Modulation of intercalating properties of pyrido[1,2-e]purins via side-chain modifications: NMR and MD studies

Two pyrido[1,2-e]purins with different side chain lengths have been synthes ized to test their ability to intercalate inside DNA. The interactions of t hese drugs with synthetic oligodeoxy nucleotide d(CGATCG)(2) have been stud ied with H-1 and P-31 NMR spectroscopy experiments. Molecule 1, rather amph iphilic (Log(P) = 1.3, due to its hydroxypropyl side chain) can intercalate GC sites of the mini helix, under a fast exchange mechanism and a 2 : 1 st oechiometry. The presence of a six methylen side chain in 2 (hydroxyhexyl s ide chain) is responsible for a relatively poor solubility of this molecule in water (log P = 2.3). Binding, rather than intercalation, of 2 to the ex ternal GC pairs is observed, severely limited by the formation of aggregate s. Models for the intercalation of 1. are proposed using energy minimizatio ns and Molecular Dynamics (MD) calculations subject to restraints from expe rimental nOe connectivities. Simulations and experiments both indicate fast exchange of 1 in its intercalation site.