New strategies for the synthesis of sequence selective platinum anticancer compounds

Abstract

Cancer is a leading cause of illness and death in developed countries. Current leading anticancer drugs are limited by side-effects and the ability of malignant cells to become resistant. New drugs are being developed that display the capacity to target cancerous cells, without affecting healthy cells. This can be achieved by designing novel molecules that bind to specific targets that are exclusive to, or are highly conserved within, cancer cells. Some naturally occurring groove-binding polyamides (such as netropsin and distamycin A) are already capable of such specificity, as they comprise of a series of heterocyclic rings linked by single bonds that can rotate to match the conformation of the target DNA site. This project has focused on the synthesis DNA sequence selective compounds containing terpyridineplatinum(II) based moieties. New methods for the solution phase synthesis of polyamides, containing analogues of the heterocyclic rings N-methylpyrrole and 1-methylimidazole, have been developed with a focus on simplified purification and increased reproducibility. In this study, new methods for the incorporation of [Pt(terpy)Cl]Cl into polyamides by both solid and solution phase have been explored and contrasted. It was found that machine assisted protocols were ideal for the synthesis and purification of metallopolyamides, whilst solution phase methods were prohibitively difficult and require further development. Two novel platinum metallointercalators have been synthesised and tested for biological activity, including an extensive DNA binding study by circular dichroism and 1D and 2D 1H NMR. Finally, a novel metallopolyamide derived from [Pt(terpy)Cl]Cl has been synthesised entirely by solid phase, as a proof of concept for the new method of incorporation described in this work.

Date of Award	2008
Original language	English