Near-Infrared-Activated Photocages Made to Order: Late-Stage Caging Protocol

Abstract

Nature has perfected the reversible control over the activity of molecules and biomolecules in the human body. Photocages aim to mimic this control in space and time by using light as a trigger, and the field has witnessed many excellent contributions that extend their use to the tissue-penetrating region. Yet little attention has been paid to developing simple caging strategies that are crucial to translating photocages into a widely accepted tool outside the chemistry field. Here, we report a robust and user-friendly protocol that enables the installation of complex amine, thiol, and phenol payloads in a single step under mild conditions and using bench-stable intermediates. The protocol displays excellent compatibility with a range of payloads, manifested by caging hormones, neurotransmitters, a tripeptide, and many highly complex FDA-approved drugs, including antibiotics and anticancer agents. As a proof of concept, we applied this strategy to cage the clinically approved CDK4/6 inhibitor palbociclib and evaluated its near-infrared (NIR) light-dependent activation in modulating tumor-suppressing retinoblastoma protein. We anticipate that this user-friendly synthetic approach to accessing NIR-absorbing photocages will accelerate research across various scientific disciplines.