Discovery of deoxylimonin δ-lactam derivative with favorable anti-inflammation and antinociception efficacy from chemical modified limonin/deoxylimonin analogs
- Bioorg Chem. 2020 Jul;100:103886. doi: 10.1016/j.bioorg.2020.103886.
- 1. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
- 2. Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China.
- 3. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China. Electronic address: [email protected].
- 4. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China. Electronic address: [email protected].
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.
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target: Others
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