Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
Bioorg Chem. 2024 Jan;142:106925. doi: 10.1016/j.bioorg.2023.106925. Epub 2023 Oct 18.
Thirty new tricyclicmatrinic derivatives were successively synthesized and evaluated for their inhibitory activity on the accumulation of triglycerides (TG) in AML12 cells, using 12 N-m-trifluoromethylbenzenesulfonyl matrine (1) as the hit compound. Among the analogues, compound 7n possessing 11-trimethylbutylamine quaternary exerted the highest in vitro TG-lowering potency, as well as a good safety profile. 7n significantly attenuated the hepatic injury and steatosis, and ameliorated dyslipidemia and dysglycemia in the mice with non-alcoholic fatty liver disease (NAFLD) induced by a high-fat diet. Primary mechanism study revealed that upregulation of peroxisome proliferator-activated receptors α (PPARα)-carnitine palmitoyltransferase 1A (CPT1A) pathway mediated the efficacy of 7n. Our study provides powerful information for developing this kind of compound into a new class of anti-NAFLD candidates, and compound 7n is worthy of further investigation as an ideal lead compound.
我们成功合成了 30 种新型的苦参碱衍生物，并评估了它们对 AML12 细胞内甘油三酯（TG）积累的抑制活性，以 12-N-三氟甲基苯磺酰苦参碱（1）作为先导化合物。在这些类似物中，具有 11-三甲基丁基季铵盐的化合物 7n 表现出最高的体外降 TG 活性，同时具有良好的安全性。7n 能显著减轻高脂饮食诱导的非酒精性脂肪性肝病（NAFLD）小鼠的肝损伤和脂肪变性，并改善血脂异常和糖代谢紊乱。初步机制研究表明，过氧化物酶体增殖物激活受体 α（PPARα）-肉碱棕榈酰转移酶 1A（CPT1A）通路的上调介导了 7n 的疗效。我们的研究为开发这类化合物提供了有力的信息，使其成为一类新型的抗 NAFLD 候选药物，化合物 7n 作为一种理想的先导化合物值得进一步研究。
