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PubMed1989

Oligomers with pendant isocyanate groups as tissue adhesives. I. Synthesis and characterization.

A series of methacrylate oligomers containing pendant isocyanate groups were synthesized by reacting 2-isocyanatoethyl methacrylate (IEM) and/or m-isopropenyl-alpha, alpha-dimethylbenzyl isocyanate (TMI) in ethoxyethyl acetate with methacrylates ranging from methyl to stearyl methacrylate or allyl-, cyclohexyl-, glycidyl-, i-bornyl-, or dicyclopentenyloxyethyl methacrylate. The oligomers which are stable at room temperature were characterized by IR for NCO, ester, and C = C groups and by their refractive indices. They have a small number of residual double bonds and a molecular weight low enough so that the compounds are liquids at room temperature and dissolve readily in esters and chlorinated hydrocarbons. HPLC showed no residual monomer. GPC and intrinsic viscosity of selected oligomers indicated a molecular weight range from 1400 to 2600. Isocyanate groups were determined titrimetrically and ranged from 15.9% to 5.1%. Concurrent studies have demonstrated that these oligomers bond strongly to hard and soft tissues. Thus, subject to their biocompatibility they could find many applications as tissue adhesives.

Acrylates↗
PubMed1979

[Comparative investigations on the organotropic carcinogenic effect of different N-nitroso compounds with rat after single and chronic treatment (author's transl)].

After the gavage of 200 mg N-nitrosodiethylamine per kg body weight only kidney tumors developed while long-term administration of 10 ppm N-nitrosodiethylamine induced esophageal tumors and hepatocellular carcinomas in female rats (SIV 50). This change of the organ-specific carcinogenic effect is not observed in experiments with N-methyl-N-nitrosobenzylamines substituted with a methyl group at the phenyl moiety. Both chronic treatment and single doses induced tumors of the esophagus and the pharynx.

Animals↗
PubMed2004

Structure-activity relationship of S-benzylisothiourea derivatives to induce spherical cells in Escherichia coli.

We have previously reported that a novel S-benzylisothiourea derivative, S-(3,4-dichlorobenzyl)isothiourea, tentatively named A22, induced spherical cells in Escherichia coli. To elucidate the structural element(s) required for inducing these spherical cells, the biological activity of S-benzylisothiourea derivatives and related compounds toward E. coli cells was investigated. S-(4-Chlorobenzyl)isothiourea revealed spherical cell-inducing activity, although being slightly less potent than A22, and S-benzylisothiourea itself showed much less activity. S-Cyclohexylmethylisothiourea did not show antibacterial activity and had little effect on the cell shape. S-Heptylisothiourea showed antibacterial activity and induced elongated cells rather than spherical cells. Benzylisothiocyanate inhibited cell growth but did not induce spherical cells. S-Ethylisothiourea, benzylthiocyanate, benzylisocyanate, and N-phenylthiourea did not show any activity under the present experimental conditions. These results indicate that the S-benzylisothiourea structure was necessary and sufficient for inducing spherical cells and that 3- and/or 4-chloro-substitution of the S-benzyl group enhanced this activity.

Bacteria↗
PubMed2005

Effect of repeated systemic administration of selective inhibitors of endocannabinoid inactivation on rat brain endocannabinoid levels.

Several selective inhibitors of endocannabinoid inactivation via either the fatty acid amide hydrolase (FAAH) or the putative endocannabinoid transporter have been developed so far. Here, we have studied the effect in rats of a subchronic intraperitoneal treatment with three recently developed selective inhibitors of endocannabinoid uptake (VDM-11, UCM-707 and OMDM-2) or with a selective FAAH inhibitor (N-arachidonoyl-serotonin, AA-5-HT), on the brain levels of anandamide and 2-arachidonoylglycerol (2-AG) measured by means of isotope dilution LC-MS 1, 5 and 12 h after the last treatment. OMDM-2 was the most efficacious compound at enhancing the levels of anandamide at all time points, with a maximal effect (1.9-fold enhancement) after 5h. This compound also enhanced 2-AG levels by approximately 1.3-fold, but only 5 and 12h from administration. VDM-11 slightly, albeit significantly, enhanced anandamide levels (1.3-fold) only at 1h from administration and 2-AG levels (1.3-fold) only after 5h. Finally, UCM-707 only affected 2-AG levels (by two-fold) at only 1h from administration. FAAH inhibition by AA-5-HT significantly enhanced the levels of both anandamide (between 1.3- and 1.5-fold, maximal effect after 1 h) and 2-AG (between 1.3- and 1.6-fold, maximal effect after 12 h) at all time points. Brains from rats treated with AA-5-HT did never exhibit enhanced levels of serotonin, thus pointing to the metabolic stability of this FAAH inhibitor. These data indicate that: (1) the pharmacological effects reported so far for the four compounds under study in animal models of diseases may be due to enhancement of both anandamide and 2-AG levels; (2) 2-AG seems to need a longer time after the last administration in order to be augmented; (3) OMDM-2 and AA-5-HT should be regarded as enhancers of endocannabinoid levels suitable for use in vivo.

Animals↗
PubMed2005

Preparation and biological activity of 6-benzylaminopurine derivatives in plants and human cancer cells.

To study the structure-activity relationships of aromatic cytokinins, the cytokinin activity at both the receptor and cellular levels, as well as CDK inhibitory and anticancer properties of 38 6-benzylaminopurine (BAP) derivatives were compared in various in vitro assays. The compounds were prepared by the condensation of 6-chloropurine with corresponding substituted benzylamines. The majority of synthesised derivatives exhibited high activity in all three of the cytokinin bioassays employed (tobacco callus, wheat senescence and Amaranthus bioassay). The highest activities were obtained in the senescence bioassay. For some compounds tested, significant differences of activity were found in the bioassays used, indicating that diverse recognition systems may operate and suggesting that it may be possible to modulate particular cytokinin-dependent processes with specific compounds. Position-specific steric and hydrophobic effects of different phenyl ring substituents on the variation of biological activity were confirmed. In contrast to their high activity in bioassays, the BAP derivatives were recognised with much lower sensitivity than trans-zeatin in both Arabidopsis thaliana AHK3 and AHK4 receptor assays. The compounds were also investigated for their effects on cyclin-dependent kinase 2 (CDK2) and for antiproliferative properties on cancer and normal cell lines. Several of the tested compounds showed stronger inhibitory activity and cytotoxicity than BAP. There was also a significant positive correlation of the inhibitory effects on human and plant CDKs with cell proliferation of cancer and cytokinin-dependent tobacco cells, respectively. This suggests that at least a part of the antiproliferative effect of the new cytokinins was due to the inhibition of CDK activity.

Animals↗
PubMed2004

In vivo pharmacological actions of two novel inhibitors of anandamide cellular uptake.

Two inhibitors of the cellular uptake of the endocannabinoid anandamide, (R)-N-oleoyl-(1'-hydroxybenzyl)-2'-ethanolamine and (S)-N-oleoyl-(1'-hydroxybenzyl)-2'-ethanolamine (OMDM-1 and OMDM-2, respectively), were recently synthesized, and their in vitro pharmacological activity described. Here we have assessed their activity in two typical pharmacological responses of cannabimimetic compounds. We first examined whether these compounds exert any effect per se on locomotion and pain perception in rats, and/or enhance the effects of anandamide on these two processes. We compared the effects of the novel compounds with those produced by a previously developed selective inhibitor, N-arachidonoyl-(2-methyl-4-hydroxyphenyl)amine (VDM-11). When assayed alone, OMDM-1 and OMDM-2 (1-10 mg/kg, i.p.) did not affect any of the five motor parameters under investigation, although the former compound exhibited a trend for the inhibition of ambulation, fast movements, and speed in rats. OMDM-2 and, to a lesser extent, VDM-11 (5 mg/kg, i.p.) enhanced the motor-inhibitory effects of a noneffective dose (2 mg/kg, i.p.) of anandamide, while OMDM-1 did not. In a typical test of acute analgesia, OMDM-2 and VDM-11 (1-10 mg/kg, i.p.), but not OMDM-1, significantly enhanced the time spent by rats on a "hot plate." However, the same compounds (5 mg/kg, i.p.) did not enhance the analgesic effect of a subeffective dose (2 mg/kg, i.p.) of anandamide, whereas OMDM-1 exerted a strong trend towards potentiation (P=0.06). We next explored the possible use of the two novel compounds in a pathological condition. Thus, we determined if, like other previously developed anandamide reuptake inhibitors, OMDM-1 and OMDM-2 inhibit spasticity in an animal model of multiple sclerosis-the chronic relapsing experimental allergic encephalomyelitis in mice. As previously shown with a higher dose of VDM-11, both novel compounds (5 mg/kg, i.v.) significantly reduced spasticity of the hindlimb in mice with chronic relapsing experimental allergic encephalomyelitis. We suggest that OMDM-1 and, particularly, OMDM-2 are useful pharmacological tools for the study of the (patho)physiological role of the anandamide cellular uptake process, and represent unique templates for the development of new antispastic drugs.

Animals↗
PubMed1990

Morphological transformation of Syrian hamster embryo cells by aminobenzyl alcohols and nitrobenzyl alcohols is correlated with intercellular communication.

Two aminobenzyl alcohols (ABAs) and 3 nitrobenzyl alcohols (NBAs) were studied in the Syrian hamster embryo (SHE) cell transformation system. All compounds induced statistically significant increases in morphological transformation of SHE cells. 2-ABA and 3-ABA induced dose-dependent increases in transformation, while the transformation frequencies for 2-NBA and 4-NBA decreased when concentrations were increased above 0.2 mM. When tested in an intercellular communication assay using dye transfer between SHE cells, 2-ABA inhibited communication, and 2-NBA and 4-NBA enhanced communication. Thus, the inverse dose-response of 2-NBA related to an increased intercellular communication.

Animals↗
PubMedDate not supplied

A comparison of the response to 4CMB, 4HMB and BC of 5 yeast strains differing in their radiosensitivities.

The test compounds 4CMB, 4HMB and BC were assayed for their genotoxicity using stationary phase cultures of 5 yeast strains which differ in their mutagen sensitivity. It was found that 4HMB produced no differences in survival between the 5 strains whereas 4CMB and BC caused more lethality in the triple red strain than the other 4 strains. The results indicate that both BC and 4CMB are capable of inducing DNA damage which results in cell lethality in the repair-deficient triple mutant.

Benzyl Compounds↗
PubMed1989

[Experimental methodology on pharmacological studies on crude drugs].

Properties of crude drugs are different from those of a pure synthetic compound which is prepared as a candidate for a newly developed drug in that; crude drugs are composed of innumerable ingredients and have at least some therapeutic efficacies. Accordingly, a pharmacological study of crude drugs resembles studying of a sample such as a complex combined preparation and a lot of problems upon pharmacological examination arises from properties inherent in crude drugs. In this review, these problems are discussed, being based on pharmacological studies which have been performed in several crude drugs.

Aconitine↗
PubMed1998

Effective treatment of models of multiple sclerosis by matrix metalloproteinase inhibitors.

The proinflammatory Th1 cytokine, tumor necrosis factor-alpha (TNF alpha), the cell death signaling molecule FasL, and several extracellular matrix degrading metalloproteinases have been implicated in the pathogenesis of multiple sclerosis (MS). The latter enzymes, as well as TNF alpha-converting enzyme and FasL-converting enzyme, can be blocked by matrix metalloproteinase inhibitors (MMPIs). In this study, we show that a potent MMPI was clinically effective in an animal model for MS, experimental autoimmune encephalomyelitis (EAE) in the SJL/J mouse. Efficacy was remarkable, as indicated by blocking and reversal of acute disease and reduced number of relapses and diminished mean cumulative disease score in chronic relapsing animals. Also, demyelination and glial scarring were significantly decreased in MMPI-treated mice with chronic relapsing EAE, as was central nervous system gene expression for TNF alpha and fasL. It is interesting that expression of the beneficial cytokine interleukin-4 (IL-4) was increased, and IL-4 was expressed on glial cells. The relevance of these compounds for MS was underscored by their ability to specifically inhibit TNF alpha shedding and cytotoxicity of myelin-autoreactive human cytotoxic CD4+ T-cell clones. This is the first report to show a positive effect by MMPIs on chronic relapsing EAE, its central nervous system cytokine profile, and on TNF alpha shedding by human myelin-autoreactive T cells.

Animals↗
PubMed2003

Evaluation of in vitro antifungal activity of N-benzylsalicylamide derivatives.

A series of 65 derivatives of N-benzylsalicylamide was tested against eight potentially human pathogenic fungi by microdilution broth method modified according to M27-A standard. The majority of these compounds showed only weak in vitro antifungal activity. The most significant effect was observed against filamentous fungi Trichophyton mentagrophytes, Absidia corymbifera, and Aspergillus fumigatus while yeasts, in general, were less susceptible. N-(4'-Chlorobenzyl) salicylamides, N-(3',4'-dichlorobenzyl)-salicylamides, and partially N-benzylsalicylamides exhibited relatively high in vitro antifungal activity. The most efficient derivatives had MIC < or = 7.8 mumol/L against T. mentagrophytes. Regression analysis suggested an indirect relationship between MIC values and lipophilicity (log P).

Antifungal Agents↗
PubMed1975

A pharmacologic comparison of histamine receptors in isolated extracranial and intracranial arteries in vitro.

Isolated segments of cat extracranial and intracranial arteries were tested simultaneously for circular motor activity in an aerated Krebs-Ringer organ bath at constant temperature and pH. Histamine produced a strong contraction (about 850 dyn) in the extracranial arteries but a considerably weaker contraction, with a high half maximum response, in the intracranial arteries. The mode of inhibition of the latter response by antihistaminic compounds (chlorpheniramine and mepyramine) showed the response to be nonspecific; the contraction in the extracranial arteries was inhibited in a competitive manner, demonstrating the presence of histamine H1 receptors. The dilatory response was studied after the vessels had been given a tonic contraction with serotonin. Histamine produced similar dilatory effects (about 200 dyn) in both types of arteries and competitive inhibitions were obtained with burimamide, showing that the dilation was mediated through histamine H2 receptors. Dissociation constants were calculated for the receptor-antagonist complex.

Animals↗
PubMed1992

7-Alkoxyquinoline O-dealkylation by microsomes from human liver and placenta.

1. The O-dealkylation of seven 7-alkoxyquinoline derivatives by human hepatic and placental microsomes and the effect of maternal cigarette smoking on placental 7-alkoxyquinoline metabolism was studied. 2. None of several monoclonal antibodies to isoenzymes of cytochrome P450 had a clear effect on metabolism of the compounds by liver microsomes. 3. Maternal cigarette smoking induced the O-dealkylation of all of the 7-alkoxyquinoline derivatives, being greatest for 7-butoxy- and 7-benzyloxyquinoline. 4. Placental 7-alkoxyquinoline metabolism induced by smoking was partially inhibited by the monoclonal antibody 1-7-1 raised against 3-methylcholanthrene-induced rat liver P450. 5. None of the 7-alkoxyquinoline O-dealkylations could be assigned specifically to any known P450 isoenzyme in human liver or placenta.

Animals↗
PubMed2006

New substrate analogue inhibitors of factor Xa containing 4-amidinobenzylamide as P1 residue: part 1.

The trypsin-like serine protease factor Xa (fXa) is located at the convergence point of the intrinsic and extrinsic coagulation cascade, and therefore has emerged as an attractive target for the design of novel anticoagulants. During the development of substrate-analogue urokinase inhibitors we have found that the protection of the P3-dSer side chain leads to a scaffold of potent fXa inhibitors with the general structure R1-SO2-dSer(R2)-Gly-4-amidinobenzylamide. The first lead (3) with an N-terminal benzylsulfonyl group and dSer(tBu) as P3 residue inhibits human fXa with a Ki of 14 nM. A variety of derivatives with modified P4, P3, and P2 residues have been investigated in terms of inhibition of fXa and related proteases and for their anticoagulant potency and elimination behaviour. Most inhibitors were rapidly cleared from the circulation of rats. However, compound 48 (Ki= 3.5 nM), one of the most potent and selective inhibitors containing a dArg as P3 residue was relatively slowly eliminated (t1/2 approximately 1 h). Inhibitor 48 doubled clotting times in human plasma at 0.32 microM (aPTT) and 0.28 microM (PT), and is approximately 10-fold more potent than the reference fXa inhibitor DX-9065a in the inhibition of the prothrombinase complex. The structures of two inhibitors in complex with human fXa were solved by X-ray crystallography.

Animals↗
PubMed1993

Perspective on the usefulness of the mouse lymphoma assay as an indicator of a genotoxic carcinogen: ten compounds which are positive in the mouse lymphoma assay but are not genotoxic carcinogens.

The mouse lymphoma assay is commonly included in batteries of tests for the mutagenic and carcinogenic potential of chemicals. Unlike other bacterial and mammalian cell tests, it has an unacceptably high incidence of false positive results. This paper reviews data on ten chemicals, all of which are positive in the mouse lymphoma assay but negative in all other genotoxicity tests. Three are non-genotoxic rodent carcinogens acting through a variety of secondary mechanisms, while seven are not carcinogenic. It is concluded that a positive mouse lymphoma assay alone cannot be a barrier to the human use of drugs and other chemicals.

Allylbenzene Derivatives↗
PubMed2005

A series of 5-(5,6)-dihydrouracil substituted 8-hydroxy-[1,6]naphthyridine-7-carboxylic acid 4-fluorobenzylamide inhibitors of HIV-1 integrase and viral replication in cells.

Introduction of a 5,6-dihydrouracil functionality in the 5-position of N-(4-fluorobenzyl)-8-hydroxy-[1,6]naphthyridine-7-carboxamide 1 led to a series of highly active HIV-1 integrase inhibitors. These compounds displayed low nanomolar activity in inhibiting both the strand transfer process of HIV-1 integrase and viral replication in cells. Compound 11 is a 150-fold more potent antiviral agent than 1, with a CIC(95) of 40 nM in the presence of human serum. It displays good pharmacokinetics when dosed in rats and dogs.

Animals↗
PubMed2006

Block copolymer micelles as matrixes for incorporating diselenide compounds: a model system for a water-soluble glutathione peroxidase mimic fine-tuned by ionic strength.

We report on the use of block copolymer micelles of polystyrene-b-poly(acrylic acid) (PS-b-PAA) as matrixes for incorporating dibenzyl diselenide. We found that the water-insoluble diselenide, after being incorporated into the micelles, demonstrates glutathione peroxidase (GPx) activity in water. Surprisingly, the mimicking system can be adjusted to show higher GPx activity by increasing the ionic strength of the solution simply upon addition of NaCl. Moreover, dibenzyl diselenide incorporated into the micelles is quite stable and maintains its GPx activity even after exposure to the atmosphere.

Acrylates↗
PubMed2005

Di-u-hydroxo-bis{(acetonitrile)dibenzyl(6-methyl-2-pyridylmethyl)-amine-kappa2N,N]copper(II)} bis(perchlorate).

The title compound corresponds to a copper(II) dimer, [Cu2(OH)2(C2H3N)2(C21H22N2)2](ClO4)2, where the metal centres are mu2-bridged by hydroxo groups. The coordination of each copper(II) centre is a slightly distorted square-based pyramid, with two N atoms from dibenzyl(6-methyl-2-pyridylmethyl)amine (BiBzMePMA) and two hydroxo O atoms occupying the basal positions, and the acetonitrile N atom at the apical position. The dimer is centrosymmetric, with a crystallographic inversion centre midway between the two Cu atoms [Cu...Cu = 2.9522 (9) A].

Acetonitriles↗