硫醚键桥联的N-酰化半胱氨酸衍生物的合成及抗药物性肝损伤活性研究

Synthesis and anti-drug-induced liver injury activity of thioether-bridged N-acyl cysteine derivatives

关键词:  N-乙酰半胱氨酸衍生物  药物性肝损伤  对乙酰氨基酚  药代动力学

Key words:  N-acetylcysteine derivatives  drug-induced liver injury  acetaminophen  pharmacokinetics

摘要:

目的 设计并合成一系列新型硫醚键桥联的N-酰化半胱氨酸衍生物,评价其对药物性肝损伤的保护作用。方法 以L-半胱氨酸为起始原料,经巯基苄基化、氨基Boc保护及羧基缩合等步骤制备目标化合物。采用对乙酰氨基酚(APAP)诱导的LO2肝细胞损伤模型进行体外活性筛选,并选取活性较优的化合物开展小鼠体内药效学及大鼠体内药代动力学研究。结果 成功合成8个目标化合物(6a~6h),其结构经核磁共振氢谱、碳谱及高分辨质谱确证。体外实验显示,化合物6b、6c和6e可显著提升损伤肝细胞的增殖率,其中6c使细胞增殖率恢复至112%,并有效降低损伤肝细胞中丙二醛(MDA)含量。小鼠体内药效学实验表明,化合物6c在APAP诱导的小鼠急性肝损伤模型中,给药24h后能显著降低小鼠血清ALT、AST及GDH水平,效果与阳性对照NAC相当。大鼠体内药代动力学研究显示,化合物6c在SD大鼠体内的口服半衰期为5.62h,口服生物利用度为52.8%,显著高于NAC(5%~6%)。结论 化合物6c在体外与体内均表现出显著的肝保护活性及优良的药代动力学特性,具备作为先导化合物进一步研究的价值。

Abstract:

ABSTRACT: OBJECTIVE To design and synthesize a series of novel thioether-bridged N-acylated cysteine derivatives and evaluate their protective effects against drug-induced liver injury (DILI). METHODS Starting from L-cysteine, the target compounds were prepared through steps including mercapto group benzylation, amino group Boc protection, and carboxyl group condensation. An acetaminophen (APAP)-induced LO2 hepatocyte injury model was used for in vitro activity screening, and the compounds with superior activity were selected for in vivo pharmacodynamic studies in mice and pharmacokinetic studies in rats. RESULTS Eight target compounds (6a-6h) were successfully synthesized, and their structures were confirmed by 1H-NMR,13C-NMR and high-resolution mass spectrometry. In vitro experiments showed that compounds 6b, 6c, and 6e significantly increased the proliferation rate of injured hepatocytes. Among them, compound 6c restored the cell proliferation rate to 112% and effectively reduced malondialdehyde (MDA) content. Animal experiments demonstrated that in an APAP-induced acute liver injury model in mice, compound 6c significantly reduced serum ALT, AST, and GDH levels 24 hours after administration, with effects comparable to the positive control NAC. Pharmacokinetic studies revealed that compound 6c had an oral half-life of 5.62 h and an oral bioavailability of 52.8% in SD rats, which is significantly higher than that of NAC (5%-6%). CONCLUSION Compound 6c exhibits significant hepatoprotective activity both in vitro and in vivo, along with excellent pharmacokinetic properties, making it a valuable lead compound for further research.