Synthesis and evaluation of novel meso-coumarin-substituted dithieno[3,2-b]thiophene BODIPY derivatives for photodynamic therapy.

Abstract

To develop a new photosensitizer for photodynamic therapy featuring strong absorption, high efficacy, and low toxicity, a series of meso-coumarin-modified dithieno[3,2-b]thiophene BODIPY derivatives with tunable side chains were designed and synthesized. These compounds exhibit intense absorption in the 640-730 nm region and obvious photodynamic activities in vitro. Among them, compound Cou-BDP-3, bearing a diethylene glycol side chain, displayed the highest molar extinction coefficient (1.44 × 105 M-1 cm-1,at 659 nm), negligible dark toxicity (>93% cell viability at 0.12 μM), and highly efficient photodynamic activity against Eca-109 cells with an IC50 value of 19.2 nM. This compound could accumulate selectively in the endoplasmic reticulum (Rr = 0.935), produce reactive oxygen species (ROS) upon photoactivation, and trigger the cellular apoptosis. The in vivo test showed that complete tumor regression in 3 of 5 tumors (60%) at low concentration of 0.1 mg/kg and low light dose of 20 J/cm2, without detectable systemic toxicity. Therefore, Cou-BDP-3 represents a promising photosensitizer candidate for precision photodynamic therapy.