Halogen-Substituted Meso-Bodipy Ethers as Effective Photosensitizers for Antimycotic Photodynamic Therapy

Abstract

In order to develop effective photosensitizers for antimycotic photodynamic therapy based on BODIPYs dyes, we conducted a comprehensive study of the influence of the molecular structure and solvent properties on the spectral, generation characteristics, photo-, pH stability and affinity to biostructures of alkyl-, halogen-substituted meso-BODIPY ethers. All studied dyes are endowed with intense chromophoric properties (lgε ~4.60–5.02 at =497–536 nm) and quite high stability in both acidic and alkaline media. It was found that bromination or iodination at the 2,6-positions of the pyrrole rings of meso-BODIPY ethers causes a noticeable (up to 36 nm and 44 nm) red shift of the maximum of the absorption and fluorescence bands, respectively, and sharp fluorescence quenching (up to φfl ~2–32 %), which is due to the manifestation of the “heavy” atom effect. Moreover, the halogen-substituted meso-BODIPY ethers demonstrated a high ability to generate singlet oxygen (up to Ф∆ ~50–78%) regardless of the nature of the solvent, compared to alkyl-substituted analogues. It has been shown that, regardless of the peripheral substitution features, the photodegradation of halogen-substituted complexes includes the initial stages of dehalogenation and proceeds according to a photosensitized mechanism. The introduction of a bulky ether substituent into the meso-position of the dipyrromethene core increases the stability of the dyes to UV exposure up to ~2.7 times due to screening of the methine meso-spacer, which is one of the most photoactive centres of BODIPYs. In addition, the combination of meso-substitution and halogenation at the 2,6-positions of the dipyrromethene core is accompanied by an increase of up to ~1.3 times the transport efficiency of meso-BODIPY ethers through the lipid layer of the cell membrane compared to meso-unsubstituted analogues.  The tropism of BODIPYs dyes for the cytoplasmic membranes of fungi has been revealed. It has been established that the iodo-substituted meso-BODIPY ether, capable of generating singlet oxygen, has an inhibitory effect on the vital activity of fungal cells.

Keywords: meso-BODIPY ethers, photosensitizer, photo- and pH stability, singlet oxygen, affinity to biostructures, pathogenic microorganisms