Sequence Selective Molecular Recognition of Long DNA Sequences by Oligomethylene-Linked Oligoimidazole Analogs of Distamycin

Abstract

We have studied a series of homologous N-to-N oligomethylene linked bis(diimidazole) analogs 4a-f (number of methylene groups = 1 to 6, re spectively) and a dipicolinamide congener 4g that bind to long GC-containing sequences of DNA. Results from an ethidium binding assay reveal that, for 4a-f, the compounds with an even number of methylene groups have larger ap parent binding constants, K_app, than those with an odd number. The K_app values of the compounds with an odd number of methylene groups are close to that of their monomeric analog 3 suggesting that they may be binding to DNA in a monodentate fashion. The binding of these compounds to T4 DNA and their larger binding constants for poly(dG-dC) over poly(dA-dT) indicated minor groove binding selectivity and tolerance for GC sequences. The ability of com pounds 4b-f to bind selectively to DNA was illustrated by an MPE-Fe(II) foot printing study which showed that compound 4f gave the most distinct foot prints. CD titration studies on compounds 4b, d, and f further demonstrated the GC tolerance of these compounds and that they can bind to 7 ~ 8 base pairs of DNA in a bidentate fashion. The minor groove and bidentate bind ing of the ethylene linked compound 4b on the underlined sequence of