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 In both derivatives the phenol group has been replaced by a methoxy-phenyl substituent.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.

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@article{Ji2001TrisbenzimidazoleDD, title={Tris-benzimidazole derivatives: design, synthesis and DNA sequence recognition.}, author={Y. H. Ji and Daniel Bur and W E Haesler and V Runtz Schmitt and Arnulf Dorn and Christian Bailly and Michael J. Waring and Ronald Hochstrasser and W. Leupin}, journal={Bioorganic & medicinal chemistry}, year={2001}, volume={9 11}, pages={2905-19} }