The Intercalation of Planar Polyheterocyclic Compounds Into DNA Base Pair Dimers GIAMPAOLO BARONE*-CE Â LIA FONSECA GUERRA** NOEMI GAMBINO*-ARTURO SILVESTRI*-ANTONINO LAURIA*** ANNA MARIA ALMERICO*** - F. MATTHIAS BICKELHAUPT** * Dipartimento di Chimica Inorganica e Analitica ``S. Cannizzaro'', Universita Á di Palermo, Palermo ** Afdeling Theoretische Chemie, Scheikundig Laboratorium der Vrije Universiteit, Amsterdam, The Netherlands *** Dipartimento Farmaco Chimico, Tossicologico e Biologico, Universita Á di Palermo, Palermo Abstract. ± We have studied, by DFT calculations, the stacking interaction between 6 stacked and hydrogen bonded DNA base pairs AT-AT, AT-TA, GC-AT, CG- TA,GC-GC,GC-CG)withaplanarheterocycliccompoundasarepresentativemodelofa class of potentially DNA intercalating drugs. The structure of three polyheteroclycic compounds was fully optimized at the DFT BP86 level, with the TZ2P basis set. The stacking interaction was studied by the LDA functional, with the TZP basis set, by monitoringthepotentialenergysurfacePES)asafunctionofboth,theaxialdistance oftheintercalatorfromthestackedbasepairsandtheequatorialstackingpositionofthe intercalatir in between the stacked base pairs. The calculations have been performed with the ADF program. Introduction WearepresentlyinterestedinthedesignandsynthesisofDNAintercalatingdrugs. The research project includes the study of the interaction of the synthesized compounds with native DNA in solution [1] and the analysis of the pharmacological properties of the most promising compounds. In particular we are synthesizing the polyheterocyclic compound 8-methyl-5-oxo-5,8-dihydro-4H-pyrazolo[4,3-e][1,2,3]tria- zolo[1,5-a]pyrimidine-3-carbonitrile 1) as well as its 3-phenyl 2) and 3-amide 3) derivatives see Scheme 1). Analogouscompoundshavebeenrecentlysynthesized[2],showingsuitablesteric and electronic properties to intercalate DNA. One of our aims is also to perform a molecular modelling study of the drug±DNA interaction, that precedes or parallels the synthesis and the study of the interaction of such drugs with native DNA. In particular we would be interested in the knowledge of the structural details of such interaction, to understand the role of the substituents on