Recognition of a 10 base pair sequence of DNA and stereochemical control of the binding affinity of chiral hairpin polyamide-Hoechst 33258 conjugates.
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.
Reddy
Putta Mallikarjuna
PM
Department of Chemistry and Biochemistry, University of California at Santa Barbara, Santa Barbara, CA 93106, USA.
Toporowski
Joseph W
JW
Kahane
Alexandra L
AL
Bruice
Thomas C
TC
D020029:Base Pairing; D001483:Base Sequence; D001665:Binding Sites; D006690:Bisbenzimidazole / Q000031:analogs & derivatives*; D004247:DNA / Q000737:chemistry*; D007700:Kinetics; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D009757:Nylons / Q000737:chemistry*; D011758:Pyrroles / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013816:Thermodynamics
D009757:Nylons; D011758:Pyrroles; D004247:DNA; D006690:Bisbenzimidazole