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

Nature has perfected the reversible control over the activity of molecules and biomolecules in the human body. Pho- tocages aim to mimic this control in space and time 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 which are crucial to translating photocages into a widely accepted tool beyond chemical space. Here, we report a robust and user-friendly protocol that enables the installation of complex amine, thiol and phenol pay- loads in a single step under mild conditions and using bench-stable in- termediates. 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 anti-cancer agents. As a proof of concept, we applied this strategy to cage the clinically approved CDK4/6 inhibitor palbo- ciclib and evaluated its near-infrared (NIR) light-dependent activation in modulating the tumor-suppressing retinoblastoma protein. We an- ticipate that this user-friendly synthetic approach to accessing NIR- absorbing photocages will accelerate research across various scientific disciplines.