Materia Medica Development Group, Institute of Medicinal Chemistry, School of Pharmacy of Lanzhou University, Lanzhou, 730000, China.
Materia Medica Development Group, Institute of Medicinal Chemistry, School of Pharmacy of Lanzhou University, Lanzhou, 730000, China.
Eur J Med Chem. 2023 Nov 5;259:115696. doi: 10.1016/j.ejmech.2023.115696. Epub 2023 Jul 29.
Glycyrrhizin (GL) is one of the antagonists of highly conserved nuclear protein (HMGB1). The researches have shown that the glycosyl of GL is an important pharmacophore for GL binding to HMGB1, and it is the determinant factor for mechanism of action. To get the HMGB1 inhibitors with higher activity and good pharmacokinetic properties, two classes of GL analogues containing C-N glycoside bond were synthesized, and their anti-inflammatory, anti-oxidative stress and anti-septic kidney injury were evaluated. The results are as follows. First, in the anti-inflammatory assay, all the compounds inhibited NO release in some degree; among them, compound 6 displayed the strongest NO inhibitory effect with IC50 value of 15.9 μM, and compound 15 with IC50 of 20.2 μM. The two compounds not only decreased IL-1β and TNF-α levels in RAW264.7 cells and HK-2 cells, but also downregulated the levels of NLRP3, P-NF-κB p65 and HMGB1 in activated HK-2 cells in a dose-dependent manner. Second, in the renal protection assay with H2O2-stimulated HK-2 cell line, they reduced MDA level and increased SOD in HK-2 cells; additionally, they also inhibited the HK-2 cell apoptosis and downregulated the Caspase-1 p20 level. Third, in the in vivo activity tests of the septic mouse, they also showed good activities just like in vitro, decreasing the IL-1β, TNF-α, MDA, blood creatinine (Scr) and urea nitrogen (BUN) in serum, and increasing SOD levels in a dose-dependent manner. The immunoblotting results showed the two compounds downregulated the levels of HMGB1, P-NF-κB p65, NLRP3 and Caspase-1 p20 protein. All in all, the two compounds improved the renal injury of septic mice, and alleviated the tube wall structure damage and renal tubular dilation in kidney, which further proved by H&E staining. This suggests the two compounds have septic acute kidney injury activity, and they will be potential therapeutic drugs for septic acute kidney injury.
甘草酸（GL）是高度保守的核蛋白（HMGB1）的拮抗剂之一。研究表明，GL 的糖苷基是 GL 与 HMGB1 结合的重要药效团，是作用机制的决定因素。为了获得活性更高、药代动力学性能更好的 HMGB1 抑制剂，合成了两类含 C-N 糖苷键的 GL 类似物，并对其抗炎、抗氧化应激和抗脓毒症肾损伤作用进行了评价。结果如下。首先，在抗炎测定中，所有化合物均在一定程度上抑制了 NO 的释放；其中，化合物 6 对 NO 的抑制作用最强，IC50 值为 15.9μM，化合物 15 的 IC50 值为 20.2μM。这两种化合物不仅降低了 RAW264.7 细胞和 HK-2 细胞中 IL-1β 和 TNF-α 的水平，而且还下调了活化的 HK-2 细胞中 NLRP3、P-NF-κB p65 和 HMGB1 的水平，呈剂量依赖性。其次，在 H2O2 刺激的 HK-2 细胞系肾保护测定中，它们降低了 HK-2 细胞中的 MDA 水平，增加了 SOD；此外，它们还抑制了 HK-2 细胞凋亡，并下调了 Caspase-1 p20 水平。第三，在脓毒症小鼠的体内活性试验中，它们也表现出良好的活性，与体外一样，降低了血清中 IL-1β、TNF-α、MDA、血肌酐（Scr）和尿素氮（BUN）的水平，并呈剂量依赖性增加了 SOD 水平。免疫印迹结果显示，这两种化合物下调了 HMGB1、P-NF-κB p65、NLRP3 和 Caspase-1 p20 蛋白的水平。总之，这两种化合物改善了脓毒症小鼠的肾损伤，并通过 H&E 染色进一步证实了减轻了肾脏的管腔结构损伤和肾小管扩张。这表明这两种化合物具有脓毒症急性肾损伤活性，可能成为脓毒症急性肾损伤的潜在治疗药物。
