Signal transducer and activator of transcription 3 (STAT3) is a tumorigenic transcription factor that is persistently activated in various human cancers including hepatocellular carcinoma (HCC). Therefore, STAT3 is considered as a prominent target to counteract the uncontrolled proliferation of cancer cells. In the present report, pyrimidine-2,4-diones (N-methyluracil derivatives) (MNK1-MNK14) were synthesized in an ionic liquid (BMIm PF₆) medium employing a ligand-free Suzuki-Miyaura cross-coupling process. Among the 14 derivatives, compound MNK8 showed good cytotoxicity towards both the tested cell lines and did not display a toxic effect against normal hepatocytes (LO2). MNK8 significantly increased the Sub-G1 cell count in both cell lines and the cytotoxic effect of MNK8 was found to be mediated through the suppression of constitutive phosphorylation of STAT3^Y705. It also decreased the DNA interaction ability of nuclear STAT3 in HCC cells. MNK8 downregulated the levels of apoptosis-related proteins (such as Bcl-2, cyclin D1, survivin) and increased cleaved caspase-3 inferring the apoptogenic effect of MNK8. It also reduced the CXCL12-triggered cell migration and invasion in in vitro assay systems. Overall, MNK8 has been demonstrated as a new inhibitor of STAT3 signaling cascade in HCC cells.

信号转导和转录激活因子 3 (STAT3) 是一种致瘤转录因子，在包括肝细胞癌 (HCC) 在内的各种人类癌症中持续激活。因此，STAT3 被认为是对抗癌细胞失控增殖的重要靶点。在本报告中，嘧啶-2,4-二酮（N-甲基尿嘧啶衍生物）（MNK1-MNK14）在离子液体（BMIm PF ₆) 培养基采用无配体 Suzuki-Miyaura 交叉偶联过程。在这 14 种衍生物中，化合物 MNK8 对两种受试细胞系均表现出良好的细胞毒性，并且对正常肝细胞 (LO2) 没有表现出毒性作用。MNK8 显着增加了两种细胞系中的 Sub-G1 细胞计数，并且发现 MNK8 的细胞毒作用是通过抑制 STAT3 ^Y705的组成型磷酸化来介导的。它还降低了 HCC 细胞中核 STAT3 的 DNA 相互作用能力。MNK8 下调凋亡相关蛋白（如 Bcl-2、cyclin D1、survivin）的水平并增加切割的 caspase-3 推断 MNK8 的凋亡作用。它还在体外减少了 CXCL12 触发的细胞迁移和侵袭化验系统。总体而言，MNK8 已被证明是 HCC 细胞中 STAT3 信号级联的新抑制剂。