1 research outputs found
Latent Warheads for Targeted Cancer Therapy: Design and Synthesis of pro-Pyrrolobenzodiazepines and Conjugates
Pyrrolobenzodiazepines
(PBDs) and their dimers (bis-PBDs) have
emerged as some of the most potent chemotherapeutic compounds, and
are currently under development as novel payloads in antibody–drug
conjugates (ADCs). However, when used as stand-alone therapeutics
or as warheads for small molecule drug conjugates (SMDCs), dose-limiting
toxicities are often observed. As an elegant solution to this inherent
problem, we designed diazepine-ring-opened 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
ring-closing 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 which in turn is
a part of a reductively labile self-immolative linker system. To prove
the range of applications for this new class of latent DNA-alkylators,
we designed and synthesized several novel latent warheads: pro-PBD
dimers and hybrids of pro-PBD with other sequence-selective DNA minor
groove binders. Preliminary preclinical pharmacology studies showed
excellent biological activity and specificity