Pyridinium- and bromine-substituted distyryl-BODIPY dyes for mitochondria-targeted photodynamic therapy

A series of 1-methylpyridinium-substituted brominated distyryl-BODIPY dyes, PyBXI (X = H, M, or Br), was synthesized to achieve cooperative singlet oxygen (¹O₂) production through qualitatively different dual intersystem crossing (ISC) pathways: spin-orbit charge-transfer ISC (SOCT-ISC) and heavy-atom-induced ISC. Upon photoexcitation of the PyBXI dyes, charge-transfer states were preferentially formed through photoinduced electron transfer from the distyryl-BODIPY core to the 1-methylpyridinium moiety, however, followed by nonradiative charge recombination rather than the desired SOCT-ISC. This resulted in negligible fluorescence and ¹O₂ quantum yields in the non-brominated dye PyBHI. The introduction of bromine atoms improved ¹O₂ quantum yield from 0.0034 for the mono-brominated dye PyBMI to 0.0061 for the di-brominated dye PyBBrI, attributable to the heavy atom effect. Nonetheless, the ¹O₂ production efficiency of these dyes remained limited, as photoinduced electron transfer was considered to occur nearly two orders of magnitude faster than singlet-to-triplet ISC. In vitro assays using MCF-7 and HeLa cells demonstrated that PyBBrI induced significant cell death, with IC₅₀ values of ca. 95 and 220 nM, respectively, confirming its potential for use in cancer therapy.