State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou, Gansu 730000, China.
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou, Gansu 730000, China.
Free Radic Biol Med. 2018 Aug 20;124:342-352. doi: 10.1016/j.freeradbiomed.2018.06.021. Epub 2018 Jun 21.
Altered redox homeostasis including higher levels of copper, reduced glutathione (GSH) and reactive oxygen species (ROS) in cancer cells than in normal cells illustrates their redox vulnerability, and has opened a window for developing prooxidative anticancer agents (PAAs) to hit this status. However, how to design PAAs with high selectivity in killing cancer cells over normal cells remains a challenge. Herein we designed a 3-hydroxyflavone-inspired copper pro-ionophore (PHF) as a potent PAA based on the GSH-mediated conversion of 2,4-dinitrobenzenesulfonates to enols. Mechanistic investigation reveals that it is capable of exploiting increased levels of GSH in cancer cells to in situ release an active ionophore, 3-hydroxyflavone, inducing redox imbalance (copper accumulation, GSH depletion and ROS generation) and achieving highly selective killing of cancer cells upon specific transport of small amounts of Cu(II). To the best of our knowledge, it is the first example of Cu(II) pro-ionophore type of PAA which hits (changes) the three birds (abnormal copper, GSH and ROS levels in cancer cells) with one stone (PHF) in terms of its ability to induce preferentially redox imbalance of cancer cells by copper accumulation, GSH depletion and ROS generation.
与正常细胞相比，癌细胞中的氧化还原稳态发生改变，包括铜、还原型谷胱甘肽 (GSH) 和活性氧 (ROS) 水平升高，这表明它们的氧化还原状态脆弱，并为开发促氧化抗癌剂 (PAA) 提供了机会，以利用这种状态。然而，如何设计对癌细胞具有高选择性的 PAA 以杀死正常细胞仍然是一个挑战。在此，我们受 3-羟基黄酮启发设计了一种铜质子载体（PHF）作为一种有效的 PAA，其基于 GSH 介导的 2,4-二硝基苯磺酸盐向烯醇的转化。机理研究表明，它能够利用癌细胞中升高的 GSH 水平原位释放活性质子载体 3-羟基黄酮，诱导氧化还原失衡（铜积累、GSH 耗竭和 ROS 生成），并通过少量 Cu(II) 的特异性转运实现对癌细胞的高选择性杀伤。据我们所知，这是首例 Cu(II) 质子载体型 PAA 的例子，它能够通过铜积累、GSH 耗竭和 ROS 生成来诱导癌细胞优先发生氧化还原失衡，从而“一石三鸟”（改变癌细胞中异常的铜、GSH 和 ROS 水平）。
