Structure–activity relationships in glycosylated 2-phenyl-indoles, 2-phenyl-benzo[b]thiophenes and 2-phenyl-benzo[b]furans as DNA binding and potential antitumor agents

Abstract

In earlier investigations we have described the synthesis and biological evaluation of a panel of novel glycosylated heteroaromatics (1–12). It was found that these compounds can bind to DNA in vitro and are cytotoxic against several cancer cell lines at low micromolar concentration. We report here structure–activity studies of these molecules with respect to DNA binding and cytotoxicity. In particular the structure of the linker moiety between the carbohydrate and the intercalator, the stereochemistry at the anomeric position, and the substituents and stereochemistry at C-4 in one of the carbohydrate residues (4-amino-2,3,4,6-tetradeoxy-α-l-threo-hexopyranose) are investigated. All these structural features were identified to have a clear influence on DNA binding; however, only the substituents at C-4 in the carbohydrate residue exhibited an obvious impact on cytotoxicity. It was found that the amino group at C-4 was favored over all other substituents with regard to both DNA binding and cytotoxicity. The information gathered from these structure–activity investigations suggested that future work on the preparation of additional analogues should focus on molecules containing an amino sugar moiety.