Folic acid (FA) is a high affinity natural ligand that binds to the folate receptor which is over-expressed on the cell surface in a variety of cancers. The pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) are a group of antitumor antibiotics which exert their biological activity by sequence-selective DNA minor-groove binding that form a covalent aminal bond between their C11-position and the C2-NH<sub>2</sub> groups of guanine bases. The PBD dimers which contain two alkylating imines could form nondistorting interstrand DNA cross-links. They exhibited potent cytotoxicity, antitumor activity, and antibacterial activity. Unfortunately, all PBDs and their conjugates cause undesired off-target toxicity. In an attempt to improve the therapeutic index of PBD conjugates, we designed a novel class of prodrugs referred to as pro-PBDs. In our approach, the imine moiety in the PBD molecular framework was converted to its two parental integral parts: an aromatic amine and an aldehyde. Next, we integrated the aldehyde into the oxazolidine ring system. This pro-PBD motif was further connected to FA through an enzymatically-cleavable peptide-based linker system and a spacer unit. When such a conjugate enters diseased cells upon receptor targeting and receptor-mediated endocytosis, an active PBD will be formed as a result of enzymatic fragmentation of the linker system.

Pro-Pyrrolobenzodiazepine (pro-PBD) bioconjugates, part 2: Design and synthesis of pro-PBD conjugates containing an enzyme-responsive linker

254th National Meeting (2017)

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