CHAPTER 9. Duocarmycins as Antibody–Drug Conjugate (ADC) Payloads

The duocarmycins are a family of natural products first described in 1978 with the discovery of CC-1065. These DNA alkylating spirocyclopropyl-cyclohexadienones demonstrate ultrapotent cytotoxic activity, provided by the sequence-selective alkylation of the N3 of adenine. The medicinal chemistry community immediately saw great potential in the picomolar potency of the duocarmycins in cell lines, but inherent toxicity in vivo has hindered their progression through to clinical use. Consequently, a variety of strategies have been developed to harness the power of the duocarmycins and to begin to realise the potential of their highly interesting mode of action, the most exciting of which is the development of antibody–drug conjugates (ADCs). This chapter will present the most recent understanding of the mechanism of action of the duocarmycins and the downstream effects of DNA alkylation. Innovative approaches to the synthesis of the duocarmycins, including stereoselective synthesis and new approaches for solid-phase synthesis, are discussed. This chapter also highlights the approaches of medicinal chemists to harness the duocarmycins for clinical use and an overview of prodrug strategies is presented, emphasising the most effective and creative methods to release the duocarmycins at the desired site of action. Finally, the use of duocarmycins as ADCs is reviewed, underlining the inventive chemical approaches to direct and deliver this ultrapotent payload.