The multifunctional transcription factor, nuclear factor-κB (NF-κB), is broadly involved in multiple human diseases, such as cancer and chronic inflammation, through abnormal modulations of the NF-κB signaling cascades. In patients with several types of cancer diseases, NF-κB is excessively activated, which could result in the stimulation of proliferation and/or suppression of apoptosis. Herein, we present a new series of 1,2,3,4-tetrahydroisoquinoline derivatives with good anticancer activities against various human cancer cell lines, which are rationally designed based on our novel NF-κB inhibitors. The SAR studies demonstrated that compound 5d with a methoxy group at the R₃ position exhibits the most anti-proliferative activity with GI₅₀ values, ranging 1.591 to 2.281 μM. Similar to KL-1156, the compound 5d (HSR1304) blocked NF-κB nuclear translocation step in LPS-stimulated MDA-MB-231 cells, probably leading to cytotoxic potency against tumor cells. Together with known potent NF-κB inhibitors containing diverse core heterocyclic moieties, the 1,2,3,4-tetrahydroisoquinoline derivatives can provide structural diversity, enhancing a potential for the development of a novel class of anticancer drugs.

多功能转录因子核因子-κB (NF-κB) 通过对 NF-κB 信号级联的异常调节广泛参与多种人类疾病，例如癌症和慢性炎症。在多种癌症疾病患者中，NF-κB过度激活，可能导致增殖刺激和/或细胞凋亡抑制。在此，我们提出了一系列新的 1,2,3,4-四氢异喹啉衍生物，它们对各种人类癌细胞系具有良好的抗癌活性，这些衍生物是基于我们的新型 NF-κB 抑制剂合理设计的。SAR 研究表明，在 R ₃位置具有甲氧基的化合物5d对 GI ₅₀表现出最大的抗增殖活性值，范围为 1.591 至 2.281 μM。与 KL-1156 类似，化合物5d (HSR1304) 阻断了 LPS 刺激的 MDA-MB-231 细胞中的 NF-κB 核转位步骤，可能导致对肿瘤细胞的细胞毒性效力。与含有多种核心杂环部分的已知强效 NF-κB 抑制剂一起，1,2,3,4-四氢异喹啉衍生物可以提供结构多样性，增强开发新型抗癌药物的潜力。