Levine Matthew S, Sen Sajal, Maier Esther Y, Mota Mireya, Won Miae, Li Jiexi, Arambula Jonathan F, Lynch Vincent M, Kim Jong Seung, DePinho Ronald A, Iverson Brent, Sessler Jonathan L
Department of Chemistry, The University of Texas at Austin, 105 East 24th Street Stop A 5300, Austin, Texas 78712-1224, United States.
Innovating 4 Health, College of Pharmacy, The University of Texas at Austin, 1400 Barbara Jordan Blvd, Austin, Texas 78723, United States.
J Am Chem Soc. 2025 Jul 9;147(27):23574-23582. doi: 10.1021/jacs.5c03455. Epub 2025 Jun 26.
Immunogenic cell death (ICD) is a form of regulated cell death that engages the immune system by releasing damage-associated molecular patterns, making it a promising target for cancer immunotherapy. Presented here is the synthesis and evaluation of a series of asymmetric redox-active water-soluble Au(I) bis-N-heterocyclic carbenes (Au(I) bis-NHCs). We explore the structure-activity relationships between redox activity, water solubility and ICD induction, building on our previous work with a redox-active Au(I) bis-NHC () that effectively induced ICD but suffered from poor water solubility. To overcome this limitation, we synthesized several water-soluble redox-active Au(I) bis-NHCs, derivatives , by modifying the imidazole moiety. Compound was identified as the lead, balancing water solubility and ICD induction efficacy. This compound, featuring a naphthoquinone moiety, and was found to generate reactive oxygen species (ROS) and trigger key ICD biomarkers, including calreticulin (CRT) translocation, ATP release, and high mobility group box 1 (HMGB1) secretion. A control compound lacking the redox active naphthoquinone failed to elicit these ICD markers or promote ROS production. Across the series a correlation was observed between ROS generation and ICD biomarker expression. In vivo studies in syngeneic immunocompetent mice demonstrated that compound not only prevents CT26 colorectal cancer tumor growth upon challenge with live cancer cells but also elicits a long-lived immune response upon rechallenge 12 months later.
免疫原性细胞死亡（ICD）是一种程序性细胞死亡形式，通过释放损伤相关分子模式激活免疫系统，使其成为癌症免疫治疗的一个有前景的靶点。本文介绍了一系列不对称氧化还原活性水溶性金（I）双氮杂环卡宾（Au（I）双氮杂环卡宾）的合成与评价。我们基于之前对一种氧化还原活性Au（I）双氮杂环卡宾（）的研究，该化合物能有效诱导ICD，但水溶性较差，在此基础上探索氧化还原活性、水溶性与ICD诱导之间的构效关系。为克服这一局限性，我们通过修饰咪唑部分合成了几种水溶性氧化还原活性Au（I）双氮杂环卡宾衍生物。化合物被确定为先导化合物，平衡了水溶性和ICD诱导效果。该化合物具有萘醌部分，被发现能产生活性氧（ROS）并触发关键的ICD生物标志物，包括钙网蛋白（CRT）易位、ATP释放和高迁移率族蛋白B1（HMGB1）分泌。一种缺乏氧化还原活性萘醌的对照化合物未能引发这些ICD标志物或促进ROS产生。在整个系列中，观察到ROS产生与ICD生物标志物表达之间存在相关性。在同基因免疫活性小鼠体内的研究表明，化合物不仅在受到活癌细胞攻击时能抑制CT26结肠直肠癌肿瘤生长，而且在12个月后再次攻击时能引发长期的免疫反应。
