CHAPTER 10: CXI Dimers as Antibody–Drug Conjugate (ADC) Payloads

The CXI dimers [dimers containing, for example cyclopropapyrroloindole (CPI), cyclopropabenzindole (CBI) or cyclopropathienoindole (CTI) moieties] first emerged in the late 1980s, and were composed of two units of the active pharmacophore present in duocarmycin natural products. They are among the most potent cytotoxic agents ever synthesised and have been successfully utilised by various groups as payloads for antibody–drug conjugates (ADCs). Their ability to cross-link DNA, selectively alkylating adenines in the minor groove, differentiates them from other known payload classes and even other cross-linking agents. This chapter reviews the various forms of CXI dimers that have been reported, including several examples where they have been shown to outperform approved ADCs both in vitro and in vivo.