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.
College of Food Engineering, Ludong University, Yantai 264025, China.
Molecules. 2023 Jan 30;28(3):1307. doi: 10.3390/molecules28031307.
Pyxinol skeleton is a promising framework of anti-inflammatory agents formed in the human liver from 20-protopanaxadiol, the main active aglycone of ginsenosides. In the present study, a new series of amino acid-containing derivatives were produced from 12-dehydropyxinol, a pyxinol oxidation metabolite, and its anti-inflammatory activity was assessed using an NO inhibition assay. Interestingly, the dehydrogenation at C-12 of pyxinol derivatives improved their potency greatly. Furthermore, half of the derivatives exhibited better NO inhibitory activity than hydrocortisone sodium succinate, a glucocorticoid drug. The structure-activity relationship analysis indicated that the kinds of amino acid residues and their hydrophilicity influenced the activity to a great extent, as did / stereochemistry at C-24. Of the various derivatives, with an -Boc-protected phenylalanine residue showed the highest NO inhibitory activity and relatively low cytotoxicity. Moreover, derivative could dose-dependently suppress iNOS, IL-1β, and TNF-α via the MAPK and NF-κB pathways, but not the GR pathway. Overall, pyxinol derivatives hold potential for application as anti-inflammatory agents.
吡辛醇骨架是一种有前途的抗炎药物框架，它在人体肝脏中由 20-原人参二醇形成，20-原人参二醇是人参皂苷的主要活性苷元。在本研究中，从吡辛醇氧化代谢物 12-去氢吡辛醇中生成了一系列新的含氨基酸衍生物，并通过 NO 抑制测定评估了其抗炎活性。有趣的是，吡辛醇衍生物在 C-12 处脱氢大大提高了其效力。此外，有一半的衍生物的 NO 抑制活性优于氢化可的松琥珀酸钠，一种糖皮质激素药物。构效关系分析表明，氨基酸残基的种类及其亲水性以及 C-24 的立体化学在很大程度上影响了活性。在各种衍生物中，带有-Boc 保护的苯丙氨酸残基的 显示出最高的 NO 抑制活性和相对较低的细胞毒性。此外，衍生物 可以通过 MAPK 和 NF-κB 途径，但不是 GR 途径，剂量依赖性地抑制 iNOS、IL-1β 和 TNF-α。总的来说，吡辛醇衍生物具有作为抗炎药物应用的潜力。
