Naturally occurring pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) are a group of highly potent antitumor antibiotics, isolated from various streptomycin species. PBDs covalently bond and cross-link with discrete sequences of base pairs in the minor groove of DNA. A wide range of synthetic PBDs and PBD dimers have been shown to be highly potent cytotoxic agents, and have been used as payloads in antibody drug conjugates (ADCs). However, all PBDs as stand-alone agents or as delivered via small molecule drug conjugates (SMDCs), cause undesired off-target toxicity. Recently, we designed folate conjugated pro-PBDs, masking the imine moiety with its synthetic precursors: namely, 1,3-oxazolidine carbamate and an aromatic amine. The 1,3-oxazolidine carbamate provided a conjugation site for attachment of pro-PBD to a targeting ligand. After delivery to the targeted cell and internalization, reductive cleavage of the linker system results in the generation of a 1,3-oxazolidine. The oxazolidine reacts with water to form an aldehyde which subsequently reacts intramolecularly to ultimately form the PBD diazepine ring. Herein, we report the design and synthesis of folate conjugates of pro-PBDs and self-immolative sterically hindered disulfide linker systems, which pave the way toward novel, highly-specific therapeutics which have the potential to minimize off-target toxicities.

pro-Pyrrolobenzodiazepine (pro-PBD) bioconjugates, part 3: Design and synthesis of pro-PBD conjugates containing a self-immolative substituted disulfide linkers

256th National Meeting (2018)

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