Pyrrolobenzodiazepines (PBDs) and their dimers (bis-PBDs) have emerged as some of the most potent chemotherapeutic compounds, and are widely used as payloads in antibody drug conjugates. However, when used as stand-alone therapeutics or as the warhead for small molecule drug conjugates (SMDCs), the reactive imine functionality has the potential to cause off-target toxicities. As an elegant solution to this inherent problem, we designed conjugated prodrugs lacking the imine moiety. Once the prodrug (pro-PBD) conjugate enters a targeted cell, cleavage of the linker system triggers the generation of a reactive intermediate possessing an aldehyde and aromatic amine. An intramolecular reaction subsequently takes place as the aromatic amine adds to the aldehyde with the loss of water to give the imine, and as a result, the diazepine ring. In our pro-PBDs, we mask the aldehyde as a hydrolytically sensitive oxazolidine moiety as part of a reduction-cleavable disulfide linker system for conjugation. We designed and synthesized several novel warheads: pro-PBD dimers and hybrids of pro-PBD with DNA minor groove binders.

Pro-Pyrrolobenzodiazepine (pro-PBD) bioconjugates, part 1: Design and synthesis of pro-PBD conjugates containing a cleavable disulfide linker

254th National Meeting (2017)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.