The interactions of substituted pyrido[1,2-e]purines with oligonucleotides depend on the amphiphilic properties of their side chain. |
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Authors: | J C Debouzy S Crouzy V Dabouis A Gueiffier B Brasme C Bachelet A Favier J P Simorre L Mazet A Peinnequin |
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Institution: | CRSSA, Unité de Biophysique Cellulaire et Moléculaire, 24 Av. des maquis du Grésivaudan, La Tronche cedex, 38702, France. |
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Abstract: | Three pyrido1,2-e]purines of increasing hydrophilicity have been synthesized to evaluate as anticancer agents. These drugs interact quite differently with a synthetic oligodeoxynucleotide d(CGATCG)2. 1] is very hydrophobic due to a phenyl residue in its side chain. It only shows limited interactions with the minihelix without any evidence of intercalation. 2] and 3], on the other hand, have one (2]) or two (3]) hydroxyl groups in their acyl chain and present rather amphiphilic properties. The result is a similar intercalation of these derivatives between C and G base pairs as revealed by intermolecular nOe, 1H and 31P chemical shift variations. Models for the intercalation of 2] are proposed using energy minimizations and molecular dynamics (MD) calculations subject to restraints from nOe connectivities. Simulations and experiments indicate weak stability and thus fast exchange of 2] in its intercalation site. |
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