Synthesis of Amide-Linked Minor Groove Binders (MGBs) to Target the Androgen Response Element (ARE) Sequence

Minor groove binders (MGBs) are molecules which bind selectively to the minor groove of DNA. Distamycin 1 and netropsin 2 are naturally occurring MGBs, and are members of the polypyrrole class of compounds. These compounds consist of two and three methylpyrrole monomers linked by amides, with a head and tail group also linked by amides. They have potential antiviral, antibiotic, and antioncolytic properties, however they are also toxic. These biological effects arise from the molecule binding to DNA in regions where there are short runs of A:T base pairs. Much work has been carried out to develop analogues of distamycin and netropsin which have improved biological activity and a reduced toxicity profile. The aim of this project is to synthesize amide-linked minor groove binders as potential antibacterial and anticancer agents. The proposed analogues of distamycin have low molecular weight and enhanced lipophilicity to improve their binding with the minor groove of DNA and increase the absorption and the cell permeability of these compounds to offer them better chances of becoming commercial drugs. In this thesis, we describe a successful development of novel routes for the synthesis of distamycin analogue compound (Thiazotropsin C).