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

Department of Chemistry Furman University Greenville, SC 29613

Clint Walker

Department of Chemistry Furman University Greenville, SC 29613

Monica Cooper

Department of Chemistry Furman University Greenville, SC 29613

Steven M. Forrow

Department of Oncology University College London Medical School London, W1P 8BT, U.K.

John A. Hartley

Department of Oncology University College London Medical School London, W1P 8BT, U.K.

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

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