Unraveling solvent and substituent effects in the photodynamics of light-dependent microtubule inhibitors for cancer phototherapy

In photopharmacology, molecular photoswitches enable light-controlled drug activities, offering precision in targeting biomolecular functions while minimizing side effects. For instance, photostatins (PSTs) have recently been designed to inhibit tubulin polymerization for cancer treatment in a light-dependent manner. However, the influence of substituents and molecular environments on their photochemistry remains unclear. In this work, the cis-to-trans photodynamics of five PSTs (PST1 to PST5) in the vacuum and aqueous solution were simulated using the ab initio multiple spawning (AIMS) coupled with correlated multireference electronic structure calculations. Four distinct minimum energy conical intersections (MECIs) were discovered and confirmed by optimizations using highly accurate multireference methods, and they serve as major non-radiative decay channels. The aqueous environment slows photoisomerization and lowers its quantum yields. Substituent position and electronegativity significantly impact the isomerization kinetics by altering energy gaps between MECIs and the S1 state at the Franck-Condon region. We also suggest a multiscale approach to preparing initial conditions for non-adiabatic dynamics simulations in order to generate unbiased results. These findings provide useful insights into designing next-generation phototherapeutics for cancer.