Computational Study on the Mechanism of the Photouncaging Reaction of Vemurafenib: Toward an Enhanced Photoprotection Approach for Photosensitive Drugs.

The photochemical behavior of the photosensitive first-line anticancer drug vemurafenib (VFB) is of great interest due to the impact of such behavior on its pharmacological activity. In this work, we computationally elucidated the mechanism of the photoinduced release of VFB from the 4,5-dimethoxy-2-nitrobenzene (DMNB) photoprotecting group by employing various density functional theory (DFT)/time-dependent DFT (TD-DFT) approaches. The computational investigations included a comparative assessment of the influence of the position of the photoprotecting group as a substituent on the thermodynamics and kinetics of the photouncaging reactions of two VFB-DMNB prodrugs, namely pyrrole (N) and sulfonamide (N). With the aid of the DFT calculations concerning the activation energy barrier (∆G), the obtained results suggest that the step of the photoinduced intramolecular proton transfer of the DMNB moiety is not detrimental concerning the overall reaction profile of the photouncaging reaction of both prodrugs. However, the obtained results suggested that the position of the substitution position of the DMNB photoprotecting group within the prodrug structure has a substantial impact on the photouncaging reaction. In particular, the DMNB-N-VFB prodrug exhibited a notable increase in ∆G for the key step of ring opining within the DMNB moiety indicative of potentially hindered kinetics of the photouncaging process compared with DMNB-N-VFB. Such an increase in ∆G may be attributed to the electronic influence of the N fragment of the prodrug. The results reported herein elaborate on the mechanism of the photoinduced release of an important anticancer drug from photoprotecting groups with the aim of enhancing our understanding of the photochemical behavior of such photosensitive pharmaceutical materials at the molecular level.