Abstract
Self‐immolative linkers that use p‐amino/hydroxy‐benzyloxycarbonyl (PABC/PHBC) spacers are essential to the mechanism of many prodrugs. However, a highly reactive (aza)quinone methide is generated as a potential toxic byproduct. To remove the methide as it forms, we synthesized a series of novel tripartite prodrugs, comprising different triggers (nitro, amide, azide, boronate) and a PABC/PHBC‐type self‐immolative spacer with an integrated nucleophile (amine). Upon reductive, hydrolytic or oxidative trigger activation, the release of the cargo is facilitated via a 1,6‐elimination that generates a reactive (aza)quinone methide. With the built‐in nucleophile, the (aza)quinone methide is rapidly self‐quenched to generate tetrahydroisoquinolines (THIQs). One of the selected THIQs does not exhibit an anti‐proliferative effect on the A431 mammalian tumor cell line. The new prodrug strategy has broad scope, enabling the use of a trigger that matches the targeted stimulus, while allowing for a diverse range of drug/cargo attachment. This proof‐of‐concept study adds a new linker strategy that quenches the electrophilic (aza)quinone methide generated in many self‐immolative linker systems and could find applications in prodrug and antibody‐drug conjugate strategies, or as a linker for probes in chemical biology.