In Silico Investigation of Structure-Activity Relationships in Thiophene-Containing BODIPY Photocages

As the development of small molecule drugs continues at rapid pace, off-target side effects and toxicities have emerged as major causes for concern. To this end, a range of photoliable protecting groups (PPGs) have been proposed as possible strategies to mitigate such side effects through selective uncaging only at affected areas. However, many photocages suffer from poor reactivity, toxicity and the need for high-energy ultraviolet radiation for uncaging. In this study, comprehensive structure-activity relationships of an emerging PPG, thiophene-containing boron-dipyrromethene (BODIPY), have been investigated via ab initio Density Functional Theory (DFT) calculations. Singlet-triplet gaps and Spin Orbit Coupling Matrix Elements (SOCME) were calculated for all tested compounds, and the El-Sayed’s rule was employed to rationalise differences in singlet-triplet intersystem crossing (ISC) rates between compounds. Through these analyses, we propose optimal thiophene-containing BODIPY structures that exhibit good absorption at longer wavelengths and promising intersystem crossing rates, findings that will certainly aid in the optimisation of future photodynamic therapies.