Tris-benzimidazole derivatives: design, synthesis and DNA sequence recognition.
Two tris-benzimidazole derivatives have been designed and synthesized based on the known structures of the bis-benzimidazole stain Hoechst 33258 complexed to short oligonucleotide duplexes derived from single crystal X-ray studies and from NMR. In both derivatives the phenol group has been replaced by a methoxy-phenyl substituent. Whereas one tris-benzimidazole carries a N-methyl-piperazine at the 6-position, the other one has this group replaced by a 2-amino-pyrrolidine ring. This latter substituent results in stronger DNA binding. The optimized synthesis of the drugs is described. The two tris-benzimidazoles exhibit high AT-base pair (bp) selectivity evident in footprinting experiments which show that five to six base pairs are protected by the tris-benzimidazoles as compared to four to five protected by the bis-benzimidazoles. The tris-benzimidazoles bind well to sequences like 5'-TAAAC, 5'-TTTAC and 5'-TTTAT, but it is also evident that they can bind weakly to sequences such as 5'-TATGTT-3' where the continuity of an AT stretch is interrupted by a single G*C base pair.
Ji
Y H
YH
F. Hoffmann-La Roche Ltd, Pharma Research Preclinical Gene Technologies and Infectious Diseases, CH-4070, Basel, Switzerland.
Bur
D
D
Häsler
W
W
Runtz Schmitt
V
V
Dorn
A
A
Bailly
C
C
Waring
M J
MJ
Hochstrasser
R
R
Leupin
W
W
D001483:Base Sequence; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000378:metabolism*; D001665:Binding Sites; D006690:Bisbenzimidazole; D002942:Circular Dichroism; D018983:DNA Footprinting; D015195:Drug Design; D005456:Fluorescent Dyes; D015394:Molecular Structure; D009838:Oligodeoxyribonucleotides / Q000737:chemistry / Q000378:metabolism*
D001562:Benzimidazoles; D005456:Fluorescent Dyes; D009838:Oligodeoxyribonucleotides; D006690:Bisbenzimidazole; C017807:bisbenzimide ethoxide trihydrochloride