Abstract

Some methoxy-, hydroxyl-, pyridyl-, or fluoro-substituted 3,5-bis(arylidene)-4-piperidones (BAPs) could reduce inflammation and promote hepatoma cell apoptosis by inhibiting activation of NF-κB, especially after introduction of trifluoromethyl. Herein, a series of trifluoromethyl-substituted BAPs (4-30) were synthesised and the biological activities were evaluated. We successfully found the most potential 16, which contains three trifluoromethyl substituents and exhibits the best anti-tumour and anti-inflammatory activities. Preliminary mechanism research revealed that 16 could promote HepG2 cell apoptosis in a dose-dependent manner by down-regulating the expression of Bcl-2 and up-regulating the expression of Bax, C-caspase-3. Meanwhile, 16 inhibited activation of NF-κB by directly inhibiting the phosphorylation of p65 and IκBα induced by LPS, together with indirectly inhibiting MAPK pathway, thereby exhibiting both anti-hepatoma and anti-inflammatory activities. Molecular docking confirmed that 16 could bind to the active sites of Bcl-2, p65, and p38 reasonably. The above results suggested that 16 has enormous potential to be developed as a multifunctional agent for the clinical treatment of liver cancers and inflammatory diseases.

摘要

一些甲氧基、羟基、吡啶基或氟取代的 3,5-双(亚芳基)-4-哌啶酮 (BAP) 可以通过抑制 NF-κB 的激活来减轻炎症并促进肝癌细胞凋亡，尤其是在引入三氟甲基后. 在此，合成了一系列三氟甲基取代的 BAPs ( 4-30 ) 并对其生物活性进行了评价。我们成功地发现了最有潜力的16，它含有三个三氟甲基取代基并表现出最好的抗肿瘤和抗炎活性。初步机制研究表明，16可通过下调Bcl-2的表达、上调Bax、C-caspase-3的表达，以剂量依赖性方式促进HepG2细胞凋亡。同时，16通过直接抑制p65和IκB的磷酸化NF-κB的抑制活化α由LPS诱导的，用间接抑制MAPK途径在一起，从而同时表现出抗肝癌和抗炎活性。分子对接证实16可以与Bcl-2、p65和p38的活性位点合理结合。上述结果表明，16具有巨大的潜力，可开发为临床治疗肝癌和炎症性疾病的多功能药物。