[COMPARATIVE TOXICITY OF CHLORIDE COMPOUNDS OF TOLUENE: BENZYL CHLORIDE, BENZAL CHLORIDE AND BENZOTRICHLORIDE].
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Animals↗
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Carcinogenicity of benzyl chloride, benzal chloride, benzotrichloride and benzoyl chloride in mice by skin application.
The carcinogenicity of benzyl chloride (BYC), benzal chloride (BAC), benzotrichloride (BTC) and benzoyl chloride (BOC), which were suspected as causative agents of lung cancer and maxillary malignant lymphoma of workers employed in factories producing BOC, was examined by skin applications in female ICR mice. After rather high dose exposure, BTC exhibited leukemogenic and pulmonary tumorigenic activities as well as potent dermal carcinogenic activity. After administration of the chemicals at the dose of 2.3 microliter/animal, twice a week for 50 weeks, BTC induced 68% incidence of skin cancers and 58% incidence of pulmonary tumors (including 10% of lung carcinomas) within 399 days. Incidence of skin cancers was 58% for BAC, 15% for BYC and 10% for BOC within 560 days. Considering the extent of possible exposure of the workers to these chemicals in the working environment and the carcinogenic potency of the chemicals tested, it can be concluded that BTC was very probably responsible for causing the cancers seen int he workers employed in manufacturing BOC.
Animals↗
[A study on determination of occult blood with leucomalachite green (author's transl)].
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Aniline Compounds↗
3,5-Bis-benzylidene-4-piperidones and related compounds with high activity towards P388 leukemia cells.
3,5-Bis(benzylidene)-4-piperidones and related compounds were prepared and found to have between 100 and 9700 times the activity of N,N'-bis(2-chloroethyl)-N-nitrosourea towards P388 leukemia cells. The shapes of six of these molecules--determined by X-ray crystallography--were compared, but no correlation between the stereochemistry of the molecules or their electronic properties and cytotoxicity was apparent. Molecular modification of the compounds by forming two mono-benzylidene compounds, a related acyclic derivative and an N-acyl compound resulted in diminished but retained high cytotoxicity. Two representative compounds lowered glutathione levels of liver following their intraperitoneal injection into mice. Two quaternary ammonium compounds were shown to bind in the minor groove of DNA, while four related non-quaternary ammonium derivatives did not demonstrate this property. We conclude that the modes of action of these highly cytotoxic compounds include alkylation of cellular thiols and DNA binding, but interference with other biochemical processes is also probably involved.
Animals↗
[The search for new compounds with anticonvulsant action in the 5-benzylidene derivatives of 3-o, 3-m and 3-p-chlorophenylhydantoin].
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Animals↗
Synthesis and antitumor activity of 10-substituted benzylidene anthrone.
Fifteen compounds of 10-substituted benzylidene anthrone were prepared with moderate yield by reaction of anthrone and substituted benzaldehydes under the presence of pyridine and piperidine as catalyst. Their antitumor activities in vitro were evaluated. The results show that the electron-withdrawing substitutes decrease the activities, the electron-donor substitutes increase the activities; the compound with substitute at ortho or para position has stronger activities than that of compound with the same substitute but located at the meta position. There are six compounds which appear as strong effective inhibition for A-549 cancer cell growth. This is a kind of good leading compound which is worth researching further.
Anthracenes↗
Alpha7 nicotinic receptor mediated protection against ethanol-induced cytotoxicity in PC12 cells.
Ethanol caused a concentration-dependent loss of PC12 cells over a 24 h interval, accompanied by an increase in intracellular calcium. The specific alpha7 nicotinic receptor partial agonist DMXB attenuated both of these ethanol-induced actions at a concentration (3 microM) found previously to protect against apoptotic and necrotic cell loss. The alpha7 nicotinic receptor antagonist methylylaconitine blocked the neuroprotective action of DMXB when applied with but not 30 min after the agonist. These results indicate that activation of alpha7 nicotinic receptors may be therapeutically useful in preventing ethanol-neurotoxicity.
Aniline Compounds↗
Inhibition of tumor necrosis factor-induced cell death in MCF7 by a novel inhibitor of neutral sphingomyelinase.
A high throughput screen for neutral, magnesium-dependent sphingomyelinase (SMase) was performed. One inhibitor discovered in the screen, GW4869, functioned as a noncompetitive inhibitor of the enzyme in vitro with an IC(50) of 1 microm. It did not inhibit acid SMase at up to at least 150 microm. The compound was then evaluated for its ability to inhibit tumor necrosis factor (TNF)-induced activation of neutral SMase (N-SMase) in MCF7 cells. GW4869 (10 microm) partially inhibited TNF-induced sphingomyelin (SM) hydrolysis, and 20 microm of the compound was protected completely from the loss of SM. The addition of 10-20 microm GW4869 completely inhibited the initial accumulation of ceramide, whereas this effect was partially lost at later time points (24 h). These data therefore support the inhibitory action of GW4869 on N-SMase not only in vitro but also in a cellular model. The addition of GW4869 at both 10 and 20 microm did not modify cellular glutathione levels in response to TNF, suggesting that the action of GW4869 occurred downstream of the drop in glutathione, which was shown previously to occur upstream of the activation of N-SMase. Further, whereas TNF treatment also caused a 75% increase of de novo synthesized ceramide after 20 h of incubation, GW4869, at either 10 or 20 microm, had no effect on this pathway of ceramide generation. In addition, GW4869 did not significantly impair TNF-induced NF-kappaB translocation to nuclei. Therefore, GW4869 does not interfere with other key TNF-mediated signaling effects. GW4869 was able, in a dose-dependent manner, to significantly protect from cell death as measured by nuclear condensation, caspase activation, PARP degradation, and trypan blue uptake. These protective effects were accompanied by significant inhibition of cytochrome c release from mitochondria and caspase 9 activation, therefore localizing N-SMase activation upstream of mitochondrial dysfunction. In conclusion, our results indicate that N-SMase activation is a necessary step for the full development of the cytotoxic program induced by TNF.
Aniline Compounds↗
Biochemical properties of mammalian neutral sphingomyelinase 2 and its role in sphingolipid metabolism.
Neutral sphingomyelinase (N-SMase) is one of the key enzymes involved in the generation of ceramide; however, the gene(s) encoding for the mammalian N-SMase is still not well defined. Previous studies on the cloned nSMase1 had shown that the protein acts primarily as lyso-platelet-activating factor-phospholipase C. Recently the cloning of another putative N-SMase, nSMase2, was reported. In this study, biochemical characterization of the mouse nSMase2 was carried out using the overexpressed protein in yeast cells in which the inositol phosphosphingolipid phospholipase C (Isc1p) was deleted. N-SMase activity was dependent on Mg(2+) and was activated by phosphatidylserine and inhibited by GW4869. The ability of nSMase2 to recognize endogenous sphingomyelin (SM) as substrate was investigated by overexpressing nSMase2 in MCF7 cells. Mass measurements showed a 40% decrease in the SM levels in the overexpressor cells, and labeling studies demonstrated that nSMase2 accelerated SM catabolism. Accordingly, ceramide measurement showed a 60 +/- 15% increase in nSMase2-overexpressing cells compared with the vector-transfected MCF7. The role of nSMase2 in cell growth was next investigated. Stable overexpression of nSMase2 resulted in a 30-40% decrease in the rate of growth at the late exponential phase. Moreover, tumor necrosis factor induced approximately 50% activation of nSMase2 in MCF7 cells overexpressing the enzyme, demonstrating that nSMase2 is a tumor necrosis factor-responsive enzyme. In conclusion, these results 1) show that nSMase2 is a structural gene for nSMase, 2) suggest that nSMase2 acts as a bona fide N-SMase in cells, and 3) implicate nSMase2 in the regulation of cell growth and cell signaling.
Aniline Compounds↗
Effect of beta-glucuronidase inhibitor on azoxymethane-induced colonic carcinogenesis in rats.
In this study of the role of microfloral beta-glucuronidase in colonic carcinogenesis, the effect of beta-glucuronidase inhibitor was evaluated. Starting at 5 weeks of age, male Donryu rats were fed either a semisynthetic diet or the same diet containing 0.1% beta-glucuronidase inhibitor as N-cyclohexyl-5-O-acetyl-2,4-O-p-methoxybenzylidene) -D-glucaro-1-amide-6,3-lactone (C-GAL). All animals were given s.c. injections of 7.4 mg azoxymethane (AOM) per kg body weight once a week for 11 weeks and followed for an additional 20 weeks. Most animals receiving the colonic carcinogen developed tumors in the colon, and a few also developed tumors in the small intestine. However, the number of tumors in the large intestine of the rats given C-GAL at the same time as AOM was significantly lower than in the control rats, especially in the proximal half of the colon, but those given C-GAL after AOM treatment had almost the same number of colon tumors as did the controls. It is concluded that, since bacterial beta-glucuronidase activity in the feces of rats given 0.1% C-GAL was significantly inhibited, intestinal microfloral beta-glucuronidase may play an important role in colonic carcinogenesis caused by AOM.
Animals↗
Molecular modelling and biological evaluation of a series of hydroxylated benzylideneanilines and benzylamines designed as tyrosine kinase inhibitors.
A series of hydroxylated benzylideneanilines and benzylamines were prepared and tested for inhibition of epidermal growth factor receptor-associated protein tyrosine kinase (PTK) activity in vitro. Molecular modelling and analysis of the biological results lead us to propose a minimal structural pharmacophore for two distinct binding sites within the PTK domain.
Aniline Compounds↗
Substituent cross-interaction effects on the electronic character of the C=N bridging group in substituted benzylidene anilines--models for molecular cores of mesogenic compounds. A 13C NMR study and comparison with theoretical results.
13C NMR chemical shifts delta(C)(C=N) were measured in CDCl3 for a wide set of mesogenic molecule model compounds, viz. the substituted benzylidene anilines p-X-C6H4CH=NC6H4-p-Y (X = NO2, CN, CF3, F, Cl, H, Me, MeO, or NMe2; Y = NO2, CN, F, Cl, H, Me, MeO, or NMe2). The substituent dependence of delta(C)(C=N) was used as a tool to study electronic substituent effects on the azomethine unit. The benzylidene substituents X have a reverse effect on delta(C)(C=N): electron-withdrawing substituents cause shielding, while electron-donating ones behave oppositely, the inductive effects clearly predominating over the resonance effects. In contrast, the aniline substituents Y exert normal effects: electron-withdrawing substituents cause deshielding, while electron-donating ones cause shielding of the C=N carbon, the strengths of the inductive and resonance effects being closely similar. Additionally, the presence of a specific cross-interaction between X and Y could be verified. The electronic effects of the neighboring aromatic ring substituents systematically modify the sensitivity of the C=N group to the electronic effects of the benzylidene or aniline ring substituents. Electron-withdrawing substituents on the aniline ring decrease the sensitivity of delta(C)(C=N) to the substitution on the benzylidine ring, while electron-donating substituents have the opposite effect. In contrast, electron-withdrawing substituents on the benzylidene ring increase the sensitivity of delta(C)(C=N) to the substituent on the aniline ring, while electron-donating substituents act in the opposite way. These results can be rationalized in terms of the substituent-sensitive balance of the electron delocalization (mesomeric effects). The present NMR characteristics are discussed as regards the computational literature data. Valuable information has been obtained on the effects of the substituents on the molecular core of the mesogenic model compounds.
Aniline Compounds↗
Effect on protein synthesis and cell survival of the benzaldehyde derivatives sodium benzylidene ascorbate (SBA) and the deuterated compound zilascorb(2H).
Three different benzaldehyde derivatives (viz. beta-cyclodextrin benzaldehyde inclusion compound (CDBA), 4, 6-O-benzylidene-D-glucose (BG) and sodium benzylidene-ascorbate (SBA) have been shown to exert anticancer effects in patients without causing side effects. The anticancer effects are, however, variable and in many cases weak. In a previous study we showed that benzaldehyde with a deuterated formyl group gave rise to a greater protein synthesis inhibition than nondeuterated benzaldehyde. Based on this deuterated benzaldehyde we have synthesized an ascorbic acid acetal; 5,6-benzylidene-d1-L-ascorbic acid (zilascorb(2H). In the present paper we compare the effect of this drug with respect to cell inactivation and inhibition of protein synthesis in human cells cultured in vitro with that of benzaldehyde, BG and SBA. It is shown that zilascorb (2H) is clearly the most effective of these drugs. The effect of zilascrob(2H) is reversible in the sense that protein synthesis regains its normal level shortly (i.e. within 1h) after removal of the drug. Even after protracted treatment inducing a cell kill of more than 99%, the few survivors appear to be without damage after removal of the drug.
Antineoplastic Agents↗
C-H...pi, pi-pi and C-H...Cl interactions in chloro-substituted Schiff bases and 4-chloro-N-[4-(dimethylamino)benzylidene]aniline.
Molecular packing analyses were carried out on 15 crystal data sets of chloro-substituted Schiff bases, including that of the title compound, C15H15ClN2. C-H...pi and pi-pi interactions play a major role in the molecular self-assembly in the crystal. The former interactions favor molecules assembling into a screw, with a non-centrosymmetric crystal structure. When the molecular dipole is small, pi-pi interactions favor a parallel, but not usually antiparallel, mode of packing. Weak C-H...X hydrogen bonds (X = Cl or Br) and X...X interactions seem to be a secondary driving force in packing. The title molecule takes the trans form and the two benzene rings are twisted around the central linkage in opposite directions. In the crystal structure, molecules interact through C-H...pi and pi-pi interactions, forming a 'dimer' and further forming double chains along [001]. The double chains are extended along [101] through C-H...Cl hydrogen bonds, forming double layers in (010). In the third direction, there are only ordinary, weaker, van der Waals interactions, which explains the crystal habit (i.e. thin plate).
Aniline Compounds↗
Immunosuppression by delta-opioid antagonist naltrindole: delta- and triple mu/delta/kappa-opioid receptor knockout mice reveal a nonopioid activity.
The delta-opioid antagonist naltrindole has been shown to inhibit graft rejection in vivo and suppress allogeneic mixed lymphocyte reaction (MLR) in vitro, similarly to cyclosporin A. We investigated whether this action is mediated by delta-opioid receptors using both genetic and pharmacological tools. Naltrindole and two related compounds, 7-benzylidene-7-dehydronaltrexone and naltriben, inhibited MLR performed with lymphocytes from wild-type and delta-opioid receptor knockout mice, with comparable potency. Furthermore, these compounds suppressed the proliferation of spleen cells from triple delta/mu/kappa-opioid receptor-deficient animals as well. Finally, the highly delta-selective, but structurally distinct, antagonist N,N-dimethyl-Dmt-Tic-OH and the general opioid antagonist naltrexone were inactive in the MLR assay. In conclusion, we demonstrate for the first time that the immunosuppressive activity of naltrindole and close derivatives is not mediated by any of the three cloned opioid receptors. Therefore, the postulated inhibitory activity of naltrindole in the graft rejection process is mediated by a target, which remains to be discovered.
Animals↗
Formation of the corannulene core by nickel-mediated intramolecular coupling of benzyl and benzylidene bromides: a versatile synthesis of dimethyl 1,2-corannulene dicarboxylate.
[reaction: see text] A practical synthesis of dimethyl 1,2-corannulene dicarboxylate (5) is reported, with the final ring-forming step achieved by the double intramolecular nickel powder mediated coupling of benzyl and benzylidene bromide groups with 60% isolated yield.
Benzyl Compounds↗
Synthesis of methyl alpha-glycosides of some higher oligosaccharide fragments of the O-antigen of Vibrio cholerae O1, serotype Inaba and Ogawa.
The title oligosaccharides, the tri- through the hexasaccharide in the Inaba series and the penta- and the hexasaccharide in the Ogawa series, have been synthesized using 1-thioglycosides of precursors to 3-O-benzyl-perosamine (4-amino-4,6-dideoxy-D-mannose) as building blocks and N-iodosuccinimide/silver triflate as a promoter. The azido groups in the assembled oligosaccharides were reduced to amino groups, which were then acylated using 2,4-O-benzylidene-3-deoxy-L-glycero-tetronic acid as the derivatizing reagent. Catalytic hydrogenolysis, simultaneously of the benzyl and benzylidene groups, gave the desired products that were characterized by 1H and 13C NMR spectroscopy.
Acylation↗
[Pyrazolidine-diones. II. Synthesis of benzylidene, of benzyl pyrazolidine-3,5-diones and 4-spiro cyclopropyl pyrazolidine-3,5-diones (author's transl)].
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Anti-Inflammatory Agents↗