Comparison of the PDT and PACT activities of a series of water-soluble AAAB, ABAB, AABB, ABBB and BBBB Sn(IV) tetraarylporphyrins

Abstract

Cancer kills more people every year than tuberculosis, malaria, and AIDS combined. More than 60% of all cases are found in Africa, Latin America, and Asia. There is an ongoing need to identify and develop new treatments to diminish the mortality rate and increase life expectancy. Chemotherapy and radiotherapy can be used to treat cancer, but due to their severe side effects, photodynamic therapy (PDT) was developed as an alternative non-invasive method. To effectively and successfully treat cancer through PDT, a photosensitiser dye, a light source and singlet oxygen are required. PDT is used to treat skin, breast and prostate cancer, among others, that are readily accessible with a fibre optic. A photosensitiser dye is administered intravenously and accumulates in cancerous tumour cells. Since laser light is involved, the dye should absorb in the phototherapeutic window (620−850 nm), since haemoglobin and other pigments absorb at shorter wavelength, while water absorbs at longer wavelength. The aim of this study is to explore how readily synthesised tetraphenyl porphyrins, which absorb weakly at the higher energy edge of the phototherapeutic window, can be structurally modified to make them more suitable for biomedical photosensitiser dye applications by introducing 4-piperidinylphenyl groups introduced at the meso-positions. The porphyrinoids synthesised will be divided into four series: AAAB (Series 1), ABAB/AABB (Series 2), ABBB (Series 3) and BBBB (Series 4). The difference across these series relates to the number of 4-piperidinylphenyl groups introduced. The Sn(IV) ion was inserted within the porphyrin central cavity since its trans-axial ligation hinders aggregation that can negatively impact the photophysical properties of the dyes. The metalation enhances the singlet oxygen quantum yield. A red shift of the lowest energy Q band of the Sn(IV) complexes of Series 1−4 to the edge of the phototherapeutic window is observed relative to the parent Sn(IV) tetraphenylporphyrin complex due to the presence of the 4-piperidinylphenyl groups. Quaterisation of the 4-piperidinylphenyl nitrogen atoms was carried out to increase the water solubility of the porphyrin ligand and enhance its suitability for biomedical applications. In vitro PDT and PACT activity studies have been carried out to assess the photodynamic activity of the porphyrinoids, and it can be elucidated that for the porphyrinoids to be photodynamically active, there should be a balance between their hydrophobicity and lipophilicity. All porphyrin analogues exhibited minimal dark cytotoxicity and high photodynamic (PDT) activity against MDA breast cancer cells. The IC50 values obtained for 3-Sn and 3-Sn-Q were > 1.79 and 1.09 μM, respectively, after irradiation with a 595 nm Thorlabs LED for 60 min. Series 1 (1-Sn-Q) and 2 (2-Sn-Q) exhibited exceptional antimicrobial activity against S. aureus bacteria with Log10 reduction values of 5.11 and 7.49, respectively, which demonstrates that the antimicrobial activity of the porphyrin analogues does not correlate with the number of charges on the quaternised nitrogen atoms of the 4-piperidinylphenyl groups. Molecular docking studies were conducted to determine the probable pharmacological properties of the porphyrin analogues, and the results demonstrate that the compounds violate Lipinski’s rule of five. Therefore, they cannot be used as orally active drugs but can administered as intravenous injections similar to Photofrin®. The porphyrinoids have exceptional ADMET properties and are predicted to be non-carcinogenic.