线粒体已成为抗癌治疗的重要靶点之一。随后，小分子抗癌药物被引导至线粒体以提高治疗效果。然而，通过单个探针同时成像和损伤线粒体仍然是一个重大挑战。为了解决这个问题，本文通过简洁的策略设计并合成了包含药物、荧光团和线粒体归巢部分的嵌合小分子（CSM）。对一组癌细胞系（HeLa、MCF7、A549 和 HCT-116）中 CSM 的筛选表明，其中一种包含吲哚美辛 V 的 CSM 表现出显着的宫颈癌细胞 (HeLa) 杀伤作用 (IC50 = 0.97 μM)。这种先导 CSM 在 1 小时内进入 HeLa 细胞的线粒体，随后导致线粒体损伤并产生活性氧 (ROS)。这种新型基于吲哚美辛 V 的 CSM 介导的线粒体损伤可诱导程序性细胞死亡（细胞凋亡）。我们预计该 CSM 可用作了解疾病状态下细胞器化学生物学中药物作用的工具。© 2023 Wiley-VCH GmbH。

Mitochondrion has appeared as one of the important targets for the anti-cancer therapy. Subsequently, small molecule anti-cancer drugs are directed to the mitochondria for improved therapeutic efficacy. However, simultaneous imaging and impairing mitochondria by a single probe remained a major challenge. To address this, herein chimeric small molecules (CSMs) encompassing drugs, fluorophore and mitochondria homing moiety were designed and synthesized through a concise strategy. Screening of the CSMs in a panel of cancer cell lines (HeLa, MCF7, A549 and HCT-116) revealed that one of the CSMs comprising indomethacin V exhibited remarkable cervical cancer cell (HeLa) killing (IC50 = 0.97 μM). This lead CSM homed into the mitochondria of HeLa cells within 1h followed by mitochondrial damage and reactive oxygen species (ROS) generation. This novel indomethacin V-based CSM-mediated mitochondrial damage induced programmed cell death (apoptosis). We anticipate this CSMs can be used as tools to understand the drug effects in organelle chemical biology in diseased states.© 2023 Wiley-VCH GmbH.