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

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 (λmax 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 (λmax 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.