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PubMed1993

Synergistic activity of polynuclear aromatic hydrocarbon mixtures as aryl hydrocarbon (Ah) receptor agonists.

The relative potencies of benzo[a]pyrene and a complex mixture of polynuclear aromatic hydrocarbons (PAHs) produced as by-products of manufactured gas plant (MGP) residues as inducers of hepatic microsomal ethoxyresorufin O-deethylase (EROD) activity were determined in the B6C3F1 mouse. The ED50 values for the induction response were 78 and 65 mg/kg for benzo[a]pyrene and the MGP-PAH mixture, respectively. Analysis of the MGP-PAH mixture indicated that benzo[a]pyrene and other compounds containing four or more rings and which are known to induce EROD activity were only present as trace components of this mixture. A comparison of the EROD induction potencies of benzo[a]pyrene and the MGP-PAH mixture showed that the mixture was approximately 706 times more potent than expected based on its benzo[a]pyrene content (0.17%). This induced P-450 activity could significantly increase the metabolism of the carcinogenic PAHs and thereby modulate the overall carcinogenicity of the mixture. The apparent synergistic activity of the MGP-PAH mixture was further investigated by comparing the activities of this mixture and benzo[a]pyrene for several other aryl hydrocarbon (Ah) receptor-mediated responses including (i) induction of hepatic CYP1A1 mRNA levels, (ii) transformation of the rat cytosolic Ah receptor to a complex which binds to a dioxin responsive element, (iii) induction of EROD activity and (iv) antiestrogenicity in MCF-7 human breast cancer cells, and (v) inhibition of the splenic plaque-forming cell (PFC) response to both T cell-dependent and independent antigens in B6C3F1 mice. For the EROD and CYP1A1 mRNA induction and cytosolic transformation activities and immunosuppressive effects, the MGP-PAH mixture was approximately 100-900 times more potent as an Ah receptor agonist than expected based on its benzo[a]pyrene content. The synergistic activity was lower (19-fold) for the antiestrogenic response in MCF-7 cells. The reason for the synergistic effects of the MGP-PAH mixture were not due to contamination of the mixture by 2,3,7,8-tetrachlorodibenzo-p-dioxin and related compounds and the results suggest that the enhanced potency of the mixture is due to unknown interactions between the individual PAHs present in the mixture.

Animals↗
PubMed2006

Neurosteroid analogues. 11. Alternative ring system scaffolds: gamma-aminobutyric acid receptor modulation and anesthetic actions of benz[f]indenes.

Benz[f]indenes are tricyclic compounds with a linear 6-6-5 fused carbocyclic ring system. When properly substituted, benz[f]indenes can satisfy the pharmacophore requirements of the critical hydrogen-bond donor and acceptor groups found in neuroactive steroids that modulate gamma-aminobutyric acidA (GABAA) receptor function. Thus, the benz[f]indene ring system provides an opportunity to extend the previously well-studied GABAA receptor structure-activity relationships (SAR) of neuroactive steroids to a different ring system. Depending on whether the stereochemistry of the 6-6-5 ring fusions are trans-trans or cis-trans, either planar or nonplanar benz[f]indenes are obtained. We found that the planar trans-trans benz[f]indenes are active, but less active than the steroids they were designed to mimic, whereas the nonplanar cis-trans compounds have little, if any, activity. The results provide new insight into the importance of the steroid framework for the actions of neuroactive steroids at GABAA receptors.

Animals↗
PubMed1993

Characterization of various classes of protein adducts.

Analysis of the types of protein adducts formed by chemical carcinogens indicate that adducts may be categorized into various classes according to the nature of the carcinogen as well as the amino acid with which they react. Tryptophan(214) of serum albumin was previously shown to react specifically with N-sulfonyloxy-N-acetyl-4-aminobiphenyl. The same residue is now shown to also react with the sulfate esters of N-hydroxy-N-acetyl-2-aminofluorene and N-hydroxy-N,N'-diacetylbenzidine. Thus, Trp-214 appears to be a binding site for a variety of activated N-aryl hydroxamic acids. Epoxides and diol epoxides derived from polynuclear aromatic hydrocarbons alkylate carboxylic groups in hemoglobin and serum albumin. Because the esters formed are readily hydrolyzed to dihydrodiols and tetrahydrotetrols which can be determined by GC-MS, it is possible to analyze for a wide range of polyaromatic hydrocarbon (PAH) epoxide adducts. With this approach it was shown that human subjects experiencing exposure to ambient levels of environmental PAH do take up and metabolize chrysene and benzo[a]pyrene. Feral, bottom-dwelling fish inhabiting contaminated waters were also examined. Globin adducts containing certain dihydroxy groups such as those arising in anti-diol epoxide adducts were concentrated by boronate affinity chromatography and further analyzed by HPLC with diode-array UV/visible detection. Four compounds were detected that exhibited spectra characteristic of a polynuclear chromophore. Two of these appeared to be isomers. Further instrumental analysis is needed to elucidate the structure of these unknown putative adducts.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed2005

Synthesis and antitumor activity of A-ring modified hexacyclic analogues of camptothecin.

AIM: To improve the biological activity of A-ring modified analogues of camptothecin. METHODS: A-ring modified camptothecins were synthesized from 10-hydroxycamptothecin or 7-ethyl-10-hydroxycamptothecin (SN-38) in three or four steps. Their cytotoxicity was evaluated using MTY assay, and their in vivo antitumnor activity against mouse liver cancer H22 was tested. Results Five hexacyclic camptothecins (6a, 6b, 6c, 7a and 7b) are target compounds, and ten camptothecin derivatives are new compounds. CONCLUSION: The modification of a 1,4-oxazine-2-one ring fused with positions 9 and 10 of A-ring will reduce the antitumor activity of camptothecins.

Animals↗
PubMed1990

[Hydrophobic constant values (delta RMO) of functional groups. II. Interpretation of fragment interactions].

The delta RM0(-CH2-) values have been calculated from fragment values of various alkyl groups (methyl, ethyl, n-propyl). On the basis of delta RM0(-CH2-) values it has been established that the value of the so-called "second" methyl group from aromatic ring has slightly differed from that of the so-called third methylene group and the value of methylene functional group is constant independently from positions of substituents and from electronic interactions. The delta RM0 Me values of methyl group--which is directly attached to aromatic ring--have been regarded as the so-called first methylene group from aromatic ring since value of free energy needed for transfer of methyl group as well as the other physico-chemical data (mole volume, parachor) are nearly the same as those of methylene group according to the literature. Fragment values of methyl groups substituted at various positions have been compared to relating delta RM0(-CH2-) value which is free practically from electronic interactions and it has been ascertained that fragment values have been higher as well as lower. In accordance with literature lower delta RM0 Me values have been interpreted with hyperconjugation effect of aromatic system. On the other hand lower methylene fragment values of alkyl substituted compounds at N1 atom have been attributed to sigma conjugation. In literature higher delta RM0 Me values than relating delta RM0(-CH2-) value are known only in case of orto position to another functional group or by a methyl group on a sterically hindered aromatic ring. Results of tests have shown that values of delta RM0 Me can substantially increase with extension of conjugated aromatic system or with simultaneous substitutions of methyl, methylene groups, respectively at certain locations. The authors have assigned that increase to change of solvate cuver which surrounds the molecule. The same has been manifested by methyl fragment values of quinazoline derivates (tetrahydropyrroloquinazoline, hexahydroazepinoquinazoline) of different electronic distributions. On basis of calculations it has been proved that delta RM0 2-Me and delta RM0 6-Me fragment values of monosubstituted pyrido (1,2-a)-pyrimidine (PP) derivatives have significantly differed from delta RM0 Me values of at other positions (3,7,8,9) methyl substituted compounds. Among disubstituted derivatives only delta RM0 7-Me and delta RM0 8-Me values of 2-phenyl- and 3-carbetoxymethyl-PP derivatives have not differed from each other but methyl fragment values of other positions (6,9) have significantly differed from each other and from other fragment values too.(ABSTRACT TRUNCATED AT 400 WORDS)

Chemical Phenomena↗
PubMed2002

Interactions by carcinogenic metal compounds with DNA repair processes: toxicological implications.

Even though compounds of nickel, arsenic, cobalt and cadmium are carcinogenic, their mutagenic potentials are rather weak. In contrast, they exert pronounced comutagenic effects, which may be explained by disturbances of different DNA repair systems. Thus, cobalt, arsenic, nickel and cadmium interfere with base and nucleotide excision repair, even though they affect different steps of the respective repair systems and act by different, not yet completely understood mechanisms. Potential target molecules for some metal ions are so-called zinc finger structures in DNA repair proteins, but each zinc finger protein exerts its own sensitivity towards toxic metal ions. Possible consequences of repair inhibitions are discussed in more detail for soluble and particulate nickel compounds, which have recently been shown to interfere with the repair of stable DNA adducts induced by benzo[a]pyrene (B[a]P). Since nickel compounds and polycyclic aromatic hydrocarbons such as B[a]P are frequently associated in the ambient air, in cigarette smoke and at many workplaces, an impaired removal of B[a]P-derived DNA adducts will lead to persistent DNA damage and thus increase the risk of mutations and tumor formation.

Animals↗
PubMed2006

Specific interactions with intra- and intermolecular G-quadruplex DNA structures by hydrosoluble coronene derivatives: a new class of telomerase inhibitors.

In developing G-quadruplex interactive telomerase inhibitors two main features have to be taken into account: the hydrophobic interactions with the G-quartet plane and the electrostatic interactions with the negatively charged phosphates of the four grooves. In this paper, we report the synthesis of four hydrosoluble coronene derivatives, which are characterized by a large hydrophobic aromatic core and four orthogonal hydrophilic side chains. We have studied their ability to induce both inter- and intramolecular G-quadruplex structures and found a significant selectivity of all the coronene derivatives for the intramolecular G-quadruplex. The efficiency in inhibiting human telomerase has been evaluated in a cell-free system and the experimental results correlate with the relative affinities of these compounds for the G-quadruplex monomeric structure, as derived by molecular modelling simulations. Thus, the coronene derivatives can be considered as a new class of telomerase inhibitors, although further investigations are surely necessary to fully exploit their features.

Cell-Free System↗
PubMed1991

Bioactivity of neolignans from fructus Schizandrae.

Fructus Schizandrae sinensis Baill, a traditional Chinese medicine, used as tonic and sedative, has been shown at the beginning of 70's to lower the elevated serum glutamic-pyruvic transaminase (SGPT) levels of patients suffering from chronic viral hepatitis. During past 20 years, a series of neolignans have been isolated and identified as effective principles. Pharmacological studies revealed that they increased liver protein and glycogen synthesis, antagonized liver injuries from CCl4 and thioacetamide. The mechanism of SGPT lowering was considered as a hepato-protective and membrane stabilize action, although inhibition of the activity of liver GPT may also be existed. It was found that some principles of Schizandrae have an inducing effect on hepatic microsomal drug-metabolizing enzyme system P-450, thus explained their anti-toxic, anti-carcinogenic and anti-mutagenic effects. A synthetic derivative compound of Schisandrin called DDB has most of the above mentioned actions now used widely in China as a hepato-protective drug with high effectiveness in normalizing liver functions and very low side effects. From natural Schisandrin to synthesized DDB, pointed out a successful way in the development of new drugs from natural products.

Alanine Transaminase↗
PubMed1994

UV-A coexposure enhances the toxicity of aromatic hydrocarbons, munitions, and metals to Photobacterium phosphoreum.

Johnson et al. (1993) showed that coexposure to UV-A between 300-400 nm enhanced the toxicity of nitrotoluenes to Photobacterium phosphoreum, a marine bioluminescent bacteria used in the Microtox test (Microbics Inc.). This paper reports that UV-A photoenhanced the toxicity of polynuclear aromatic hydrocarbons, other types of organic compounds, and some transition metals to P. phosphoreum. Coexposure to 400 muw/cm2 for 15 min increased the toxicity of psoralen, alpha-terthienyl, anthracene, acridine, fluoranthene, TNT, Cu2-, As3-, Ni2, and Cd2+. Phenanthrene was photoenhanced after 30 min coexposure at 400 muw/cm2-, and Mn2+ at 800 muw/cm2 after 15 min. Naphthalene was not enhanced at 800 muw/cm2 for 30 min.

Metals↗
PubMed2002

Concise synthesis and transannular inverse electron demand Diels-Alder reaction of [3](3,6)pyridazino[3](1,3)indolophane. Rapid access to a pentacyclic indoloid system.

[reaction: see text] The title compound was synthesized concisely from indole. A 2-fold sequential hydroboration/Suzuki-Miyaura cross-coupling was employed to generate the cyclophane. When heated in N,N-diethylaniline, it underwent a transannular inverse electron demand Diels-Alder (IEDDA) reaction to form a pentacyclic product, which appears to be well suited as a precursor to a variety of indole alkaloids such as strychnine.

Indicators and Reagents↗
PubMed2005

Dibenzocyclooctadiene lingnans: a class of novel inhibitors of P-glycoprotein.

PURPOSE: To determine if five dibenzocyclooctadiene lingnans, a class of naturally occurring compounds from Schisandra chinensis (Turcz.) Baill, have the activities to reverse P-glycoprotein (P-gp) mediated multidrug resistance (MDR). METHODS: The IC(50)s of four MDR cell lines (K562/Adr, MCF-7/Adr, KBv200, and Bcap37/Adr) toward daunorubicin, vincristine, and paclitaxel in the presence or absence of one of the dibenzocyclooctadiene lingnans were determined by a FACscan assay. The intracellular daunorubicin accumulation in the four MDR cell lines was determined by incubation of cells with daunorubicin (2 microg/ml) in the presence or absence of one of the dibenzocyclooctadiene lingnans by a FACscan assay. The interaction of the five dibenzocyclooctadiene lingnans with P-gp was assayed by their inhibition of (3)H-azidopine photoaffinity labeling of P-gp. RESULTS: Among the five lingnans, while schisandrin A and B, and schisantherin A demonstrated strong and comparable activities to reverse the drug resistance and the intracellular drug accumulation in four MDR cell lines, schisandrol A and B showed very limited activities. The poor activities of schisandrol A and B are possibly caused by the hydroxyl groups on the cyclooctadiene ring, because the activities of the molecules resumed when the hydroxyl group was esterified to form a benzoate. Further studies demonstrated that these compounds physically interacted with P-gp. CONCLUSION: Schisandrin A and B, and schisantherin A are potent P-gp inhibitor and is of potential for future clinical application.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1987

Binding of polynuclear aromatic hydrocarbons to the rat 4S cytosolic binding protein: structure-activity relationships.

The relative competitive binding affinities of benzo[a]pyrene (B[a]P), benzo[e]pyrene, benzo[g, h, i]perylene, picene, 7,12-dimethylbenz [a]anthracene, 1,2,3,4-dibenz[a]anthracene, 1,2,5,6-dibenz[a]anthracene, perylene, 4H-cyclopenta[d,e,f]-phenanthrene, benz[a] anthracene, triphenylethylene and triptycene for the rat hepatic cytosolic 4S binding protein were determined using [3H]benzo[a]pyrene as the radioligand. With the exception of triphenlethylene, triptycene and 4H-cyclopenta[d,e,f]phenanthrene, the EC50 values for the remainder of these compounds were between 1.25 X 10(-7) and 2.5 X 10(-8) M with 1,2,5,6-dibenz[a]anthracene being the most active ligand. A comparison of the relative cytosolic Ah (9S) receptor binding affinities and aryl hydrocarbon hydroxylase (AHH) induction potencies of these hydrocarbons with their 4S protein binding affinities demonstrated the following: five compounds, namely 1,2,5,6-dibenz[a]-anthracene, 1,2,3,4-dibenz[a]anthracene, picene, benzo[a]pyrene and 3-methylcholanthrene exhibited high to moderate binding affinities for the 4S and 9S cytosolic proteins (EC50 values less than 10(-6) M) and induced AHH in rat hepatoma cells; three compounds, namely perylene, benzo[e]pyrene and benzo[g,h,i]perylene exhibited high affinities for the 4S binding protein (1.25 X 10(-7), 4.4 X 10(-8) and 2.9 X 10(-8) M, respectively) and low affinities (EC50 values greater than 10(-5) M) for the Ah receptor protein; moreover these three compounds did not induce AHH in rat hepatoma H-4-II E cells in culture. These data suggest that the 4S binding protein may not play a significant role in AHH induction although the results do not rule out a function for this protein in the transregulation of AHH and its associated cytochromes P-450.

Animals↗
PubMed1991

Gas chromatographic-mass spectrometric analysis of tar compounds formed during pyrolysis of rice husks.

Pyrolysis of agricultural waste to produce fuel gas involves formation of tars as noxious by-products. In this paper the qualitative analysis of tars formed during pyrolysis of rice husks is presented, based on identification by gas chromatography-mass spectrometry and interpolation of retention times on a polyaromatic hydrocarbon index scale. The influence of some reaction parameters on product formation is briefly discussed.

Gas Chromatography-Mass Spectrometry↗
PubMed1986

Hydrocarbons and aromatic hydrocarbons in groundwater surrounding an earthen waste disposal pit for produced water in the Duncan oil field of New Mexico.

Samples of groundwater and soil were collected from test pits placed 25 m intervals on five axes extending from an earthen waste disposal pit for produced water near the San Juan River of northwest New Mexico. Samples were obtained at depths of 1.2 to 1.5 m and were analyzed using GC and GC/MS techniques for purgable hydrocarbons, including benzenes, and for solvent extractable organic compounds. Water samples from test pits down-gradient from the disposal pit contained purgable and extractable hydrocarbons that were similar to contents of the waste disposal pit. In contrast, water samples obtained from test pits up-gradient from the waste pit were free of detectable organic components. Major purgable components in the waste pit and in surrounding groundwater included saturated/unsaturated hydrocarbons and aromatic/alkylated aromatic hydrocarbons. Samples collected 25 m from the waste pit contained concentrations of all compounds greater than in samples taken at 50 m in distance on the same exis. Total concentration of purgable aromatic hydrocarbons in groundwater from test plots ranged from a high of 200 ppb at 25 m, to a low of 12 ppb at 50 m on an axis through the plume center.

Fuel Oils↗
PubMed1981

Inhibition of metabolic cooperation between mammalian cells in culture by tumor promoters.

The influence of phorbol-related tumour promoters and non-promoters on metabolic cooperation between wild-type and mutant Chinese hamster cells has been studied. The recovery, in medium containing 8-azaguanine, of hypoxanthine phosphoribosyl transferase-deficient (HPRT-) V79 cells co-cultured with an excess (2 x 10(6) per 9 cm petri-dish) of wild-type cells was determined in the presence and absence of each compound. Under the latter conditions (solvent treatment only) metabolic cooperation consistently reduced the cloning efficiency of HPRT- cells to approximately 10% of that in cultures without wild-type cells. However, 12-O-tetradecanoyl-phorbol-13-acetate (TPA), the most potent known tumour promoter, almost totally reversed the effect of wild-type cells on mutant recovery when included in the medium at concentrations as low as 1 nM. TPA also markedly enhanced the expression, in crowded cultures, of HPRT- mutants induced by the carcinogen N-methyl-N-nitrosourea. This property was not shared by other phorbol esters which are inactive as tumour promoters, or by polycyclic aromatic hydrocarbons, but was exhibited to a lesser degree by mezerein, a diterpene ester of significant but weaker promoting activity than TPA. Confirmation that the effect of TPA on mutant expression is the result of inhibition of metabolic cooperation was obtained in experiments using autoradiography, which showed that low doses are able to block the transfer of [3H]-uridine nucleotides from prelabelled V79 cells to unlabelled V79 cells in contact. These findings have prompted us to formulate a working hypothesis for the mode of action of TPA in vivo as a tumour promoter based on its interference with this type of intercellular communication.

Carcinogens↗
PubMedDate not supplied

Role of the lung in total body clearance of circulating drugs.

Attention in recent years has focused upon the ability of lung to accumulate and/or to metabolise circulating hormones, drugs and other xenobiotic agents. Although often studied in broken cell preparations, such functions must be examined in intact lung before extrapolation to the situation in vivo is possible. The role of lung in total body clearance of xenobiotic agents is often considered to be small, as compared with the liver it usually has much lower concentrations of degradative enzymes and a smaller mass. However, consideration of such factors as organ blood flow or stimulation of drug metabolising enzymes suggests that the contribution of the lung to total body clearance of some drugs is greater than previously recognised. This may explain some of the alterations in drug clearance seen clinically. For example, cigarette smoking may increase the clearance of certain xenobiotic compounds by stimulating pulmonary drug metabolising enzymes. Pulmonary drug disposition may also be altered by conditions affecting cardiac output, such as exercise, hypoxia, and circulatory shock, or those affecting acid-base balance, such as hyperventilation. In addition, pneumotoxicants may affect pulmonary clearance of circulating drugs and xenobiotics.

Animals↗
PubMed1994

Hispidospermidin, a novel phospholipase C inhibitor produced by Chaetosphaeronema hispidulum (Cda) Moesz NR 7127. II. Isolation, characterization and structural elucidation.

Hispidospermidin (1) is a novel phospholipase C inhibitor produced by Chaetosphaeronema hispidulum (Cda) Moesz NR 7127. Its structure (C25H47N3O) has been elucidated as a cage compound with a trimethylspermidine side chain based on various NMR studies, including 1H-1H COSY, 13C-1H COSY, HOHAHA, HMBC, COLOC and long range J C-H resolved 2D spectroscopy. The absolute configuration of 1 has been elucidated by modified Mosher's method on the (R)- and (S)-MTPA amides of a derivative of 1.

Chaetomium↗
PubMed2005

Synthesis of diindeno-fused 4H-cyclopenta[def]phenanthren-4-ones and related compounds via benzannulated enediynyl propargylic alcohols.

[reaction: see text] Treatment of propargylic diols 5-7 with thionyl chloride promoted a cascade sequence of reactions leading to dichlorides 10-12 and, after reduction with tributyltin hydride, the diindeno-fused 4H-cyclopenta[def]phenanthrenes 13-15 in a single operation. Hydrolysis of 13 and 14 furnished 4H-cyclopenta[def]phenanthren-4-ones 16 and 17, respectively. Air oxidation of an alkaline solution of dichloride 11 produced diketone 18.

Alcohols↗