RESUMEN
Several acyclonucleosides have been synthesized. Series 8 could liberate 5-FU and acrolein selectively in the tumour tissue whilst 9 only discharge 5-FU. The conformational analysis of 8 and 9 has been carried out by means of Molecular Mechanics, using the MM2 force field. It was observed that the open chain linked to the N-1 of the 5-FU moiety mimics the conformational structure of the sugar of desoxyuridine. Biological assays have been carried out in vitro on tumour growth in Ehrlich ascitic cells with the consequent decrease of 35% in the cellular mitosis. IC50 showed values between 3-45 microM for series 8 whilst series 9 were less active than 5-FU. Compared with that of 5-FU the acute and chronic toxicity is considerably decreased.
Asunto(s)
Antineoplásicos/síntesis química , Pirimidinas/síntesis química , Animales , Antineoplásicos/farmacología , Antineoplásicos/toxicidad , Diseño de Fármacos , Humanos , Conformación Molecular , Pirimidinas/farmacología , Pirimidinas/toxicidadRESUMEN
Quinolinic acid, an endogenous excitotoxin, and kynurenic acid, an antagonist of excitatory amino acid receptors, are believed to be synthesized from tryptophan after the opening of the indole ring. They were measured in the rat brain and other organs using gas chromatography-mass spectrometry or HPLC. The enzyme indoleamine 2,3-dioxygenase, capable of cleaving the indole ring of tryptophan, was induced by administering bacterial endotoxins to rats, which significantly increased the brain content of both quinolinic and kynurenic acids. Nicotinylalanine, an analogue of kynurenine, inhibited this endotoxin-induced accumulation of quinolinic acid while potentiating the accumulation of kynurenic acid. The possibility of significantly increasing brain concentrations of kynurenic acid without a concomitant increase in quinolinic acid may provide a useful approach for studying the role of these electrophysiologically active tryptophan metabolites in brain function and preventing the possible toxic actions of abnormal synthesis of quinolinic acid.