The utilisation of Fmoc solid phase chemistry as a novel approach to the generation of duocarmycin analogues

The family is characterised by a common spirocyclopropylcyclohexadienone pharmacophore. This unusual structural motif is responsible for exceptionally efficient alkylation of adenine bases following activation through conformational changes induced by non-covalent recognition of DNA’s minor groove. This thesis describes the conception and multi-gram synthesis of a duocarmycin SA alkylation subunit suitably substituted to serve as a building block for Fmoc based solid phase synthesis and initial investigations into its application. Chapter two describes the pilot and subsequent large scale racemic synthesis of the desired duocarmycin building block, and its preparative chiral resolution by supercritical fluid chromatography. The synthesis includes a novel route to an early indole intermediate, and represents one of the shortest available strategies to access a previously reported di-Boc-protected duocarmycin structure. The large scale synthesis afforded over 8 g of the racemic Fmoc-protected building block, representing a 3 % overall yield over 13 steps. In chapter three, application of the building block to the conjugation of amino acids through solid phase synthesis is explored. This work highlights the importance of careful resin selection and the need to optimise cleavage conditions. A small library of duocarmycin analogues was generated, and subsequent assays revealed the effects of C-terminal amino acid substituents on biological activity. This work has demonstrated the potential utility of this building block for the future development of novel peptide linked antibody drug conjugates of duocarmycin SA. Finally, chapter four explores incorporation of the building block into polypyrrole structures, highlighting the potential for the direct solid phase synthesis of sequence selective bifunctional hairpin polyamides which contain the alkylation subunit of duocarmycin SA