Comparative fluorometric study of benzo(a)pyrene and aza-aromatic hydrocarbon penetration and metabolism kinetics in the skin of hairless mice.

The kinetics of penetration and metabolism of BaP, BACs, DB(a,h)ACs and DB(c,g)Cs in the skin of hairless mice was studied. The relative fluorescence intensities were measured during three hours after applying 10 nmoles of the compound to the interscapular region of the mice. By using a kinetical model which combines a non-steady diffusion of a hydrocarbon through the stratum corneum and the metabolic oxidation by epidermal cells, the rate constants for the two processes were calculated. It has been shown that B(a)AC, B(c)AC and 12-MB(a)AC penetrate into the skin and are oxidized by epidermal cells more efficiently than BaP. In contrast, alkyl-DB(a,h)ACs (except 14-MDB(a,h)AC) show a great stability in the mouse skin. The carcinogenic BaP, 7-MB(c)AC and DB(a,h)AC have average rates of elimination from the skin.

Chemometric approach in a QSAR study: the antibacterial and antimicotic activities of benzofused heteroaromatic derivatives.

In order to establish quantitative relationships between the antibacterial activities of a number of thienyl- and furyl-benzimidazoles and benzoxazoles, the biological data were measured homogeneously for a selected set of 16 representative compounds of the available set of 103. The data were analyzed by the PLS method. The results of linear PLS modelling and PLS response surface modelling permitted a straightforward interpretation of the structural features relevant to the activities and the prediction of a possible optimal structure.

New heterocyclic derivatives of benzimidazole with germicidal activity--VII--2-(5'-nitro-2'-furyl or 2'-thienyl) benzimidazoles with different substituents in the 5-position.

In continuation of our previous research, the synthesis of 13 2-(5'-nitro-2'-furyl or 2'-thienyl) benzimidazoles with different substituents in 5 position is described. The new compounds were tested in vitro against 5 (Gram+) and 4 (Gram-) strains and a mycete Candida Albicans. All the derivatives showed a certain degree of antibacterial and antimycotic activity, which in some cases was fairly good.

[New heterocyclic derivatives with germicidal activity. VI. Synthesis and activity of new 2-benzoxazoyl-2'-furanes and -thiophenes variously substituted in 5 and 5' positions]. / Nuovi derivati eterociclici ad attività germicida. VI. Sintesi ed attività di nuovi 2-benzossazolil-2'-furani e-tiofeni, variamente sostituiti in 5 e 5'.

Seventeen derivatives of 2'-furyl-2-benzoxazole and three derivatives of 2'-thienyl-2-benzoxazole, having different substituents in the benzene moiety (position 5) and in the furanic or thiophenic ring (position 5'), are described, with the aim of studying antibacterial and antimycotic structure-activity relationships. None of the compounds show an important antibacterial and/or antimycotic activity, when tested against nine bacteria and Candida albicans cultures; in any case it was much lower than that previously reported for the corresponding benzimidazoles. It seems that the = NH group of the imidazole ring, which is absent in the benzoxazole derivatives, might be important for the biological activity of this class of compounds.

[New heterocyclic derivatives of benzimidazole with germicidal activity. V. Synthesis and activity of new derivatives of di-2-benzimidazolyl-2,5-furan]. / Nouveaux derives heterocycliques du benzimidazole a activite germicide. V. Synthese et activité de nouveaux di-2-benzimidazolyl-2,5-furranes asymétriques.

In continuation of the research in the field of germicidal and antimycotic agents, the synthesis of 14 new derivatives of di-2-benzimidazolyl-2,5-furan is described. These derivatives are differently substituted (R not equal to R') in the position 5 of the two benzene rings. These new compounds showed no germicidal or fungicidal activity, when tested on different cultures. New compounds are under investigation.

New heterocyclic derivatives of benzimidazole with germicidal activity. IV--In vivo anticandida activity of 5-fluoro-2-(5'-nitro-2'-furyl) benzimidazole (F-O-NO2).

We have studied the possible in vitro and in vivo antibacterial activity of 5-fluoro-2-(5'-nitro-2'-furyl)benzimidazole (F-O-NO2). Our data demonstrate that F-O-NO2 is able to inhibit the in vitro growth of different mycetes and bacteria, including Candida albicans and Cryptococcus neoformans. We also tested the possible in vivo activity against Candida albicans. The results clearly show that treatment with F-O-NO2 is able to significantly augment the survival of all treated animals; in particular, when injected i.p. at the dose of 120 mg/kg, 30' or 1 hr after Candida albicans challenge, it givens a MST (Medium Survival Time) longer than 60 days. These data demonstrate that F-O-NO2 has antibacterial and antimycotic activity.

[New heterocyclic derivatives of benzimidazole with germicidal activity. III. Synthesis and activity of derivatives of (formyl-5'-furyl-2')-2-benzimidazole with different substitutions at position 5]. / Nouveaux dérivés hétérocycliques du benzimidazole à activité germicide. III--Synthèse et activité de derivés du (formyl-5'-furyl-2')-2-benzimidazole, différemment substitués en position 5.

The synthesis and germicidal properties of 28 new derivatives of furyl-2-benzimidazole are described. The compounds are substituted both in position 5 of the benzene moiety and in position 5' of the heterocycle moiety. The germicidal properties of the new molecules were tested using 9 strains of bacteria and Candida albicans. Some of them exhibited germicidal properties versus Gram + bacteria and versus Candida. Some derivatives were also tested using Mycobacterium aurum: two isonicotinoylhydrazones derivatives exhibited tubercolostatic activity comparable to that of streptomycin and not much lower than that of isoniazide.

[New heterocyclic derivatives of benzimidazole with germicidal activity. II. Mechanism of action of fluoro-5-(nitro-2'-furyl)-2-benzimidazole in B. subtilis and C. albicans]. / Nouveaux dérivés heterocycliques du benzimidazole à activité germicide. II. Etude du mecanisme d'action du fluoro-5-(nitro-2'-furyl)-2-benzimidazole sur B. subtilis et C. albicans.

Study of the microbiological activity of 5-fluoro-(2'-nitrofuryl)-2-benzimidazole F-O-NO2 (I) was continued. The substance was tested on cultures of B. subtilis and C. albicans. From the microbial strains studied, the mortality rate, the minimum inhibitory and bacterial concentrations and the cytotoxicity were determined. The action mechanism was studied using tritiated leucin, uracil and thymidine. Acute toxicity in the mouse (DL50 = 275 mg/kg) was also determined. The germicidal activity of (II), homologous N-ethyl derivative of (I), was also studied. On the basis of the results obtained, a possible mechanism of action of compound (I) is discussed.

[N1-substituted 1H-indazole-3-ethyl carboxylates and 1H-indazole-3-hydroxamic acids]. / 1H-Indazole carboxylates d'éthyle-3 N1-substitués et acides 1H-indazole hydroxamiques-3.

Sixty five new derivatives of ethyl-1H-indazole-3-carboxylate are described; they contain in N1 various aliphatic or aromatic acyl radicals. Moreover halogens or methyl groups are present as substituents at the 5 position or methyl groups at 5,6. The synthesis of seven 1H-indazole-3-hydroxamic acids, substituted at 6 and/or 5 as above, is also described. Some of the synthesized derivatives have preliminarily been tested on rats to investigate acute toxicity, possible antiarthritic effects on primary or secondary arthritis, and their action on weight gain. Some of these indazole derivatives had an antiarthritic effect at doses much lower than the toxic ones; among the compounds tested up to now, the ethyl-5-methyl-N1-p-chlorobenzoyl-1H-indazole-3-carboxylate gave the best results. Weight gain as not affected by any of the examined compounds.

A quantitative structure-activity analysis of the mutagenic and carcinogenic action of 43 structurally related heterocyclic compounds.

Quantitative structure-activity relationships for the carcinogenicity and mutagenicity (against Salmonella typhimurium his- TA98, TA100 and TA1537 strains) of 43 structurally related heterocyclic compounds were formulated. The compounds investigated belong to the following two series of congeners : (a) benzo(thio)-pyranoquinolines and (b) benzo(thio)pyranoindoles. Their biologic activities were correlated with the following parameters : (a) the minimal topological difference (describing the fit of the considered molecules with a possible receptor, enzyme or DNA) and (b) the lipophilicity constants. The computed regression equations suggest that the structural requirements for carcinogenicity are different from those responsible for mutagenicity in the Ames test.

Mutagenicity of 43 structurally related heterocyclic compounds and its relationship to their carcinogenicity.

43 heteropolycyclic compounds belonging to a homologous series were investigated for mutagenicity. The results are compared with carcinogenicity data obtained with the same batches of compounds under conditions identical for all of them. Mutagenicity was tested in the Ames test with Salmonella typhimurium strains TA1535, TA1537 and TA100 in the presence and absence of liver 10 000 g supernatant from rats treated with Aroclor 1254. Carcinogenicity was tested by injection of the compounds into subcutaneous tissue of XVIInc/Z mice. 18 test compounds showed carcinogenic activity, some strongly, others only weakly. Of these, 17 were detected as mutagens: one weak carcinogen did not revert the Salmonella strains. No quantitative correlation was observed between the extents of the mutagenic and the carcinogenic effects. Of the 25 substances that did not produce tumours, 13 showed mutagenicity (12 in the presence, 2 in the absence, of the liver homogenate). The mutagenic effects of these compounds were quantitatively similar to those of the compounds that produced tumours. The most sensitive strain of Salmonella typhimurium was TA100. It detected all 30 mutagens. TA98 was mutated by 25 compounds, TA1537 by 16 compounds. No mutagenic effects were seen with TA1535. Possible reasons for the high percentage of apparently "false positives" in the Ames test and the lack of a quantitative correlation between the potency of the mutagenic and carcinogenic effects are discussed. It is suggested that the complexity of the metabolism of these heterocyclic compounds may lead to critical differences in metabolism in mouse subcutaneous tissue in vivo and in liver homogenates from rats treated with Aroclor. Therefore the present study will be extended to life-long oral and intrahepatic carcinogenicity tests leading to a higher proportion of metabolism in the liver.

Carcinogenicity and polarographic behaviour of dibenzo[a,h]pyrene, 4,11-diazadibenzo[a,h]pyrene and 7,14-diazadibenzo[a,h]pyrene.

In a simultaneous test of carcinogenicity the writers have studied the activities of dibenzo[a,h]pyrene (I), 4,11-diazadibenzo[a,h]pyrene (II) and 7,14-diazadibenzo[a,h]pyrene (III). 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 (I) and (II) was 23 and 16 respectively. The compound (III) has proved wholly inactive. Tumorigenicity of (I) and (II) was found to be proportional to their electron donation and inversely proportional to their electron acceptance in the performed polarographic test. Inactivity of (III) is being discussed from the aspect of molecular geometry.

Binding of dibenzo(a,e)fluoranthene, a carcinogenic, polycyclic hydrocarbon without K-region, to nucleic acids in a subcellular microsomal system.

Dibenzo(a,e)fluoranthene (DBF), a highly carcinogenic polycyclic hydrocarbon without an apparent K-region, binds covalently to DNA, transfer RNA, and polyribonucleotides when incubated with hepatic microsomal fractions under standard conditions. Optimal binding conditions for [3H]DBF were established. Methylcholanthrene-pretreated mouse liver microsomes induced a higher level of binding of [3H]DBF to DNA than did similarly induced rat liver microsomes. 7,8-Benzoflavone strongly inhibited the binding of this polycyclic aromatic hydrocarbon to DNA, while cyclohexene oxide and trichloropropene oxide had an enhancing effect when used in the presence of rat liver microsomes. An unexpected inhibitory effect was observed with cyclohexene oxide in mouse liver microsome-enriched medium. [3H]DBF bound twice as much to denatured as to native DNA. Incubation of [3H]DBF in the presence of liver microsomes and polyribonucleotides (polyadenylate, polyuridylate, polyguanylate, and polyinosinate) indicated that binding occurs mainly with guanine. Binding of [3H]DBF to DNA of various origins was found to be directly proportional to the amount of GC pairs. Preliminary results indicate a covalent bond between DBF and nucleic acids.

Enhancement of 5-iododeoxyuridine-induced endogenous C-type virus activation by polycyclic hydrocarbons: apparent lack of parallelism between enhancement and carcinogenicity.

When mouse MLg cells were treated with 3-methylcholanthrene or 7,12-dimethylbenz[alpha]anthracene in the presence of microsomal enzymes and NADPH after 5-iododeoxyuridine (IUDR) treatment, the induction rate of the endogenous C-type virus was increased fivefold to sixfold in comparison with the culture treated with IUDR only. In this reaction, both the microsomal enzymes and NADPH were indispensable. 7,8-Benzoflavone, an inhibitor of the metabolism of hydrocarbons in hamster embryo cultures, inhibited the reaction. For detecting the enhancing activity, the concentration of IUDR for the pretreatment, the concentration of the test products, and the duration of the treatment with the products were important factors. In screening 30 polycyclic hydrocarbons, we were unable to detect a correlation between the in vivo carcinogenicity in the skin and the enhancing activity in the conditions tested.

[New chloro derivatives of benzothiopyrano indoles and quinolines]. / Nouveaux derives chlores d'indoles et de quinoleines benzothiopyranniques

Some chloro derivatives of the carcinogenic [1]benzothiopyrano[4,3-b] indoles and 6H[1] benzothiopyrano[4,3-b] quinolines have been synthesized from 7- and 8-chlorothiochroman-4-one. Mass spectral data of these compounds are comparated with those of benzothiopyranoindole. Biological tests for carcinogenic activity are in progress.

[Inhibitory effect of ellipticine (dimethyl-5,11-(6H) pyrido (4,3-b) carbazole on the induction of liver cancer by BT6 (N,N-dimethyl-p-(benzothiazolylazo) analine) and its effect on the levels of cytochrome P450 and arginase activity]. / Effet inhibiteur de l'ellipticine (diméthyl-5.11 (6H) pyrido (4.3-b) carbazole) sur la cancérisation du foie induite chez le rat par le BT6 (N, N-diméthyl-p-(6 benzothiazolylazo) aniline): ses incidences sur les taux de cytochrome P 450 et sur l'activité de l'arginase

Under the conditions of our tests, ellipticine inhibits remarkably the carcinogenic action of BT6 on the liver, characterized, in particular, by the swiftness of its outbreak. Under the influence of this carcinostatic compound, a considerable activation of liver metabolism is observed, resulting in an hyperproduction of cytochrome P450, while the arginase capital is restored after an appreciable fall, as if ellipticine played a favourable part in the safeguard of this enzyme, recognized as one of the targets of liver carcinogens. The relationships between various effects of ellipticine are discussed.