Fan Zhuo, Teng Kun-Xu, Xu Yuan-Yuan, Niu Li-Ya, Yang Qing-Zheng
Institution Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing, 100875, P. R. China.
Angew Chem Int Ed Engl. 2025 Jan 2;64(1):e202413595. doi: 10.1002/anie.202413595. Epub 2024 Nov 14.
Although Type-I photodynamic therapy has attracted increasingly growing interest due to its reduced dependence on oxygen, the design of effective Type-I photosensitizers remains a challenge. In this work, we report a design strategy for Type-I photosensitizers by the involvement of hydrogen atom transfer (HAT). As a proof of concept, a HAT-involved Type-I PS, which simultaneously generates superoxide and carbon-centered radicals under light-irradiation, was synthesized. This photosensitizer is comprised of a fluorene-substituted BODIPY unit as an electron acceptor covalently linked with a triphenylamine moiety as an electron donor. Under light-irradiation, photo-induced intramolecular electron transfer occurs to generate the BODIPY anion radical and triphenylamine cation radical. The former transfers electrons to oxygen to generate O ⋅, while the latter loses a proton to produce a benzyl carbon-centered radical which is well characterized. The resulting carbon-centered radicals efficiently oxidize NADH by HAT reaction. This photosensitizer demonstrates remarkable photocytotoxicity even under hypoxic conditions, along with outstanding in vivo antitumor efficacy in mouse models bearing HeLa tumors. This work offers a novel strategy for the design of Type-I photosensitizers by involvement of HAT.
尽管I型光动力疗法因其对氧气的依赖性降低而越来越受到关注，但设计有效的I型光敏剂仍然是一项挑战。在这项工作中，我们报告了一种通过氢原子转移（HAT）来设计I型光敏剂的策略。作为概念验证，合成了一种涉及HAT的I型光敏剂，其在光照下同时产生超氧阴离子和碳中心自由基。这种光敏剂由芴取代的BODIPY单元作为电子受体与作为电子供体的三苯胺部分共价连接而成。在光照下，发生光诱导的分子内电子转移，生成BODIPY阴离子自由基和三苯胺阳离子自由基。前者将电子转移给氧气生成O₂•，而后者失去一个质子产生一个特征明确的苄基碳中心自由基。产生的碳中心自由基通过HAT反应有效地氧化NADH。这种光敏剂即使在缺氧条件下也表现出显著的光细胞毒性，在携带HeLa肿瘤的小鼠模型中具有出色的体内抗肿瘤疗效。这项工作通过涉及HAT为I型光敏剂的设计提供了一种新策略。
