Pergamon Te~rahcdron, Vol. 53, No. 24. pp. zyxwvutsrqponmlkjihgfed 8105-8120. 1997 Q 1597 Ekevier Science Ltd All rights reserved. Prinred in Great Britain PIh S0040-4020(97)0050 1-2 oO4042w7 Sl7.00 + 0.00 Design, Synthesis, and Characterization of a Novel Hexa-azacyclophane and Interactions with d(CGCA,T,GCG),, ctDNA and T4DNA. Thomas C. Bruice*, Yu Chi Yip, Andrei Blask6, Felice C. Lightstone, Kenneth A. Browne, Mark E. Petyak, and Jia Luo Department of Chemistry, University of California. Santa Barbara,CA 93106 Abstrad: A novel polyazacyclophanehexa-amine(1) has been designed, synthesized and characterized zyxwvutsrqponmlkjihgf by X-ray crystallography. ‘H NhfR and fluorescence spectroscopy. 1 has the structural shape and disposition of charges complementary to the major groove of B-DNA. Acid dissociation constants for the protonatcd 1 were p&,(D) = 4.8 and p&(D) = 8.5. Equilibriumconstants for the binding of 1 to ctDNA and T4 DNA were 1.2 x Iti and 1.8 x IO”. respectively. 0 1997 Elsevier Science Ltd. INTRODUCTION Synthetic DNA-recognizing organic molecules am of great interest in rational drug design.’ Approaches to B-DNA recognition include sequence specific binding into minor and major grooves, intercalating to base pairs, and hybrids of these binding modes. Synthetic molecules which bind to minor groove or intercalate include lexitropsins’, microgonotropens’. cationic steroids’, pseudopeptide-intercalator conjugatess Approaches targeted to the major groove of B-DNA have received less attention. A number of natural occurring proteins, such as those of transcription factorsP the helix-tum-helix,6 and zinc finger’ present their binding motifs to the major groove of the dsDNA. Antisense oligonucleotidesP as well as peptide nucleic acid9 and thymidyl deoxynucleic guanidine (DNG)” form triple helices on reaction with double stranded DNA or RNA. Gresh et al.” has designed cationic prophyrin-oligopeptide conjugates which both intercalate and exhibit major groove recognition. Barton et al.‘* have synthesized various rhodium and ruthenium phenanthrolines which bind to the major groove through intercalation, there is yet to exist examples of non-organometallic and non-peptide “ organic” molecules which bind, in a non-intercalating manner and without invasion, to the major groove of dsDNA. zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA 1 As a continuing effort to study the interaction between organic molecules and dsDNA,” we set out to design, synthesize and study compounds which complex to dsDNA by binding in the major groove. An 8105