Abstract
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.
Highlights
Since their discovery in Streptomyces bacteria over half a century ago, pyrrolo[2,1-c][1,4]benzodiazepine (PBD) structures have been of interest as possible chemotherapeutic agents
PBD structures have been found to form covalent bonds with some guanines in the DNA minor groove more frequently than others, those flanked by purine bases,5,9 more recent data suggest kinetic preferences when guanines are flanked by pyrimidines
We investigated some of these uncertainties through the systematic shortening of a C8-linked monomer (13, Figure 1C) containing a pyrrole−benzofuran motif which has been previously explored in both noncovalent distamycin25 and covalent duocarmycin analogues26 and the subsequent generation of a library of 19 C8-linked PBD monomers
Summary
Since their discovery in Streptomyces bacteria over half a century ago, pyrrolo[2,1-c][1,4]benzodiazepine (PBD) structures have been of interest as possible chemotherapeutic agents. PBD structures have been found to form covalent bonds with some guanines in the DNA minor groove more frequently than others, those flanked by purine bases, more recent data suggest kinetic preferences when guanines are flanked by pyrimidines.10 This potential for relative selectivity of binding is of interest, given that the pathogenesis of many cancers is associated with the aberrant binding of transcription factors, such as nuclear factor kappa B (NF-κB), to sequence-specific promoter regions of DNA.− The conjugation of subunits, capable of noncovalent interactions with DNA bases, to the C8 position of the PBD structure (via a carbon linker of variable length) has led to the development of hybrid molecules that can interact selectively with longer sequences of DNA than the typical purine− guanine−purine motifs of unmodified PBD structures. The effect of the reduction of the noncovalent element of the hybrid on both transcription factor activity and overall cytotoxicity was evaluated
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call