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<p>Phenols are extremely difficult to release the hydrogen radical (H<sup>•</sup>) due to the disfavored O–H bond dissociation energy (BDE) and undergo O–H homolysis under strong ultraviolet-C (UVC) light. In this work, we provided a method to modulate the O–H BDE of phenols by <i>π</i>-conjugation to electron-donating heteroaromatics. Calculations on a phenol-cored photosensitizer (BTP-1) revealed drastic declines of O–H BDE (80.5 vs. 28.1 kcal mol<sup>−1</sup>) by comparing the ground state (S<sub>0</sub>) and triplet excited state (T<sub>1</sub>). Consequently, BTP-1 was sensitive to visible light and generated H<sup>•</sup> after O–H scission. With glutathione (GSH) serving as an ultimate H<sup>•</sup> donor, the BTP-1-based photosystem was efficient in catalyzing H<sup>•</sup> generation under physiological conditions. This kind of hydrogen atom-based photochemistry is distinct from traditional type I/II photosensitizing pathways that are electron or energy transfer-based. We applied the photosystem to solve the obstacle in hypoxia-activated prodrugs (HAPs) that face a dilemma with the heterogeneously hypoxic level of tumors. <i>In vitro</i> studies demonstrated that the photosystem boosted the chemotherapy performance of TH-302 (a representative HAP) under moderate hypoxia. With the capability to target redox bonds in HAPs and good compatibility with near-infrared two-photon laser, the photosystem is promising for cancer precision therapy.</p>

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Hydrogen radical-based prodrug photoactivation by modulating bond dissociation energy of a phenolic photosensitizer

  • 期刊论文

  • 发表日期：

    2025年4月23日

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  • Jian Sun,
  • Jinlei Peng,
  • Junwei Zhou,
  • Xiaoran Zhang,
  • Chuanwei Zhu,
  • Rong Wang,
  • Fude Feng,
  • Shu Wang

摘要

Phenols are extremely difficult to release the hydrogen radical (H•) due to the disfavored O–H bond dissociation energy (BDE) and undergo O–H homolysis under strong ultraviolet-C (UVC) light. In this work, we provided a method to modulate the O–H BDE of phenols by π-conjugation to electron-donating heteroaromatics. Calculations on a phenol-cored photosensitizer (BTP-1) revealed drastic declines of O–H BDE (80.5 vs. 28.1 kcal mol−1) by comparing the ground state (S0) and triplet excited state (T1). Consequently, BTP-1 was sensitive to visible light and generated H• after O–H scission. With glutathione (GSH) serving as an ultimate H• donor, the BTP-1-based photosystem was efficient in catalyzing H• generation under physiological conditions. This kind of hydrogen atom-based photochemistry is distinct from traditional type I/II photosensitizing pathways that are electron or energy transfer-based. We applied the photosystem to solve the obstacle in hypoxia-activated prodrugs (HAPs) that face a dilemma with the heterogeneously hypoxic level of tumors. In vitro studies demonstrated that the photosystem boosted the chemotherapy performance of TH-302 (a representative HAP) under moderate hypoxia. With the capability to target redox bonds in HAPs and good compatibility with near-infrared two-photon laser, the photosystem is promising for cancer precision therapy.