Duocarmycin SA is the archetypal member of one of the most potent families of antitumor antibiotics yet isolated. Their antitumor activity is derived from non-covalent recognition of AT rich regions of DNA's minor grove, which induces a destabilising conformational change in the compounds structure, leading to the exceptionally efficient alkylation of adenine. The terminal ester and amide functionality of the duocarmycin alkylation subunit suggested that it would be suitable as a building block for solid phase synthesis. We describe the first synthesis of a duocarmycin subunit suitably substituted for Fmoc-based solid phase synthesis and preliminary studies of its use in the synthesis of duocarmycin analogues.  Figure 1: Structure of the duocarmycin alkylation subunit building block for Fmoc based solid phase synthesis.

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

248th National Meeting (2014)

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