Effects of Systematic Shortening of Noncovalent C8 Side Chain on the Cytotoxicity and NF-κB Inhibitory Capacity of Pyrrolobenzodiazepines (PBDs)

Abstract

The systematic shortening of the non-covalent element of a C8-linked pyrrolobenzodiazepine (PBD) conjugate (13) led to the synthesis of a 19-member library of C8-PBD monomers. The critical elements of 13, which were required to render the molecule cytotoxic, were elucidated by an annexin V assay. The effects of shortening the non-covalent element of the molecule on transcription factor inhibitory capacity were also explored through an ELISA-based measurement of nuclear NF-κB upon exposure of JJN3 cells to the synthesised molecules. While shortening the non-covalently interactive element of 13 had a lesser than expected effect upon compound cytotoxicity due to reduced DNA interaction, the transcription factor inhibitory capacity of the molecule was notably altered. This study suggests that a relatively short non-covalent side chain at the C8-position of PBD is sufficient to confer cytotoxicity. The shortened PBD monomers provide a new ADC payload scaffold due to their potent cytotoxicity and drug-like properties.