A facile method of assembling oxindole and phthalide units through a Lewis based catalyzed allylic alkylation reaction of Morita–Baylis–Hillman carbonates of isatins and 3-cyanophthalides was recently developed. The method efficiently delivers a hybrid of 3,3′-disubstituted oxindole with a valuable phthalide pharmacophore. In the present study, we proved the deleterious effects of 5h2c, a screened synthesis compound, against hepatocellular carcinoma (HCC) in both in vitro and in vivo models. 5h2c strongly decreased cell viability, caused over-release of lactate dehydrogenase, inhibited cell migration, and enhanced the apoptosis rate in HepG2 and PLC/PRF/5 cells. 5h2c led to an increase in intracellular reactive oxygen species levels and a decrease in mitochondrial membrane potential. In HepG2-and PLC/PRF/5-xenograft tumor mouse models, treatment with 5h2c inhibited tumor growth without affecting the animals' bodyweight or organ functions. Proteome profiling of tumor tissues after 24-h exposure to 5h2c showed significantly enhanced expression levels of Bcl-2 associated X protein, cleaved caspase −3, −8, and −9, nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), heme oxygenase-2, paraoxonase 2, catalase, and factor associated suicide ligand, and reduced the expression levels of B-cell lymphoma-2, B-cell lymphoma-extra large, heat shock protein 27, heat shock protein 60, and heat shock protein 70 in HepG2 and PLC/PRF/5 cells. All of our data confirmed that oxidative stress-mediated mitochondrial apoptosis (especially the Nrf-2/HO-1 pathway) is responsible for 5h2c-induced HCC damage.

最近开发了一种简便的方法，该方法通过基于路易斯的Isatin和3-氰基酞菁碳酸盐的Morita-Baylis-Hillman碳酸盐的烯丙基烷基化反应来组装羟吲哚和邻苯二甲酸酯单元。该方法有效地递送了3，3'-二取代的羟吲哚与有价值的邻苯二甲酸酯药效团的混合物。在本研究中，我们证明了5h2c（一种筛选的合成化合物）在体外和体内对肝细胞癌（HCC）的有害作用楷模。5h2c大大降低了细胞活力，导致乳酸脱氢酶过度释放，抑制了细胞迁移，并提高了HepG2和PLC / PRF / 5细胞的凋亡率。5h2c导致细胞内活性氧水平升高，线粒体膜电位降低。在HepG2和PLC / PRF / 5-异种移植肿瘤小鼠模型中，用5h2c处理可抑制肿瘤生长，而不会影响动物的体重或器官功能。暴露于5h2c 24小时后肿瘤组织的蛋白质组分析显示Bcl-2相关X蛋白，裂解的caspase -3，-8和-9，核因子红系2相关因子2（Nrf2），血红素的表达水平显着提高加氧酶1（HO-1），血红素加氧酶2，对氧磷酶2，过氧化氢酶和因子相关的自杀配体，并降低了B细胞淋巴瘤2的表达水平，B细胞淋巴瘤超大，HepG2和PLC / PRF / 5细胞中的热休克蛋白27，热休克蛋白60和热休克蛋白70。我们所有的数据证实，氧化应激介导的线粒体凋亡（尤其是Nrf-2 / HO-1途径）是5h2c诱导的HCC损伤的原因。