Mule Ravindra D, Kumar Akhilesh, Sancheti Shashank P, Senthilkumar B, Kumar Himanshu, Patil Nitin T
Division of Organic Chemistry, CSIR-National Chemical Laboratory Dr Homi Bhabha Road Pune - 411008 India
Academy of Scientific and Innovative Research Ghaziabad - 201 002 India.
Chem Sci. 2022 Aug 25;13(36):10779-10785. doi: 10.1039/d2sc03756d. eCollection 2022 Sep 21.
Immunogenic Cell Death (ICD) is a unique cell death mechanism that kills cancer cells while rejuvenating the anticancer immunosurveillance, thereby benefiting the clinical outcomes of various immuno-chemotherapeutic regimens. Herein, we report development of a library of benzo[]quinolizinium-based Au(i) complexes through an intramolecular amino-auration reaction of pyridino-alkynes. We tested 40 candidates and successfully identified BQ-AurIPr as a novel redox-active Au(i) complex with potent anticancer properties. BQ-AurIPr efficiently triggered generation of DAMPs - the hallmarks of ICD - and was superior in terms of efficiency compared to FDA-approved drugs known to induce ICD. BQ-AurIPr significantly increased immunogenicity of cancer cells enhancing their phagocytosis when co-cultured with immune cells. Our investigation reveals that BQ-AurIPr induces oxidative stress inside mitochondria leading to mitophagy, as the mechanism for immunogenic cell death in A549 cells.
免疫原性细胞死亡（ICD）是一种独特的细胞死亡机制，它在杀死癌细胞的同时恢复抗癌免疫监视功能，从而改善各种免疫化疗方案的临床疗效。在此，我们报告了通过吡啶炔的分子内氨基金化反应开发的一系列苯并[]喹啉鎓基金（I）配合物。我们测试了40种候选物，并成功鉴定出BQ-AurIPr是一种具有强大抗癌特性的新型氧化还原活性金（I）配合物。BQ-AurIPr有效地触发了ICD的标志——损伤相关分子模式（DAMP）的产生，并且在效率方面优于已知可诱导ICD的FDA批准药物。当与免疫细胞共培养时，BQ-AurIPr显著提高了癌细胞的免疫原性，增强了它们的吞噬作用。我们的研究表明，BQ-AurIPr在线粒体内诱导氧化应激，导致线粒体自噬，这是A549细胞中免疫原性细胞死亡的机制。
