Synthesis and Biological Activities of Novel Benzamide Based DNA Minor Groove Binding Agents

Abstract

This thesis describes the synthesis and DNA binding studies of benzamide DNA minor groove binding agents (MGB). MGB are an extensively studied class of compounds due to their potential use as anticancer agents. Some pyrrole based natural antibiotics such as distamycin and netropsin are potent DNA MGB. In order to increase the DNA binding affinity, sequence specificity and alkylating activity, and to minimise the unwanted physiological activities associated with these natural DNA binders, many synthetic oligopeptides have been prepared. Most of the reported MGB are based on five-membered heterocyclic moieties. Some simple symmetrical benzamide based MGB are also known and have shown good DNA binding activities but the fact that they lack active alkylating groups and have few possible structural sites that can be modified has limited their utility for further research. This thesis reports on the synthesis and biological activities of novel nonsymmetrical benzamide MGB. The initial synthetic studies were focused on establishing new and efficient routes towards the synthesis of non-symmetrical di- and triaryl amides derived from dinitrobenzenes that are compatible with azide, amine, ether and chloride functional groups. Once these routes were established, a number of different polybenzamides having diverse alkylating groups at the benzylic position and a variety of amino-alkyl groups at the ends were prepared in order to explore their stability and thereafter establish the effect of such functional groups on DNA groove binding. The different derivatives were then tested for antiproliferative activities against various cancer cell lines and DNA binding and alkylating activities using different analytical techniques such as DNA melting point analysis, competitive ethidium displacement assays, and mass spectrometry. Our investigations revealed that triaryl derivatives bearing a large-sized group at a benzylic position and a longer amino-alkyl chain at the end of the ligand have the best DNA and antiproliferative activities in this novel class of benzamide MGB.