Engineering Rapid Payload Release Rate in 1,6‐Elimination Processes of Self‐Immolative Linkers

ABSTRACT Stimuli‐responsive prodrugs form the foundation of targeted medicine. These compounds, once activated at the site of interest, release their bioactive payload, often through elimination from self‐immolative linkers (SILs). However, payload release rates from activated SILs can vary widely depending on the SIL's (electronic) structure. Low release rates do not compete with diffusion of the activated prodrug from the target site, which compromises the spatial resolution and diminishes the practical utility. Here we report a new strategy to engineer the payload release rate from SILs through the introduction of cation‐stabilizing substituents, which yields an up to 10 4 ‐fold improvement in rate constant compared to the reference SIL. Relating the DFT‐computed stabilities of an ion pair intermediate with the first order rate constants for self‐immolation revealed a strong correlation, providing a robust rational basis for our strategy. Furthermore, we discovered that lipophilicity of the SIL‐payload conjugate is a key, and hitherto overlooked, factor affecting the rate, based on which we propose a new model for the overall payload release reaction. Lastly, we show the practical utility of our strategy, through demonstrating the superiority of our SILs in releasing the anticancer drug palbociclib and studying radiation‐dependent enzyme inhibition and cell‐cycle alteration.