DNA bis-intercalators: Design, synthesis and DNA binding properties of potential anti-cancer agents based on rigid polynorbornyl molecular scaffolds

DNA bis-intercalating agents constitute an important class of compounds for cancer chemotherapy. The work presented in this dissertation deals with the synthesis of a new class of DNA bis-intercalating agents of type I containing rigid polynorbomyl molecular frameworks. The highly rigid molecular framework is designed to place and orient the two intercalating chromophores (the DNA-reactive entities) optimally for specific binding to a known nucleotide sequence. The chromophores are attached to the rigid framework via short flexible tethers, allowing some degree of conformational mobility while maintaining well-defined maximum and minimum inter-chromophore separations. A modular approach to synthesis has been adopted to prepare the bis-intercalators that involved initial preparation of a series of complementary A-BLOCKs II and B-BLOCKIII (Scheme I), each of which contains one intercalating chromophore. These BLOCKs contain different end-functionality (A-BLOCK: alkene; B-BLOCK: epoxide) which react with each other stereospecifically, but not with themselves to produce the desired product IV. The wide range of topologically well defined products generated by this approach show variations which include spacer length, chromophore type and nature of the tether joining the chromophores to the rigid molecular framework. In particular, the BLOCK approach has permitted the preparation of the most comprehensive range of asymmetrical bis-intercalators containing rigid spacers yet described. Representative products derived from this methodology, include the bisacridine V and the acridine-naphthalimide mixed derivative VI. In addition, significant advances have been made to control the hydrophilicity of these drugs, thereby enhancing the bio-compatibility of these novel molecules. DNA binding experiments have been performed on the bis-intercalators prepared in this study. Polynucleotide structural selectivity was observed and sequence-selectivity was associated with the binding of two of the compounds with the highest affinity for DNA. Some features that enhance binding selectivity and affinity have been identified so that the synthesis of more selective compounds for effective gene targeting in chemotherapy can proceed in the future. The results which have helped to define more clearly the parameters of drug-DNA interaction represent a good example of how organic chemistry can be a useful tool to help elucidate and understand biological phenomena. The ground work has been completed providing a solid foundation from which the preparation of novel synthetic targets of medicinal interest using the BLOCK coupling concept can now be approached with less trepidation.