Hepatocellular carcinoma (HCC) is considered one of the most common primary liver cancers and the second leading cause of cancer-associated mortality around the world annually. Therefore, it is urgent to develop novel drugs for HCC therapy. We synthesized a novel 4-substituted-methoxybenzoyl-aryl-thiazole (SMART) analog, (5-(4-aminopiperidin-1-yl)-2-phenyl-2H-1,2,3-triazol-4-yl) (3,4,5-trimethoxyphenyl) methanone (W436), with higher solubility, stability, and antitumor activity than SMART against HCC cells in vivo. The purpose of this study was to investigate the mechanisms by which W436 inhibited cell growth in HCC cells. We observed that W436 inhibited the proliferation of HepG2 and Hep3B cells in a dose-dependent manner. Importantly, the anticancer activity of W436 against HCC cells was even higher than that of SMART in vivo. In addition, the antiproliferative effects of W436 on HCC cells were associated with G2/M cell cycle arrest and apoptosis via the activation of reactive oxygen species-mediated mitochondrial apoptotic pathway. W436 also induced protective autophagy by inhibiting the protein kinase B/mammalian target of rapamycin pathway. At the same time, W436 treatment inhibited the cell adhesion and invasion as well as the process of epithelial-to-mesenchymal transition Taken together, our results showed that W436 had the promising potential for the therapeutic treatment of HCC with improved solubility, stability, and bioavailability.

中文翻译：

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W436 是一种新型 SMART 衍生物，通过在体外和体内诱导细胞凋亡和 G2/M 细胞周期停滞并诱导保护性自噬来表现出抗肝癌活性

肝细胞癌（HCC）被认为是最常见的原发性肝癌之一，也是全球每年癌症相关死亡的第二大原因。因此，开发治疗肝癌的新药迫在眉睫。我们合成了一种新型 4-取代-甲氧基苯甲酰基-芳基-噻唑 (SMART) 类似物，(5-(4-aminopiperidin-1-yl)-2-phenyl-2 H-1,2,3-三唑-4-基）（3,4,5-三甲氧基苯基）甲酮 (W436)，在体内对 HCC 细胞具有比 SMART 更高的溶解度、稳定性和抗肿瘤活性。本研究的目的是研究 W436 抑制 HCC 细胞生长的机制。我们观察到 W436 以剂量依赖性方式抑制 HepG2 和 Hep3B 细胞的增殖。重要的是，W436 在体内对 HCC 细胞的抗癌活性甚至高于 SMART。此外，W436 对 HCC 细胞的抗增殖作用通过激活活性氧介导的线粒体凋亡途径与 G2/M 细胞周期停滞和细胞凋亡有关。W436 还通过抑制雷帕霉素途径的蛋白激酶 B/哺乳动物靶点诱导保护性自噬。同时，