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.
Briehn
Christoph A
CA
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
Weyermann
Philipp
P
Dervan
Peter B
PB
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