Chiral hairpin polyamides linked to a Hoechst 33258 analogue at the alpha-position of the hairpin turn amino acid (1,2) were synthesized on solid phase by adopting Fmoc and ivDde techniques. The DNA-binding properties of enantiomeric conjugates 1 and 2, and N-terminal linked conjugate 3 for 8-14bp sequences were determined by spectrofluorometric and thermal melting studies. Conjugates 1 and 2 recognize a 10bp sequence, while conjugate 3 recognizes a 9bp sequence. Interestingly, R-enantiomer 1 exhibited 10- to 30-fold higher binding affinities than S-enantiomer 2 for the DNA sequences studied. These binding differences were accounted for by molecular modeling studies, which revealed that the amide proton nearest to the chiral center in R-conjugate 1 is better positioned to form hydrogen bonds to the DNA bases, while S-conjugate 2 does not.
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