Advanced Pyrrolidine‐Carbamate Self‐Immolative Spacer with Tertiary Amine Handle Induces Superfast Cyclative Drug Release

Abstract Amine‐carbamate self‐immolative (SI) spacers represent practical and versatile tools in targeted prodrugs, but their slow degradation mechanism limits drug activation at the site of disease. We engineered a pyrrolidine‐carbamate SI spacer with a tertiary amine handle which strongly accelerates the spacer cyclization to give a bicyclic urea and the free hydroxy groups of either cytotoxic (Camptothecin) or immunostimulatory (Resiquimod) drugs. In silico conformational analysis and p K a calculations suggest a plausible mechanism for the superior efficacy of the advanced SI spacer compared to state‐of‐art analogues.