Biomedical subjects
C Viel
Publications and source records attributed to C Viel.
Efficient breakage of DNA apurinic sites by the indoleamine related 9-amino-ellipticine.
The aromatic amine, 9-NH2-ellipticine, is a synthetic DNA intercalating derivative of the antitumor agent ellipticine, which breaks circular DNA containing apurinic sites. This breakage is inhibited when the apurinic (AP) sites are reduced. The concentration of 9-NH2-ellipticine required to get a significant effect (0.1 microM) is the lowest known among chemicals which induce the same breakage reaction. Comparison with the action of structurally related amines shows that the amino-indole structure is specific for AP sites. The ability of ellipticine derivatives to induce breakage in DNA containing apurinic sites is related to the nucleophile substituent in position 9. Two ellipticine derivatives with known antitumor activity, BD 40 and 9-OH-ellipticine, were able to break purified DNA at apurinic sites.
[Vanadic oxidation of khellin. Study of its reactional mechanism].
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[Inhibition of lithogenesis by ethylphosphocitrate].
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[Iodo carboxamidino-1 phenyl-4 piperazine, a new adrenomedullary imaging agent: comparison with metaiodobenzylguanidine].
This report describes the comparison between two adrenal medulla imaging agents, mIBG and I-CPP. Biodistribution demonstrated an early and preferential uptake by both adrenal glands and heart and then storage in the adrenal gland of both agents, however I-CPP is less stable in vivo than mIBG. Reserpine depletion study in rat indicated that the I-CPP and mIBG uptake mechanisms are not similar.
Identification and molecular characterization of the isoquinoline rat intestinal binding site using 6,7-dimethoxy-4-(4'-amino-3'-[125I]iodobenzyl) isoquinoline.
The mechanism of the relaxant action of isoquinolines on smooth muscle is conjectural. In order to gain further insight into the intestinal action of isoquinolines, we have synthesized an isoquinoline derivative which can be radioiodinated, resulting in the obtention of a ligand with a high specific activity. 6,7-Dimethoxy-4-(4'-aminobenzyl) isoquinoline (DMABI) is an arylamine analogue of the most relaxating isoquinoline derivative, i.e., 6,7-dimethoxy-4-(4'-chlorobenzyl) isoquinoline. Its iodinated derivative, 6,7-dimethoxy-4-(4'-amino-3'-[125I]iodobenzyl) isoquinoline (125I-DMABI) binds reversibly to rat intestinal membranes. Binding is rapid, saturable, and temperature dependent. The binding of 125I-DMABI to intestinal membranes is competitively inhibited by identical concentrations of unlabeled DMABI or iodo-DMABI in the range between 10(-8) and 10(-5)M. Scatchard analysis indicates the existence of two classes of binding sites: a class with a low capacity (14 +/- 2 pmol/mg of protein) and a Kd = 0.10 +/- 0.02 microM, and a class with a high capacity (240 +/- 31 pmol/mg of protein) and a Kd = 8.0 +/- 1.1 microM. Specific binding of the radioiodinated ligand is inhibited by a variety of 4-benzyl isoquinolines and 1-benzyl isoquinolines. Structure-activity relationship demonstrates the primordial role of C-6 and C-7 methoxy groups and the important role of 4-benzyl on configuration related to the isoquinoline nucleus. A high significant correlation between competitive binding (Ki) and relaxant effect in rat intestine (IC50) is observed and strongly suggests that the isoquinoline-binding site mediates the pharmacologic response. Upon photolysis, this ligand incorporates irreversibly into rat intestinal membranes. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiography reveal a major 125I-DMABI-labeled protein with molecular weight of 36,000 and two minor proteins with molecular weights of 52,000 and 26,000. The labeling of these proteins is specific since it is completely abolished by 100 microM DMABI. Scanning of autoradiographs and integration of peaks show that the probe binds with the same apparent affinity to the three proteins. These findings indicate the utility of this novel high affinity radioiodinated probe as a tool for elucidating the mechanism of action of isoquinoline.
Metabolism of 6,7-dimethoxy 4-(p-chlorobenzyl)-isoquinoline. I. Single-dose pharmacokinetics in the rat and mouse.
The pharmacokinetics of 6,7-dimethoxy 4-(p-chlorobenzyl) isoquinoline (PV 2) in mouse and rat show that it is 52% absorbed after oral administration and undergoes a marked hepatic first-pass effect (83%). Tissue distribution shows an affinity for the aorta, cardiac tissues and cerebral blood vessels. It is excreted in the urine (20% dose) and faeces (70%); biliary excretion is high (80% dose). It is metabolized mainly by O-demethylation to 6- and 7-desmethyl-PV 2 and 6,7-didesmethyl-PV 2, as well as to six other non-identified metabolites.
Meta-iodobenzylguanidine adrenal medulla localization: autoradiographic and pharmacologic studies.
In order to investigate the mechanism of uptake of meta-iodobenzylguanidine (mIBG) by the adrenal glands, autoradiographic and pharmacologic studies were performed in mice and dogs receiving radioiodinated mIBG. In mice, on macroautoradiography of whole body sections 48 h after 125I-mIBG, most of the radioactivity was focused in the adrenal glands. On microautoradiography, silver grains were exclusively located in the adrenal medulla. Tissue counting after phenoxybenzamine, cocaine, and desipramine treatment resulted in 45%, 35%, and 0% inhibition of mIBG uptake, respectively. Tissue counting and scintigraphic studies demonstrated a more than 50% mIBG release from the adrenal glands after reserpine. These data indicate the high affinity of mIBG for adrenal medulla and suggest that the mIBG and catecholamine uptake mechanisms are only partially the same.
[Approach to the synthesis of methoxyellipticines and obtainment of 1,4-dimethyl-6-methoxycarbazole by cyclization of diphenylamines].
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Comparative affinity chromatography of acetylcholinesterases from five vertebrate species.
The efficacy of N-methylacridinium affinity chromatography in the purification of acetylcholinesterases from chicken, rat, calf and human brain and from the electric organ of the electric fish Torpedo marmorata has been investigated. Retention of the enzymes on the N-methylacridinium columns exceeded 90% in all instances except for the chicken enzyme, where 40-80% retention was observed depending on the acridinium concentration. Sucrose density gradient centrifugation profiles revealed no difference between the distribution of molecular forms in the crude extracts and in the partially purified fractions eluted from the columns by decamethonium iodide.
[Human data on the metabolism and pharmacokinetics of an analog of papaverine: 6,7-dimethoxy-4-(4-chlorobenzyl)-4-isoquinoline].
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[In vitro metabolism of 4-benzylisoquinolines, analogs of papaverine].
A comparative study was made on sliced Rat liver of the in vitro disappearance of papaverine, PV 2 6,7-dimethoxy-4-(parachlorobenzyl)isoquinoline and its mono and di isopropoxy derivatives. Data show that papaverine and PV 2 are equally sensitive to oxygenases, although 7 mono and 6,7 di-isopropoxy derivatives are much less so, being more bulky and undergo in enzymic O-dealkylation less easily. The data also show that PV 2 and 6-isopropoxy desmethoxy PV 2 disappear at the same rate, more readily than the 7 isopropoxy isomer. This confirms the in vivo results previously reported. The antispasmodic in vitro activity of these compounds is reported.
[Determination of the radioprotective activity of imipramine analogs].
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[Syntheses designed to produce 8-amino ellipticine. Synthesis and pharmacological properties of 8-nitro ellipticine].
The synthesis of 8-nitro ellipticine starting from 6-nitro indole is reported. It is the first derivative of ellipticine substituted in position 8 obtained by total synthesis. In contrast to 9-nitro ellipticine the 8-nitro derivative could until now not be reduced to 8-amino ellipticine. To obtain the latter it was intended to arylate an enamine of the 2,5,8-trimethyloctahydroisoquinolone-6 by 1-chloro 2,4-dinitrobenzene, followed by a reductive cyclization and N-demethylating aromatization. Since the yield of the arylation step was low, the isoquinolone was replaced by 2,5-dimethyl cyclohexanone and the synthesis would have to be completed by addition of a pyridine ring. In the case the yield of the aromatisation was 37%, but the carbazole derivative resisted all formylation attempts. 8-Nitro ellipticine was investigated for its DNA affinity, its cytotoxic activity on L 1210 tumors cells and its toxicity in the mouse. The results obtained were compared with those for 9-nitro ellipticine and in regard to cytotoxicity, with those for the 8- and 9-hydroxy ellipticines.
[9-Nitro- and 9-amino-ellipticines and derivatives: synthesis and pharmacologic properties].
Preparation of 9-nitroellipticine starting from 1,4-dimethyl-6-nitrocarbazole and its reduction according to the Béchamp method followed by acetylation. The salts of 9-nitro-2-methyl- and 9-amino-2-methyl ellipticinium were tested for cytotoxic activity on different tumor strains for mutagenicity, for affinity for DNA and cytochrome P450 and for toxicity in the mouse. The results obtained were compared with those found under the same conditions with 9-hydroxyellipticine and its corresponding ellipticinium salt.
[Isolation of aristolochic acid from two Madagascar Aristolochiaceae. Determination of its toxicity on vegetal cells. Comparison with animal cells (author's transl)].
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