Studies toward the duocarmycin prodrugs for the antibody prodrug therapy approach

A tricyclic precursor for the synthesis of the prodrugs of pro-1,2,9,9a-tetrahydrocyclopropa[c]benz-[e]indole-4-one tetramethoxyindolecarboxamide (CBI-TMI) was prepared using the ring-closing metathesis approach. The tricyclic intermediate was converted to an advanced precursor of a CBI-TMI prodrug equipped with a linker presumably suitable for activation using the aldolase catalytic antibody 38C2. An attempted 38C2-catalyzed two-step activation of the hydroxy-pro-CBI intermediate involving retro-aldol and the β-elimination reactions was also examined.

Graphical abstractA tricyclic intermediate was prepared using the ring-closing metathesis approach, which serves as a precursor to the synthesis of CBI analogs and their prodrugs, including one designed for the aldolase Ab 38C2-catalyzed activation.Download full-size image