School of Pharmacy, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Yantai University, Yantai, 264005, China.
School of Pharmacy, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Yantai University, Yantai, 264005, China.
Eur J Med Chem. 2020 Sep 15;202:112507. doi: 10.1016/j.ejmech.2020.112507. Epub 2020 Jun 26.
Ocotillol-type sapogenins (OTS) are major ginsenoside metabolites in human hepatic tissue. In order to better utilize OTS and derivatives thereof as anti-inflammatory compounds, present study produced multiple novel 3-amino acid OTS derivatives and evaluated their anti-inflammatory activity in vitro. The nitric oxide (NO) inhibitory activity of these compounds was used for OTS structure-activity relationship (SAR) evaluations, revealing that both R/S stereochemistry at C-24 and the amino acid type at C-3 influence such NO inhibitory activity. This activity was highest for an N-Boc-protected neutral aliphatic amino acid derivative of 24R-OTS (5a), which performed better than even hydrocortisone sodium succinate in vitro. Compound 5a was also able to markedly suppress the LPS-induced upregulation of TNF-α, IL-6, iNOS, and COX-2 via the NF-κB and MAPK pathways. This suggests that OTS derivatives may be valuable anti-inflammatory compounds worthy of further preclinical evaluation.
毛喉萜型甾体皂甙元（OTS）是人体肝组织中人参皂苷的主要代谢物。为了更好地利用 OTS 及其衍生物作为抗炎化合物，本研究合成了多种新型的 3-氨基酸 OTS 衍生物，并在体外评估了它们的抗炎活性。这些化合物的一氧化氮（NO）抑制活性用于 OTS 的构效关系（SAR）评估，结果表明 C-24 的 R/S 立体化学和 C-3 上的氨基酸类型均影响这种 NO 抑制活性。24R-OTS 的 N-Boc 保护的中性脂肪族氨基酸衍生物（5a）的活性最高，其在体外的活性甚至优于琥珀酸氢化可的松。化合物 5a 还可以通过 NF-κB 和 MAPK 途径显著抑制 LPS 诱导的 TNF-α、IL-6、iNOS 和 COX-2 的上调。这表明 OTS 衍生物可能是有价值的抗炎化合物，值得进一步进行临床前评估。
