Optimized xanthenium photocages with fused ring systems for photoactivated chemotherapy and GPCR photopharmacology

Photocages are light-responsive chemical protecting groups that enable the controlled release of bioactive molecules. As the need for precise spatiotemporal manipulation in increasingly complex systems continues to grow, the development of novel photocage scaffolds remains essential. Herein, we show how the structural and electronic properties of xanthenium photocages determine their ground state stability. Based on rational design, we introduce their next generation built on the julolidine auxochrome, resulting in ultra efficient, green to red light activatable photocages, X590 and X600H. X590 was applied in the light-controlled delivery of a potent tubulin inhibitor, monomethyl auristatin E (MMAE) and a topoisomerase inhibitor (SN38) with low light doses above 600 nm. The light activatable prodrugs possess excellent photoindices both in 2D cell cultures and 3D tumor spheroids and show anti-tumor effects in the chorioallantoic membrane (CAM) assay in live chicken embryos. The versatility of this new scaffold was demonstrated using a caged agonist for the light activation of serotonin 2C G protein-coupled receptor. Overall, these photocages should find wide applications in photopharmacology and the detailed studies presented herein could contribute to the clinical translation of photoactivated chemotherapy.