Synthesis, Structure-Property Relationships, and Photodynamic Activity of Heavy-Atom-Free BODIPY Photosensitizers Based on Spin-Orbit Charge Transfer.

Abstract

The geometrically orthogonal donor-acceptor (D-A) architecture, which favors spin-orbit charge-transfer intersystem crossing (SOCT-ISC), has emerged as a promising strategy for developing heavy-atom-free photosensitizers. However, systematic structure-property relationship (SPR) studies for such systems remain limited. In this work, we designed and synthesized 18 orthogonal D-A BODIPY derivatives modified with diverse electron-donating and electron-withdrawing groups. SPR investigation established that the meso-anthryl moiety and quaternary ammonium groups at the 3,5- and 2,6-positions significantly enhanced D-A interaction, reduced ΔEST, strengthened spin-orbit coupling (SOC), and thereby promoted SOCT-ISC, leading to markedly increased ROS generation (∼20-fold vs Chlorin e6). Importantly, the optimized compound An-DQA-OM, formulated as nanoparticles (ADO NPs), exhibited potent oxygen-independent photocytotoxicity (IC50 ≈ 0.39 μM in normoxia and 0.79 μM in hypoxia) and strong in vivo antitumor efficacy. This work presented a SPR paradigm for the rational design of efficient, heavy-atom-free BODIPY photosensitizers via the SOCT-ISC mechanism.

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