Antiproliferative activity of meso-substituted BODIPY photocages: Effect of electrophiles vs singlet oxygen

Abstract

A series of BODIPY compounds with a methylphenol substituent at the meso-position and halogen atoms on the BODIPY core, or OCH₃ or OAc substituents at the phenolic moiety was synthesized. Their spectral and photophysical properties and the photochemical reactivity upon irradiation in CH₃OH were investigated. The molecules with the phenolic substituent at the meso-position undergo more efficient photo-methanolysis at the boron atom, while the introduction of the OCH₃ group at the phenolic moiety changes the reaction selectivity towards the cleavage at the meso-position. The introduction of the halogen atoms into the BODIPY increases the photo-cleavage reaction efficiency, as well as the ability of the molecules to sensitize oxygen and form reactive oxygen species (ROS). The efficiency of the ROS formation was measured in comparison with that of tetraphenylporphyrin. The antiproliferative effect of BODIPY molecules was investigated against three human cancer cell lines MCF-7 (breast carcinoma), H460 (lung carcinoma), HCT116 (colon carcinoma), and two non-cancer cell lines, HEK293T (embryonic kindey) and HaCaT (keratinocytes), with the cells kept in the dark or irradiated with visible light. For most of the compounds a modest or no antiproliferative activity was observed for cells in the dark. However, when cells were irradiated, a dramatic increase in cytotoxicity was observed (more than 100-fold), with IC₅₀ values in the submicromolar concentration range. The enhancement of the cytotoxic effect was explained by the formation of ROS, which was studied for cells in vitro. However, for some BODIPY compounds, the effects due to the formation of electrophilic species (carbocations and quinone methides, which react with biomolecules) cannot be disregarded. Confocal fluorescence microscopy images of H460 cells and HEK293T show that the compounds enter the cells and are retained in the cytoplasm and membranes of the various organelles. When the cells treated with the compounds are irradiated, photo-processes lead to cell death by apoptosis. The study performed is important because it provides bases for the development of novel photo-therapeutics capable of exerting photo-cytotoxic effects in both oxygenated and hypoxic cells.

Keywords: Antiproliferative activity; BODIPY; Photocages; Quinone methides; Reactive oxygen species.