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PubMed1991

[Exposure to carcinogens in industry. Evaluation of the situation and proposition of an information system].

This article presents an estimate of occupational exposure from carcinogens in the industrial plants belonging to the former departments of chemistry and light industry. The occurrence of 13 compounds listed as carcinogens in the list prepared in 1985 by the Chief Sanitary Inspector and 40 substances suspected of carcinogenic effects on the basis of the list prepared by the Institute of Occupational Medicine was taken into account. In the industries mentioned, 11 thousand persons were found to be exposed to the factors considered to be carcinogenic. The most numerous group constituted the employees working in contact with benzene (50%), vinyl chloride (19%), polycyclic aromatic hydrocarbons (17%) and asbestos (11%). A system of collection, analysis and qualitative evaluation of the information on exposure to those factors is necessary to enable efficient control of exposure to those factors. Basing on the experiences gained in the course of data collection and verification, the guidelines and documentation for "A System of Information on Carcinogenic Substances" presented in this article, have been prepared.

Asbestos↗
PubMed1989

Comparative carcinogenicity of the PAHs as a basis for acceptable exposure levels (AELs) in drinking water.

The carcinogenicity of various polynuclear aromatic hydrocarbons (PAHs) has generally been demonstrated by their ability to act as complete carcinogens in the development of cancers in rodent skin tests. In order to develop proposed acceptable concentration levels for various PAHs in drinking water, we reviewed the studies that formed the basis for determining that these specific PAHs were carcinogenic in animals. We found that the relative potency of these PAHs varied over a range of many orders of magnitude. For example, the carcinogenic strength of benz[a]anthracene (BaA) is found to be about 1/2000th that of benzo[a]pyrene (BaP). We have used the calculated carcinogenic potency of the various PAHs relative to that of BaP as a means for proposing specific acceptable concentration levels in drinking water for each of the specific PAHs. BaP is the only carcinogenic PAH for which EPA has published an acceptable concentration level based on carcinogenicity. Based on the level EPA set for BaP (0.028 micrograms/liter), this methodology has provided for the specific PAHs a determination of proposed acceptable concentration levels quantitatively based on the same data that were used to qualitatively determine them to be animal carcinogens. We have proposed acceptable concentration levels for the carcinogenic PAHs in drinking water that range from 0.03 micrograms/liter for BaP to 6.5 micrograms/liter for BaA. We recommend that acceptable concentration levels for the various PAHs be based on their relative carcinogenic potencies rather than the EPA method of using the potency of only one specific PAH, BaP, to serve as the exposure level determinant for all PAHs. We further suggest that this methodology may be applicable to other classes of carcinogenic compounds. We have also found useful for the determination of acceptable concentration levels for the noncarcinogenic PAHs an analogous methodology based on the relative toxicities of the noncarcinogenic PAHs.

Animals↗
PubMed1992

Antitumor agents. 134. New shiraiachrome-A- and calphostin-C-related perylene derivatives as cytotoxic and antiviral agents and inhibitors of protein kinase C.

Shiraiachrome-A and -B have been isolated from the mycelium of the Chinese bamboo fungus Shiraia bambusicola as the cytotoxic principles. A series of new perylene derivatives (7-27) related to Shiraiachrome-A and -B as well as Calphostin-C have been synthesized and evaluated for their cytotoxicity, antiviral activity, and inhibitory activity against protein kinase C. The results indicated that 11 and 12 are potent cytotoxic agents against HCT-8, RPMI-7951, and TE-671 solid tumor cells, whereas 24 and 26 demonstrated strong antiviral activity against HSV-1 and HSV-2. Compound 10 is an inhibitor of protein kinase C.

Animals↗
PubMed2000

Development of a novel class of monocyclic and bicyclic alkyl amides that exhibit CB1 and CB2 cannabinoid receptor affinity and receptor activation.

CB1 and CB2 cannabinoid receptors can be activated by several different classes of agonists, including cannabinoids such as delta9-tetrahydrocannabinol and 9-nor-9beta-hydroxyhexahydrocannabinol, and eicosanoids such as arachidonylethanolamide. Structure-activity relationship studies have identified potential pharmacophoric elements for binding to cannabinoid receptors by both cannabinoids and eicosanoids. Molecular models have hypothesized conformational, spatial, and pharmacophoric distance requirements based upon radioligand binding data whereby overlap of pharmacophoric elements of the two classes disclose a low energy conformation of arachidonylethanolamide that can occupy the same receptor space as cannabinoid ligands. To test this model, we have developed a novel class of monocyclic and bicyclic alkyl amide cannabinoid receptor ligands. Further, we predicted a spatial conformation for these compounds in a molecular model based on the pharmacophoric and structural requirements for binding to the CB1 cannabinoid receptor.

Adenylyl Cyclase Inhibitors↗
PubMed2003

A potent, selective inhibitor of matrix metalloproteinase-3 for the topical treatment of chronic dermal ulcers.

The pathology of chronic dermal ulcers is characterized by excessive proteolytic activity which degrades extracellular matrix (required for cell migration) and growth factors and their receptors. The overexpression of MMP-3 (stromelysin-1) and MMP-13 (collagenase-3) is associated with nonhealing wounds, whereas active MMPs-1, -2, -9, and -14 are required for normal wound healing to occur. We describe the synthesis and enzyme inhibition profile of (3R)-3-[([(1S)-2,2-dimethyl-1-(([(1S)-2-methoxy-1-phenylethyl]amino)carbonyl)propyl]amino)carbonyl]-6-(3-methyl-4-phenylphenyl)hexanoic acid (UK-370,106, 7), which is a potent inhibitor of MMP-3 (IC(50) = 23 nM) with >1200-fold weaker potency vs MMP-1, -2, -9, and -14. MMP-13, which may also contribute to the pathology of chronic wounds, was inhibited about 100-fold less potently by compound 7. Compound 7 potently inhibited cleavage of [(3)H]-fibronectin by MMP-3 (IC(50) = 320 nM) but not cleavage of [(3)H]-gelatin by either MMP-2 or -9 (up to 100 microM). Compound 7 had little effect, at MMP-3 selective concentrations, on keratinocyte migration over a collagen matrix in vitro, which is a model of the re-epithelialization process. Following iv (rat) or topical administration to dermal wounds (rabbit), compound 7 was cleared rapidly (t(1/2) = 23 min) from plasma, but slowly (t(1/2) approximately 3 days) from dermal tissue. In a model of chronic dermal ulcers, topical administration of compound 7 for 6 days substantially inhibited MMP-3 ex vivo. These data suggest compound 7 is sufficiently potent to inhibit MMP-3-mediated matrix degradation while leaving unaffected cellular migration mediated by MMPs 1, 2, and 9. These properties make compound 7 a suitable candidate for progression to clinical trials in human chronic dermal wounds, such as venous ulcers.

Administration, Cutaneous↗
PubMed1976

High-pressure liquid chromatography of benzo(a) pyrene and benzo (ghi) perylene in oil-contaminated shellfish.

A high-pressure liquid chromatographic procedure is described for the determination of benzo(a) pyrene and benzo(ghi) perylene. These polynuclear aromatics are extracted with acetonitrile and partitioned into petroleum ether, the petroleum ether is removed, and the residue is saponified. The compounds are purified and isolated by passing the residue through a silica gel column and a high-pressure liquid chromatographic column, and detected by their ultraviolet absorption. Recoveries of standards through the procedure averaged 104%.

Benzopyrenes↗
PubMedDate not supplied

Potential for photoenhanced toxicity of spilled oil in Prince William Sound and Gulf of Alaska waters.

Photoenhanced toxicity is the increase in the toxicity of a chemical in the presence of ultraviolet light (UV) compared to a standard laboratory test conducted with fluorescent lighting (minimal UV). Oil products, weathered oil, and specific polycyclic aromatic compounds present in oil are 2 to greater than 1000 times more toxic in the presence of UV. The photoenhanced toxicity of oil to fish and aquatic invertebrates appears to occur through a process of photosensitization, rather than photomodification of the aqueous phase oil. In photosensitization, the bioaccumulated chemical transfers light energy to other molecules causing toxicity through tissue damage rather than a narcosis mechanism. The available evidence indicates that phototoxic components of oil are specific 3-5 ring polycyclic aromatic hydrocarbons (PAHs) and heterocycles. Determinants of photoenhanced toxicity include the extent of oil bioaccumulation in aquatic organisms and the spectra and intensity of UV exposure. No studies have specifically investigated the photoenhanced toxicity of spilled oil in Alaska waters. Although there are substantial uncertainties, the results of this evaluation indicate there is potential for photoenhanced toxicity of spilled oil in Prince William Sound and the Gulf of Alaska. The potential hazard of photoenhanced toxicity may be greatest for embryo and larval stages of aquatic organisms that are relatively translucent to UV and inhabit the photic zone of the water column and intertidal areas. Photoenhanced toxicity should be considered in oil spill response because the spatial and temporal extent of injury to aquatic organisms may be underestimated if based on standard laboratory bioassays and existing toxicity databases. Additionally, the choice of counter measures and oil removal operations may influence the degree of photoenhanced toxicity.

Accidents↗
PubMed1991

Intercalation binding of 6-substituted naphthothiopheneamides to DNA: enthalpy and entropy components.

N-(3-dimethylaminopropyl)naphtho[2,1-b]thiophene-4-carboxamide and the 6-substituted methoxy, methyl, fluoro, chloro, bromo, trifluoromethyl, and cyano derivatives have been shown to bind to DNA via intercalation with binding constants in the 35-900 X 10(3) range at 25 degrees C, pH 7, and [Na+] = 0.019M. Both electron-donating and -withdrawing substituents enhance intercalation binding, but the binding affinity is most enhanced by the cyano substituent. Calorimetric titrations for calf thymus DNA differ dramatically from those reported for ethidium [Hopkins et al. (1990) Biopolymers Vol. 29, pp. 449-459]. Apparent enthalpy parameters (delta HB) for intercalation are constant only at low coverage of sites and become much more positive as saturation is approached. In the plateau region, delta HB values for the parent and the cyano-, fluoro-, chloro-, and bromo-substituted compounds are nearly the same (approximately -5.9 kcal/mol). For the methyl- (-6.8 kcal/mol) and methoxy- (-7.5 kcal/mol) substituted compounds, the delta HB values are more exothermic than that for the unsubstituted compound, whereas delta HB for the trifluoromethyl compound is approximately 1 kcal/mol less exothermic. The corresponding delta SB values, corrected for mixing effects, are in the 7-15-cal/deg/mol range and are approximately linearly related to delta HB if the cyano derivative is excluded.

Calorimetry↗
PubMed1987

Antimicrobial properties of aromatic compounds of plant origin.

The antimicrobial action of 11 compounds involving guaiacyl- and syringyl-like structures (low-molecular-weight part of lignin), gallic acid and its derivatives, cinnamic acid and its derivatives, veratric acid, anisic acid and crotonic acid (a total of 25 compounds) against bacteria, yeast-like organisms and protozoa was examined. Aromatic compounds modified in the C-side chain and aldehydes were effective preferentially against Trichomonas vaginalis, whereas against bacteria and yeast-like organisms eugenol was the most effective inhibitor.

Anti-Bacterial Agents↗
PubMed2006

Cyclopentanone ring-cleaved pleuromutilin derivatives.

Ring-cleaved pleuromutilin derivatives comprised of a [5.3.1] bicyclic core structure have been synthesized and evaluated in vitro as antibacterial agents. Four of the compounds described were found to have MICs<or=4 microg/mL against marker strains of Streptococcus pneumoniae and Staphylococcus aureus.

Anti-Bacterial Agents↗
PubMed2002

Toward high-throughput synthesis of complex natural product-like compounds in the genomics and proteomics age.

In the age of high-throughput biology, novel genes and proteins are emerging quickly. The need for developing organic synthesis-derived methods that allow rapid access to polyfunctional, complex natural product-like compounds is growing constantly, largely because these small-molecule-based compounds serve as smart, powerful tools both in understanding the roles and functions of emerging biological targets and in validating their biological responses. Developing asymmetric synthesis-derived organic reactions on solid phase allows the synthesis of complex natural product-like compounds in a high-throughput manner. Solid phase organic synthesis is now commonly utilized in the library synthesis of rather simple compounds (i.e., compounds with no multiple stereogenic centers). With few exceptions, the synthesis of complex natural product-like derivatives is still in its infancy. Some recent efforts made in this area indicate opportunities yet to be explored.

Biological Factors↗
PubMed2002

Diversity-oriented synthesis of biaryl-containing medium rings using a one bead/one stock solution platform.

Diversity-oriented synthesis of structurally complex and diverse small molecules can be used as the first step in a process to explore cellular and organismal pathways. The success of this process is likely going to be dependent on advances in the synthesis of small molecules having natural product-like structures in an efficient and stereoselective manner. The development, scope, and mechanism of the oxidation of organocuprates was investigated and exploited in the atropdiastereoselective synthesis of biaryl-containing medium rings (9-, 10-, and 11-membered rings). The methodology was performed on high-capacity, large polystyrene beads by metalating aryl bromides with i-PrBu(2)MgLi, followed by transmetalating with CuCN x 2LiBr and then oxidizing with 1,3-dinitrobenzene, and was used in a diversity-oriented synthesis of biaryl-containing medium rings (library total theoretical maximum 1412 members). The high capacity beads were arrayed into 384-well plates and, using a process optimized during the development of a one bead/one stock solution technology platform, converted into arrays of stock solutions, with each stock solution containing largely one compound. These stock solutions were used in numerous phenotypic and protein-binding assays. The process described outlines a pathway that we feel will contribute to a comprehensive and systematic chemical approach to exploring biology (chemical genetics).

Animals↗
PubMed1990

[Solution of genetic problems of ecology using the automated system "Bioscreen C" (SOS-Chromotest program)].

Comparative experiments on the use of the automated system Bioscreen C (SOS-chromotest program) and the Eims tests for estimating the SOS-inducing and mutagenic activity of chemical compounds belonging to 5 different classes showed that the system was obviously promising and safe in rapid screening of environmental mutagens and carcinogens. Advantages of the system use as well as its prospects, specificity and limitations were revealed.

Aziridines↗
PubMed2006

Two new tetracyclic triterpenes from the heartwood of Ailanthus excelsa Roxb.

Two new dammarane-type triterpenes, ailexcelone and ailexcelol, together with ocotillone, malabaricol, epoxymalabaricol, lupeol, and sitosterol-3-O-beta-D-glucoside were isolated from the heartwood of Ailanthus excelsa. The structures of the new compounds were established on the basis of 1D- and 2D-NMR data. Ocotillone, malabaricol and epoxymalabaricol were isolated for the first time from A. excelsa. All of the isolates were tested for their antifungal activity.

Ailanthus↗
PubMed1994

Ohioensins and pallidisetins: novel cytotoxic agents from the moss Polytrichum pallidisetum.

Bioassay-directed fractionation of an EtOH extract of the moss Polytrichum pallidisetum (Polytrichaceae) led to the isolation of three novel benzonaphthoxanthenones, 1-O-methylohioensin B [6], 1-O-methyldihydroohioensin B [7] and 1,14-di-O-methyldihydroohioensin B [8], and two novel cinnamoyl bibenzyls, pallidisetin A [9] and pallidisetin B [10]. Their structures and relative stereochemistry were established by spectral analyses and chemical correlation. Compounds 6-10 exhibited cytotoxic activity against the human tumor cell lines RPMI-7951 melanoma and U-251 glioblastoma multiforme. These two types of compounds could hypothetically be derived from cinnamic acid and bibenzyls through different biogenetic pathways.

Animals↗
PubMed1988

[Effect of gomisin A (TJN-101), a lignan compound isolated from Schisandra fruits, on liver function in rats].

TJN-101 [+)-(6S, 7S, R-biar)-5,6,7,8-tetrahydro-1,2,3,12-tetramethoxy- 6,7-dimethyl-10,11-methylenedioxy-6-dibenzo [a, c] cyclooctenol) is one of the lignan compounds isolated from Schisandra fruits. When TJN-101 was administered orally at the doses of 3-100 mg/kg/day for 4 days, bile secretion, hepatic excretion of dye or hepatic hemodynamics 24 hr after the last dose was investigated in comparison with the phenobarbital (100 mg/kg/day)-treated group. Bile flow was dose-dependently increased; in contrast, biliary concentration of bile acids was decreased in TJN-101 (30 and 100 mg/kg/day)-treated groups. Similar changes were also observed in the phenobarbital-treated group. These results suggested that the enhancement of bile secretion caused by TJN-101 or phenobarbital was due to an increase of a bile acid-independent fraction. In the bromosulfophthalein (BSP) clearance test for liver function, both TJN-101 (30 and 100 mg/kg/day) and phenobarbital accelerated the disappearance from the blood and biliary excretion of BSP. Hepatic hemodynamics was examined by the hydrogen clearance method and measurement of liver wet and dry weight. Liver blood flow tended to increase in the TJN-101 (10-100 mg/kg/day) or phenobarbital-treated group. On the other hand, TJN-101 (3-100 mg/kg/day) or phenobarbital hardly altered the water content of the liver. These results suggested that the liver enlargement caused by both compounds was not accompanied with hepatic edema and that the enhancement of bile secretion or hepatic excretion of BSP might be related to an increase of liver blood flow.

Animals↗
PubMed1979

Use of Ames test in evaluation of shale oil fractions.

Conditions that affect the sensitivity of the Ames assay of complex hydrocarbon mixtures derived from shale oil were studied. Two fractions, one enriched in polynuclear aromatic compounds (PNA fraction), and a second fraction enriched in aromatic and heterocyclic amines (basic fraction), were selected for most of this work because of their comparatively high mutagenicity (i.e., compared with raw shale oil). The crude shale oil, as well as the basic, PNA, and tar fractions were mutagenic against the Salmonella typhimurium test strains, TA98 and TA100. Mutation was dependent on metabolic activation by microsomal (S9) enzymes. Both test strains responded equally well to the crude product and to the basic fraction; however, strain TA100 was more effective than TA198 in demonstrating the mutagenicity of the PNA fraction. The mutagenicity of the tar fraction could be most easily detected after metabolic activation in a liquid medium, as opposed to S9 activation in the top agar of the standard Ames assay. The mutagenicity of the basic fraction or 2-aminoanthracene was also demonstrated by metabolic activation in a liquid medium. In other set of experiments, the effect of chemical composition on the expression of mutagenicity in the standard Ames assay was estimated. Premutagens requiring metabolic activation were added to the basic and PNA fractions, and the numbers of revertants obtained in the presence of the fractions were compared with mutation induced by the compounds alone. The basic fraction did not interfere with the mutagenicity of 2-aminoanthracene and 7,9 dimethylbenz[c]acridine. Moreover, in certain experiments, the mutagenicity of the complex fraction plus the added compound was higher than expected on the basis of assays performed on these materials separately. Conversely, the PNA fraction prevented or strongly inhibited mutation by several polynuclear aroumatic compounds, and an acridine. However, the PNA fraction did not inhibit mutation induced by 2-aminoanthracene. The effect of the basic fraction on stability of the S9 enzymes in the standard Ames test was also determined.

Acridines↗
PubMed2000

Inhalation study on exposure to bitumen fumes. Part 2: Analytical results at two exposure levels.

During the hot application of bitumen-containing materials, e.g. in road paving or roofing, fumes are emitted that contain traces of polycyclic aromatic compounds (PACs). Although worker's exposure to these fumes is low, it might lead to health problems. For studying DNA adduct formation as a consequence of inhalation of bitumen fumes we developed and validated an inhalation system (a dynamic fume generator plus a nose only inhalation chamber). This paper presents and discusses the analytical results from the different laboratories involved in this study on the fumes sampled in the inhalation chamber during three series of experiments where the animals were exposed to fumes at the 5 mg/m3 and 50 mg/m3 level, coming from bitumen heated at 200 degrees C and, as a positive control, fumes from coal tar, heated to 110 degrees C at the 5 mg/m3 level. The following parameters were controlled: temperatures at different key places in the generator; humidity of the chamber; the bitumen or coal tar flow rate; and Total Particulate Matter (TPM). Analyses were performed for Benzene Soluble Matter (BSM), the EPA polycyclic aromatic hydrocarbon (PAH) mixture and for a number of heteroatom-containing PACs. The data show that the coal tar fumes produced at 110 degrees C were very volatile and that most of the differences in particulate matter found between the laboratories can be attributed to evaporative losses. The bitumen fumes boil 25-50 degrees C higher and contain higher boiling compounds. A comparison is made between the PAC exposure profiles for bitumen experiments aimed at 5 and 50 mg/m3. Although the same molecules are found in both fumes their proportion is dramatically different. This effect is largest with the 2- and 3-ring PACs, the ratio of the concentrations found in the 50 mg/m3 TPM concentration to that in the 5 mg/m3 experiment gradually declines from 5500 for acenaphthene to 500 for pyrene, for the 5-ring PACs this ratio is 20-30. As function of their vapour pressure, the ratios of the concentrations of the hetero PACs follow the same trend as that of the 16 EPA PAHs and are of the same order of magnitude. In conclusion, for the compounds investigated, the equipment delivers a fume atmosphere in a reproducible manner. The 50 mg/m3 bitumen fumes are not representatives of field fumes. The reason for these quantitative differences is unclear and further work would be needed to clarify this. Nevertheless it was felt that these fumes at 50 mg/m3 might be a useful tool for qualitative detection of DNA adducts in an animal exposure study.

Animals↗