Liu Xuefeng, Cui Hongmei, Li Mi, Chai Zuohu, Wang Haibo, Jin Xiaojie, Dai Fang, Liu Yongqi, Zhou Bo
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou, Gansu, 730000, China; School of Pharmacy, Lanzhou University, 222 Tianshui Street S., Lanzhou, Gansu, 730000, China; College of Pharmacy, Gansu University of Chinese Medicine, 35 Dingxi East Road, Lanzhou, Gansu, 730000, China.
School of Public Health, Lanzhou University, 222 Tianshui Street S., Lanzhou, Gansu, 730000, China.
Eur J Med Chem. 2023 Mar 15;250:115191. doi: 10.1016/j.ejmech.2023.115191. Epub 2023 Feb 6.
In comparison with normal cells, cancer cells feature intrinsic oxidative stress, thereby being more vulnerable to further production of reactive oxygen species (ROS) by pro-oxidative anticancer agents (PAAs). However, PAAs also inevitably generate ROS in normal cells, resulting in their narrow therapeutic window and toxic side effects that greatly limit their clinical application. To develop PAAs that generate ROS selectively in cancer cells over in normal cells, we rationally designed three series of 21 dietary curcumin 5-carbon mono-carbonyl analogs differentiated by either placement of the cyclohexanone, piperidone, and methylpiperidone linkers, or introduction of electron-withdrawing trifluoromethyl and electron-donating methoxyl groups on its two aromatic rings in the ortho, meta, or para position to the linkers. From the designed molecules, 2c, characterized of the presence of the meta-CF-substituted mode and the piperidone linker, was identified as a potent selective ROS-generating agent, allowing its ability to kill selectively human non-small cell lung cancer NCI-H460 (IC = 0.44 μM) over human normal lung MRC-5 cells with a selectivity index of 32.0. Additionally, it was more potent and selective than the conventional chemotherapeutic agents (5-fluorouracil and camptothecin) did. Mechanistical investigation reveals that by means of its Michael acceptor unit and structure characteristics as described above, 2c could covalently modify the Sec-498 residue of intracellular thioredoxin reductase (TrxR) to generate ROS selectively, resulting in ROS-dependent apoptosis and ferroptosis of NCI-H460 cells. Noticeably, 2c inhibited significantly the growth of NCI-H460 cell xenograft tumor in nude mice without obvious toxicity to liver and kidney. Together, this work highlights a practical strategy of targeting TrxR overexpressed in cancer cells to develop PAAs capable of generating ROS selectively, as evidenced by the example of 2c.
与正常细胞相比，癌细胞具有内在的氧化应激，因此更容易受到促氧化抗癌剂（PAA）进一步产生活性氧（ROS）的影响。然而，PAA也不可避免地在正常细胞中产生活性氧，导致其治疗窗口狭窄和毒副作用，这极大地限制了它们的临床应用。为了开发在癌细胞中比正常细胞更能选择性产生活性氧的PAA，我们合理设计了21种膳食姜黄素5-碳单羰基类似物的三个系列，它们通过环己酮、哌啶酮和甲基哌啶酮连接基的位置，或在其两个芳环上与连接基处于邻位、间位或对位引入吸电子三氟甲基和供电子甲氧基来区分。从设计的分子中，具有间位-CF取代模式和哌啶酮连接基的2c被鉴定为一种有效的选择性ROS生成剂，其对人非小细胞肺癌NCI-H460（IC = 0.44 μM）的选择性杀伤能力超过人正常肺MRC-5细胞，选择性指数为32.0。此外，它比传统化疗药物（5-氟尿嘧啶和喜树碱）更有效且更具选择性。机理研究表明，通过其迈克尔受体单元和上述结构特征，2c可以共价修饰细胞内硫氧还蛋白还原酶（TrxR）的Sec-498残基以选择性产生活性氧，导致NCI-H460细胞发生ROS依赖性凋亡和铁死亡。值得注意的是，2c显著抑制了裸鼠体内NCI-H460细胞异种移植瘤的生长，而对肝肾没有明显毒性。总之，这项工作突出了一种针对癌细胞中过表达的TrxR来开发能够选择性产生活性氧的PAA的实用策略，2c的例子证明了这一点。
