Discovery of deoxylimonin δ-lactam derivative with favorable anti-inflammation and antinociception efficacy from chemical modified limonin/deoxylimonin analogs

• Published in: Bioorganic chemistry Vol. 100; p. 103886
• Main Authors: Wang, Shaochi, Han, Xueqing, Yang, Yun, Zhou, Chen, Luo, Danmeng, He, Wensong, Zhu, Qihua, Xu, Yungen
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2020
• Subjects: Analgesics - chemistry; Analgesics - pharmacology; Analgesics - therapeutic use; Animals; Anti-inflammation; Anti-Inflammatory Agents, Non-Steroidal - chemistry; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Anti-Inflammatory Agents, Non-Steroidal - therapeutic use; Antinociception; Cyclooxygenase 2 - metabolism; Dinoprostone - metabolism; Disease Models, Animal; Downregulate Prostaglandin E2; Edema - drug therapy; Edema - metabolism; Female; Lactams - chemistry; Lactams - pharmacology; Lactams - therapeutic use; Limonin derivative; Limonins - chemistry; Limonins - pharmacology; Limonins - therapeutic use; Male; Mice; Mice, Inbred ICR; Pain - drug therapy; Pain - metabolism; Rats, Inbred Lew; Suppress Cyclooxygenase 2; Antinociception; Suppress Cyclooxygenase 2; Anti-inflammation; Downregulate Prostaglandin E2; Limonin derivative; Downregulate Prostaglandin E
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2020.103886

[Display omitted] •Chemical modifications on the A ring of limonin (1) and deoxylimonin (2) afforded 28 structural characterized derivatives with favorable anti-inflammation and antinociception efficacy.•Compound II-B-2 significantly downregulated Cyclooxygenase 2 expression and suppressed Prostaglandin E2 formation. Chemical modifications on the A ring of limonin (1) and deoxylimonin (2) afforded 28 structural characterized derivatives, which were firstly subjected to preliminary in vivo analgesic and anti-inflammatory screen by mice model. The most promising candidate, deoxylimonin analog II-B-2 (70 mg/kg) with 3,4-dimethoxyphenylethyl moiety substitued δ-lactam in the A ring, exhibited better analgesic activity than aspirin (200 mg/kg) and stronger anti-inflammatory efficacy than naproxen (150 mg/kg). Further in vivo evaluation confirmed its advantage over limonin and showed dose-response dependent manner, and follow-up research suggested that the anti-inflammatory effect of compound II-B-2 may be attributed to the downregulation of cyclooxygenase 2 expression and the suppression of prostaglandin E2 formation.