Synthesis and evaluation of benzochalcogenazole-benzimidazole derivatives as potential DNA-binding radioprotectors

Benzothiazole 6 and benzoselenazole 7, which are closely related to the bisbenzimidazole radioprotector bisbenzimidazole M2PB 20, were prepared by reaction of a common amide intermediate 13O with Lawesson's and Woolin's reagents, respectively. A simpler tellurazole derivative 19 was prepared using a different synthetic strategy. The DNA binding affinity of the three chalcogenazoles 6, 7, 19 and the parent benzimidazole 20 were assessed by means of spectrophotometric DNA titration experiments using 16-mer oligonucleotides with and without a single binding site. While M2PB 20 shows clear binding to the oligonucleotide containing an AATT binding site, no strong conclusions can be made regarding the interactions of 6, 7 or 19 with DNA, either in the presence, or absence of an AATT binding site. Fluorescence microscopy studies with HeLa cells clearly shows nuclear localisation of M2PB (20); fluorescence is almost exclusively in nuclei. By contrast, for the benzoselenazole 7, fluorescence is excluded from the nuclei. These results suggest that the proposed chalcogen bonding interactions involving S, Se and Te in 6, 7, and 20 are not strong enough to impart the DNA binding behavior which is displayed by corresponding bis-benzimidazoles such as 20. [GRAPHICS] .