The interactions of substituted pyrido[1,2-e]purines with oligonucleotidesdepend on the amphiphilic properties of their side chain

Three pyrido[1,2-e]purines of increasing hydrophilicity have been synthesiz ed to evaluate as anticancer agents. These drugs interact quite differently with a synthetic oligodeoxynucleotide d(CGATCG)(2). [1] is very hydrophobi c due to a phenyl residue in its side chain. It only shows limited interact ions 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 ac yl 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, H-1 and P-31 chemical shift variations. Models for t he intercalation of [2] are proposed using energy minimizations and molecul ar dynamics (MD) calculations subject to restraints hom nOe connectivities. Simulations and experiments indicate weak stability and thus fast exchange of [2] in its intercalation site. (C) 1999 Academic Press.