Zhang Shuo, Qiu Jingru, Zhang Hao, Chen Baolan, Zhang Xinke, Li Donghai, Li Guiling, Shan Gang
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province 250012, P. R. China.
Advanced Medical Research Institute, Meili Lake Translational Research Park, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, P. R. China.
J Med Chem. 2025 May 22;68(10):10048-10060. doi: 10.1021/acs.jmedchem.4c03075. Epub 2025 May 4.
Pyroptosis is a proinflammatory and lytic programmed cell death form, which can promote cytotoxic T lymphocyte (CTL) maturation and tumor infiltration through the release of damage-associated molecular patterns (DAMPs). Therefore, the induction of pyroptosis by small molecules is a promising strategy to activate antitumor immunity. In this work, we report the design of a new class of pyrazolo[1,5-]pyrimidine-based type-I photosensitizers (PSs) as efficient pyroptosis inducers for cancer photodynamic therapy (PDT). Among the compounds, exhibited the most excellent reactive oxygen species (ROS) generation ability and phototoxicity in vitro. It was found that induced cell pyroptosis through the caspase-3/gasdermin E (GSDME) pathway under light irradiation, characterized by bubble formation and damage-associated molecular pattern release. Furthermore, lipid nanoparticles significantly inhibited tumor growth and evoked antitumor immune responses in vivo.
细胞焦亡是一种促炎性和溶解性程序性细胞死亡形式，它可通过释放损伤相关分子模式（DAMPs）促进细胞毒性T淋巴细胞（CTL）成熟和肿瘤浸润。因此，小分子诱导细胞焦亡是激活抗肿瘤免疫的一种有前景的策略。在这项工作中，我们报道了一类新型的基于吡唑并[1,5 -]嘧啶的I型光敏剂（PSs）的设计，其作为癌症光动力疗法（PDT）中有效的细胞焦亡诱导剂。在这些化合物中， 在体外表现出最优异的活性氧（ROS）生成能力和光毒性。研究发现， 在光照下通过半胱天冬酶 - 3/ Gasdermin E（GSDME）途径诱导细胞焦亡，其特征为气泡形成和损伤相关分子模式释放。此外， 脂质纳米颗粒在体内显著抑制肿瘤生长并引发抗肿瘤免疫反应。
