Photocages Made to Order: Late-Stage Caging Protocol Enables Anti-Cancer Control with Near-Infrared Light

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 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 translate photocages into a widely accepted tool beyond chemical space. Here, we report a robust and user-friendly protocol that enables installation of amine, thiol and phenol payloads in a single step under mild conditions and using bench-stable intermediates. The protocol displays excellent compatibility with payloads, manifested by caging hormones, neurotransmitters, a tripeptide and many highly complex FDA-approved drugs, including antibiotics or anti-cancer agents. In a proof-of-concept study, we utilize this strategy to cage the clinically used CDK4/6 inhibitor palbociclib and control the activity of the tumor suppressing retinoblastoma protein in human breast cancer cells by near-infrared (NIR) light. We anticipate that normalizing the access to NIR-absorbing photocages through this protocol will empower research across various scientific disciplines.