Li Wei, Peng Yijie, Liu Jianrong, Wu Tianbo, Qiang Xin, Zhao Quanyi, He Dian
Institute of Medicinal Chemistry, School of Pharmacy of Lanzhou University, Lanzhou 730000, China.
Institute of Medicinal Chemistry, School of Pharmacy of Lanzhou University, Lanzhou 730000, China.
Bioorg Chem. 2024 Dec;153:107846. doi: 10.1016/j.bioorg.2024.107846. Epub 2024 Sep 24.
The signaling pathway mediated by high mobility group protein B1 (HMGB1) plays a key role in myocardial injury during sepsis. Glyrrhizin (GL) is a natural product that inhibits HMGB1 biological activities through forming GL-HMGB1 complex; the research shows its aglycone (GA) is the main pharmacophore binding to HMGB1, while the glycosyl mainly altering its pharmacokinetic properties and enhances the stability of the complex. GL is often metabolized to GA in the gastrointestinal tract, which has a lower efficacy in the treatment of HMGB1-mediated diseases. To obtain the GL analogs with higher activity and better pharmacokinetic properties, 24 GL analogs were synthesized by simplification the glycosyl of GL. Among all the compounds, compound 11 with furanoylpiperazine was screened. The pharmacokinetics experiments showed that compound 11 is converted to 11a in vivo, and 11 serves as its prodrug. Compound 11a displayed a lower cytotoxicity to RAW264.7 cells and three types of cardiomyocyte lines, with IC > 800 µM. In the anti-inflammatory assay, 11a not only strongly inhibited NO production (IC 5.73 µM), but also down-regulated the levels of HMGB1, IL-1β and TNF-α in a dose-dependent manner; in the anti-oxidative stress assay, compound 11a reduced the level of ROS and increased the MMP in H9c2 cells. More importantly, in the myocardial injury model of septic mice, compound 11a not only alleviated the symptom of myocardial injury by reducing inflammatory infiltration and oxidative stress, but also improved the myocardial blood supply by shrinking the inner diameter of the left ventricle and increasing the ejection fraction (EF) more dramatically (155.8 %); meanwhile, compound 11a adjusted myocardial enzymes in serum of septic mice. In addition, in molecular docking experiments, compound 11a showed stronger HMGB1 binding ability than GL. In summary, compound 11 is a prodrug, which can be converted to 11a in vivo. And compound 11a has a good activity against septic myocardial injury, as well as improving the myocardial blood supply function. This suggests compound 11 is a potential drug candidate for the treatment of septic myocardial injury and deserves further investigate.
高迁移率族蛋白B1（HMGB1）介导的信号通路在脓毒症所致心肌损伤中起关键作用。甘草酸（GL）是一种天然产物，通过形成GL - HMGB1复合物抑制HMGB1的生物学活性；研究表明其苷元（GA）是与HMGB1结合的主要药效基团，而糖基主要改变其药代动力学性质并增强复合物的稳定性。GL在胃肠道中常代谢为GA，在治疗HMGB1介导的疾病中疗效较低。为获得具有更高活性和更好药代动力学性质的GL类似物，通过简化GL的糖基合成了24种GL类似物。在所有化合物中，筛选出了含呋喃甲酰哌嗪的化合物11。药代动力学实验表明化合物11在体内转化为11a，11作为其前药。化合物11a对RAW264.7细胞和三种心肌细胞系显示出较低的细胞毒性，IC>800μM。在抗炎实验中，11a不仅强烈抑制NO生成（IC 5.73μM），还以剂量依赖方式下调HMGB1、IL - 1β和TNF - α的水平；在抗氧化应激实验中，化合物11a降低了H9c2细胞中ROS水平并增加了线粒体膜电位（MMP）。更重要的是，在脓毒症小鼠心肌损伤模型中，化合物11a不仅通过减少炎症浸润和氧化应激减轻心肌损伤症状，还通过缩小左心室内径和更显著地增加射血分数（EF，增加155.8%）改善心肌血液供应；同时，化合物11a调节了脓毒症小鼠血清中的心肌酶。此外，在分子对接实验中，化合物11a显示出比GL更强的HMGB1结合能力。综上所述，化合物11是一种前药，可在体内转化为11a。并且化合物11a对脓毒症心肌损伤具有良好活性，同时改善心肌血液供应功能。这表明化合物11是治疗脓毒症心肌损伤的潜在候选药物，值得进一步研究。
