Chlorin-based symmetrical and unsymmetrical dimers with amide linkages: effect of the substituents on photodynamic and photophysical properties

Abstract

In this study, we report syntheses, in vivo biological activity, and photophysical properties of a series of chlorin-based symmetrical and unsymmetrical dimers with amide linkages. All compounds exhibited strong absorption maxima at wavelengths ranging between λ_max 660 and 702 nm. Compared with the formylpyropheophorbide a dimer 7 and purpurin 18 dimer 9 containing electron-withdrawing substituents at peripheral positions, pyropheophorbide a dimer 6, 3-devinyl-3-(1-hexyloxyethyl)pyropheophorbide a dimer 8, and unsymmetrical dimer 12 in which the chlorin e₆ and 3-devinyl-3-(1-hexyloxyethyl)pyropheophorbide a moieties are linked with amide bonds, produced high fluorescence yields. For all photosensitizers, energy transfer from the sensitizer triplet to the ground state of oxygen is irreversible with rate constants k_TΣ ≈ 2 × 10⁹ M⁻¹ s⁻¹, a value in the diffusion-limited rate range. This energy transfer resulted in relatively high singlet oxygen quantum yields (Φ_Δ ≈ 0.50 for compounds 12 and 8; and Φ_Δ ≈ 0.30 for compounds 6 and 7). Among these dimers, compound 9 with a six-membered anhydride ring system produced the lowest singlet oxygen quantum yield (Φ_Δ 0.06). The in vivo PDT efficacy of these compounds was evaluated in DBA/2 mice bearing SMT/F tumors. Among all the dimers, the unsymmetrical dimer 12 was found to be most effective, but it was significantly less active than the related monomer 3-devinyl-3-(1-hexyloxyethyl)pyropheophorbide a2.