistance was never more sensitive than the cycloheximide resistance system. We conclude that forward mutation in strain S7a using both cycloheximide and adipic acid resistance loci is capable of detecting the genetic effects of a range of polycyclic and heterocyclic compounds with greater sensitivity than is seen in other published gene mutation assays with yeast. Although sensitivity is much lower than in bacterial assays, such yeast assays provide a reasonable alternative to bacterial genotoxicity screening for agents such as potent bactericides.

2-Aminoadipic Acid↗
PubMed1977

The epidemiology of oral cavity, pharyngeal and esophageal cancer outside of North America and Western Europe.

Geographical variations in the incidence of oral cavity, pharyngeal, and esophageal cancer were studied, with special reference to rates in countries outside of the United States and Western Europe. Although reporting techniques differ greatly and comparisons must be made with caution, significant variations are evident. Tracing such differences often reveals possible etiologic factor for these forms of cancer. The roles are discussed of known environmental carcinogens, such as N-nitroso compounds, polycyclic aromatic hydrocarbons, and such cultural habits as smoking or chewing tobacco, excessive consumption of alcoholic beverages, as well as other possible factors in the etiology of these cancer types.

Asia↗
PubMedDate not supplied

Drugs affecting the release of rheumatoid factor in a plaque-forming cell assay.

Addition of propranolol to the agarose phase of a plaque-forming cell (PFC) assay for rheumatoid factor (RF) caused reduction in the number of plaques seen. This reduction in rheumatoid factor plaque-forming cell (RF PFC) did not depend upon an effect at the beta-adrenergic receptor, since d- and 1-propranolol reduced equally well. Furthermore, in a series of polycyclic compounds with varying beta-receptor blocking capabilities there was no agreement between plaque reduction and blocking. When propranolol was tested in the agarose in an anti-sheep erythrocyte (SRC) plaque assay (anti-SRC PFC), it had no inhibitory effect, but it was capable of inhibiting the generation of new anti-SRC PFC in an in vitro culture. Propranolol is thought to exert these effects through its membrane stabilizing (anesthetic) properties.

Adrenergic beta-Antagonists↗
PubMed1975

Carcinogenesis.

An examination has been made of the major chemicals which are known to be carcinogenic, either in animals or in humans. As a result, a generalized type of chemical property seems to be a prerequisite for the carcinogenic activity. In most cases, this is some kind of reactive electrophilic intermediate produced directly from the carcinogen or from one of its immediate metabolites. This electrophilic reagent is generally a positively charged ion of some kind. In the case of the hydrocarbons it seems to be an incipient carbonium ion; in the case of nitrogen compounds, it is a corresponding nitronium ion. There are a number of possible substrate materials (nucleophilic) in a cells, but the dominant one which has been suspected is the nucleic acid component, either the DNA or the RNA. The bases of these materials all have extra pi electrons susceptible to attach by the electrophiles of the carcinogen. Such a modification, particularly of the DNA, could lead to either major or minor changes in the genetic composition of the cell. Minor changes are usually rectifiable or are not visible, and this would include a large variety of point mutations.

2-Acetylaminofluorene↗
PubMed1990

Multiple and long-range participation of benzyl groups in intramolecular C-arylation reactions of benzylated glycosides.

The intrinsic reactivity of furanosides bearing activated O-benzyl substituents (3-methoxybenzyl), in the presence of bidentate Lewis acids such as tin(IV) chloride, was explored. These glycosides were found to exhibit extremely interesting chemical properties. Thus, with three reactive substituents (at O-2,3,5), the corresponding glycosides (1 and 7) underwent a novel internal bis-C-arylation process, which involved successive alkylations of the benzyl groups at O-2 and O-3 ("multiple participation"), leading to the formal replacement of the two C-O bonds at the anomeric center of the glycoside by two C-C bonds. The bis-C-arylated constitution of the resulting polycyclic compounds 4 and 8, and the cis configuration of their fused ring system (a tetrahydro-[2]benzopyrano[3,4-d][2]benzoxepin derivative), were determined on the basis of their n.m.r.-spectral parameters. With two 3-methoxybenzyl substituents (at O-3 and O-5, compound 6), intramolecular alkylation of the benzyl group at O-3 or O-5 occurred when glycoside 6 was reacted with titanium(IV) chloride or tin(IV) chloride, respectively, thereby leading to novel bicyclic internal aryl C-glycosides (9 and 12) as major products ("long-range participation"). The constitution of compounds 9 and 12 was unambiguously established by the reactions of analogs of 6 bearing only one 3-methoxybenzyl substituent at a specific position (at O-3: 15; at O-5: 20). The unexpected divergent behavior of 6 in the presence of titanium(IV) and tin(IV) chloride remains to be explained. The availability of compound 9 made it possible to independently prepare the bis-C-arylated derivative 8 (by way of the reverse sequence of internal C-arylation reactions) and thereby to definitively demonstrate its constitution. These unprecedented reactions extend the scope of the intramolecular C-glycosidation of substituted sugars and provide novel methodologies in synthetic carbohydrate chemistry.

Benzyl Compounds↗
PubMedDate not supplied

Relationships between structure of nitrated arenes and their mutagenicity in Salmonella typhimurium; 2- and 2,7-nitro substituted fluorene, phenanthrene and pyrene.

In order to elucidate the mechanisms of mutagenic activation of nitroarenes, we studied the relationships between the mutagenic potency and chemical structure of 2-nitro- and 2,7-dinitro-arenes including nitrated fluorene (Fl), dihydrophenanthrene (DHPh), phenanthrene (Ph), tetrahydropyrene (THPy), dihydropyrene (DHPy) and pyrene (Py) together with 9-NO2-Ph, 1-NO2-Py and 1.3-diNO2-Py. The mutagenicity tests were carried out on Salmonella typhimurium TA98, TA98NR and TA98/1,8-DNP6 in the absence of S9 mix. The order of mutability of mononitro- and dinitro-arenes in TA98 is as given below: 2-NO2-THPy less than 2-NO2-Fl less than 2-NO2-DHPh less than 9-NO2-Ph less than 2-NO2-Ph less than 2-NO2-DHPy less than 1-NO2-Py less than 2-NO2-Py, and 2,7-diNO2-DHPh less than 2,7-diNO2-Fl less than 2,7-diNO2-THPy less than 2,7-diNO2-Ph less than 2,7-diNO2-DHPy less than 2,7-diNO2-Py less than 1,3-diNO2-Py. 9-NO2-Ph and 1-NO2-Py, which have been detected in environmental samples, are not as potent mutagens as 2-nitrated phenanthrene and pyrene, respectively. 2-NO2THPy (37.7 rev/nmole) was a weak mutagen, but 2,7-diNO2-THPy (3197 rev/nmole) was as potent a mutagen as 2,7-diNO2 (3925 rev/nmole). Tetrahydropyrene has a twisted form in its structure. 1,3-diNO2-Py (99660 rev/nmole) was more mutagenic than 2,7-diNO2-Py (37960.0 rev/nmole), and their mutagenicities were correlated with the behavior of the K-band in their UV spectra by the introduction of nitro groups on pyrene.

Biotransformation↗