Pharmaceutical Chemistry Division, Department of Pharmaceutical Sciences, University of Kashmir, Srinagar, India.
Department of Natural Products, National Institute of Pharmaceutical Education and Research (NIPER), Sahibzada Ajit Singh Nagar, India.
Drug Des Devel Ther. 2021 Feb 4;15:385-397. doi: 10.2147/DDDT.S291784. eCollection 2021.
Oleanolic acid, a pentacyclic triterpenic acid, is widely distributed in medicinal plants and is the most commonly studied triterpene for various biological activities, including anti-allergic, anti-cancer, and anti-inflammatory.
The present study was carried out to synthesize arylidene derivatives of oleanolic acid at the C-2 position by Claisen Schmidt condensation to develop more effective anti-inflammatory agents. The derivatives were screened for anti-inflammatory activity by scrutinizing NO production inhibition in RAW 264.7 cells induced by LPS and their cytotoxicity. The potential candidates were further screened for inhibition of LPS-induced interleukin (IL-6) and tumour necrosis factor-alpha (TNF-α) production in RAW 264.7 cells.
The results of in vitro studies revealed that derivatives 3d, 3e, 3L, and 3o are comparable to that of the oleanolic acid on the inhibition of TNF-α and IL-6 release. However, derivative 3L was identified as the most potent inhibitor of IL-6 (77.2%) and TNF-α (75.4%) when compared to parent compound, and compounds 3a (77.18%), 3d (71.5%), and 3e (68.8%) showed potent inhibition of NO than oleanolic acid (65.22%) at 10µM. Besides, from docking score and Cyscore analysis analogs (3e, 3L, 3n) showed greater affinity towards TNF-α and IL-1β than dexamethasone.
Herein, we report a series of 15 new arylidene derivatives of oleanolic acid by Claisen Schmidt condensation reaction. All the compounds synthesized were screened for their anti-inflammatory activity against NO, TNF-α and IL-6. From the data, it was evident that most of the compounds exhibited better anti-inflammatory activity.
齐墩果酸是一种五环三萜酸，广泛分布于药用植物中，是研究最多的三萜类化合物之一，具有多种生物活性，包括抗过敏、抗癌和抗炎作用。
本研究通过 Claisen-Schmidt 缩合反应在 C-2 位合成齐墩果酸的芳基烯衍生物，以开发更有效的抗炎剂。通过筛选 LPS 诱导的 RAW 264.7 细胞中 NO 产生抑制作用及其细胞毒性，对衍生物进行抗炎活性筛选。进一步筛选潜在的候选物，以抑制 LPS 诱导的 RAW 264.7 细胞中白细胞介素（IL-6）和肿瘤坏死因子-α（TNF-α）的产生。
体外研究结果表明，衍生物 3d、3e、3L 和 3o 在抑制 TNF-α和 IL-6 释放方面与齐墩果酸相当。然而，与母体化合物相比，衍生物 3L 被鉴定为 IL-6（77.2%）和 TNF-α（75.4%）的最有效抑制剂，化合物 3a（77.18%）、3d（71.5%）和 3e（68.8%）在 10µM 时对 NO 的抑制作用强于齐墩果酸（65.22%）。此外，从对接评分和 Cyscore 分析来看，类似物（3e、3L、3n）对 TNF-α 和 IL-1β 的亲和力大于地塞米松。
本研究通过 Claisen-Schmidt 缩合反应报道了一系列 15 种新的齐墩果酸芳基烯衍生物。所有合成的化合物均进行了抗 NO、TNF-α和 IL-6 活性筛选。从数据来看，大多数化合物表现出更好的抗炎活性。
