Alternative heterocycles for DNA recognition: the benzimidazole/imidazole pair.
Boc-protected benzimidazole-pyrrole, benzimidazole-imidazole, and benzimidazole-methoxypyrrole amino acids were synthesized and incorporated into DNA binding polyamides, comprised of N-methyl pyrrole and N-methyl imidazole amino acids, by means of solid-phase synthesis on an oxime resin. These hairpin polyamides were designed to determine the DNA recognition profile of a side-by-side benzimidazole/imidazole pair for the designated six base pair recognition sequence. Equilibrium association constants of the polyamide-DNA complexes were determined at two of the six base pair positions of the recognition sequence by quantitative DNase I footprinting titrations on DNA fragments each containing matched and single base pair mismatched binding sites. The results indicate that the benzimidazole-heterocycle building blocks can replace pyrrole-pyrrole, pyrrole-imidazole, and pyrrole-hydroxypyrrole constructs while retaining relative site specifities and subnanomolar match site affinities. The benzimidazole-containing hairpin polyamides represent a novel class of DNA binding ligands featuring tunable target recognition sequences combined with the favorable properties of the benzimidazole type DNA minor groove binders.
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
Christoph A
CA
Briehn
Philipp
P
Weyermann
Peter B
PB
Dervan
D001483:Base Sequence; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology*; D004247:DNA / Q000187:drug effects*; D018983:DNA Footprinting; D015246:Deoxyribonuclease EcoRI / Q000235:genetics; D003850:Deoxyribonuclease I / Q000037:antagonists & inhibitors; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000494:pharmacology*; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D007202:Indicators and Reagents; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D012150:Polymorphism, Restriction Fragment Length
D001562:Benzimidazoles; D006571:Heterocyclic Compounds; D007093:Imidazoles; D007202:Indicators and Reagents; D004247:DNA; D015246:Deoxyribonuclease EcoRI; D003850:Deoxyribonuclease I