DNA recognition by linear indole-biphenyl DNA minor groove ligands

Abstract

Linear heterocyclic cations are interesting DNA minor groove ligands due to their lack of isohelical curvature classically associated with groove-binding compounds. We determined the DNA binding properties of four related dications harboring a linear indole-biphenyl core: the diamidine DB1883, a ditetrahydropyrimidine derivative (DB1804), and their monocationic counterparts (DB1944 and DB2627). These compounds exhibit heterogeneity in binding in accordance with their structures. Whereas the monocations exhibit salt-sensitive 1:1 binding to the duplex 5'-CGCGAATTCGCG-3' (A₂T₂), the dications show a marked preference for a salt-insensitive 2:1 complex. The two binding modes are differentially modulated by salt and specific non-ionic co-solutes. For both dications, 2-methyl-2,4-pentanediol enforces 1:1 binding as observed crystallographically. Fluorescence quenching studies show self-association without DNA in a relative order that is correlated with preference for the 2:1 complex. The data support a structure-binding relationship in which favorable cation-π interactions drive dimer formation via antiparallel stacking of the linear indole-biphenyl cation motif.

Keywords: Binding modes; DNA minor groove; Dimerization; Drug-DNA interactions; Fluorescence; Heterocyclic dications.