Water-Soluble, Core-Modified Porphyrins as Novel, Longer-Wavelength-Absorbing Sensitizers for Photodynamic Therapy. II. Effects of Core Heteroatoms and Meso-Substituents on Biological Activity

Abstract

Water-soluble, core-modified porphyrins were prepared and evaluated as sensitizers for photodynamic therapy (PDT). The addition of an aromatic aldehyde to 2,5-dilithiothiophene or -selenophene gave diol 3 as a nearly equimolar mixture of meso and d,l diastereomers, which gave a single diastereomer following careful recrystallization. The condensation of pyrrole with a diol 3 using catalytic BF₃-etherate gave bispyrrolochalcogenophenes (4). Condensation of a diol 3 with 4 in the presence BF₃-etherate gave 21,23-dichalcogenaporphyrins (5). 21-Thiaporphyrins (6) were prepared by condensation of a diol 3 with excess pyrrole and benzaldehyde in the presence of tetrachlorobenzoquinone and catalytic BF₃-etherate. Sulfonation of 5 and 6 with concentrated sulfuric acid at 100 °C gave sulfonated derivatives 7−15. Bis-4-methoxy-21,23-dithiaporphyrins 5h and 5l were demethylated with BBr₃, and the resulting phenols were alkylated with ethyl bromoacetate. Saponification gave 21,23-dithiaporphyrin dicarboxylate salts 16 and 17. The 21,23-core-modified porphyrins gave band I absorption maxima (λ_max of 689−717 nm) at longer wavelengths than band I for the corresponding 21-core-modified porphyrins, but both classes had band I maxima at longer wavelengths than either TPPS₄ or Photofrin (λ_max of 630 nm for both). The core heteroatoms had little effect on either absorption maxima or quantum yields of singlet oxygen generation in 7−17. The meso substituents had a greater impact on absorption maxima. Compounds 7−17 were evaluated for phototoxicity against Colo-26 cells in culture using 4 J cm^-2 of 570−800 nm light. Compounds 8−12, 14, 16, and 17 gave a 50% cell kill in vitro at a lower concentration than Photofrin [5.7 mg (9 μmol)/kg]. Compounds 14, 16, and 17 gave a 50% cell kill with 4 J cm^-2 of light and submicromolar concentrations of sensitizer. Sensitizers 8 and 11 showed no toxicity or side effects in BALB/c mice observed for 90 days following a single intravenous injection of 10 mg/kg of sensitizer. Distribution studies show that sensitizer 8 accumulates in the tumors of BALB/c mice. PDT with 8 at 0.125 mg (0.13 μmol)/kg or 11 at 2.5 mg (2.5 μmol)/kg and 135 J cm^-2 of 694 nm light was comparable to PDT with Photofrin at 2.5 mg (4 μmol)/kg and 135 J cm^-2 of 630 nm light against Colo-26 tumors in BALB/c mice.