TAILIEUCHUNG - Báo cáo khoa học: Covalent binding to glutathione of the DNA-alkylating antitumor agent, S23906-1

The benzoacronycine derivative, S23906-1, was character-ized recently as a novel potent antitumor agent through alkylation of theN2 positionof guanines show here that its reactivity towards DNA can be modulated by glutathione (GSH). The formation of covalent adducts between GSH and S23906-1 was evidenced by EI-MS, and the use of different GSH derivatives, amino acids and dipeptides revealed that the cysteine thiol group is absolutely required for complex formation because glutathione disul-fide (GSSG) and other S-blocked derivatives failed to react covalently with S23906-1. . | Eur. J. Biochem. 270 2848-2859 2003 FEBS 2003 doi Covalent binding to glutathione of the DNA-alkylating antitumor agent S23906-1 Marie-Helene David-Cordonnier1. William Laine1 Alexandra Joubert1 Christelle Tardv1. M BB BB BB BB B F w BB BB B B BB B B B B B B B B B BB B BB B B B BB B BB im B B BB B BB IB FF BB BB BB B B BB B B B B IB B BB B B BB B BB B BB B Jean-Francois Goossens2 Mostafa Kouach3. Gilbert Briand3 Huona Doan Thi Mai4. Svlvie Michel4 Francois Tillequin4 Michel Koch4 Stephane Leonce5 Alain Pierre5 and Christian Bailly1 1INSERM U-524 et Laboratoire de Pharmacologie Antitumorale du Centre Oscar Lambret IRCL Lille France 2Laboratoire de Chimie Analytique Faculte des Sciences PharmaceutÚỊues et Biologiques et 3Laboratoire de Spectrometrie de Masse Universite de Lille Lille France 4Laboratoire de Pharmacognosie Universite Rene Descartes Paris 5 CNRS UMR8638 Faculte des Sciences Pharmaceutiques et Biologiques Paris France 5Division Recherche Cancerologie Institut de Recherches SERVIER Croissy sur Seine France The benzoacronycine derivative S23906-1 was characterized recently as a novel potent antitumor agent through alkylation of the N2 position of guanines in DNA. We show here that its reactivity towards DNA can be modulated by glutathione GSH . The formation of covalent adducts between GSH and S23906-1 was evidenced by EI-MS and the use of different GSH derivatives amino acids and dipeptides revealed that the cysteine thiol group is absolutely required for complex formation because glutathione disulfide GSSG and other S-blocked derivatives failed to react covalently with S23906-1. Gel shift assays and fluorescence measurements indicated that the binding of S23906-1 to DNA and to GSH are mutually exclusive. Binding of S23906-1 to an excess of GSH prevents DNA alkylation. Additional EI-MS measurements performed with the mixed diester S28053-1 showed that the acetate leaving group at the C1 position is the main reactive site .

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