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

The
systematic shortening of the noncovalent 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 noncovalent element of the molecule on transcription factor inhibitory
capacity were also explored through an enzyme-linked immunosorbent
assay-based measurement of nuclear NF-κB upon exposure of JJN-3
cells to the synthesized molecules. Although shortening the noncovalent
interactive element of 13 had a less 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 noncovalent side chain at the
C8 position of PBD is sufficient to confer cytotoxicity. The shortened
PBD monomers provide a new ADC payload scaffold because of their potent
cytotoxicity and drug-like properties.