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

Shaochi Wang; Xueqing Han; Yun Yang; Chen Zhou; Danmeng Luo; Wensong He; Qihua Zhu; Yungen Xu

doi:10.1016/j.bioorg.2020.103886

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. Epub 2020 Apr 24.

Authors

Shaochi Wang¹, Xueqing Han¹, Yun Yang², Chen Zhou², Danmeng Luo², Wensong He², Qihua Zhu³, Yungen Xu⁴

Affiliations

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: zhuqihua@cpu.edu.cn.
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: xyg@cpu.edu.cn.

PMID: 32371249
DOI: 10.1016/j.bioorg.2020.103886

Abstract

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.

Keywords: Anti-inflammation; Antinociception; Downregulate Prostaglandin E(2); Limonin derivative; Suppress Cyclooxygenase 2.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Analgesics / chemistry*
Analgesics / pharmacology*
Analgesics / therapeutic use
Animals
Anti-Inflammatory Agents, Non-Steroidal / chemistry*
Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
Anti-Inflammatory Agents, Non-Steroidal / therapeutic use
Cyclooxygenase 2 / metabolism
Dinoprostone / metabolism
Disease Models, Animal
Edema / drug therapy
Edema / metabolism
Female
Lactams / chemistry
Lactams / pharmacology
Lactams / therapeutic use
Limonins / chemistry*
Limonins / pharmacology*
Limonins / therapeutic use
Male
Mice
Mice, Inbred ICR
Pain / drug therapy
Pain / metabolism
Rats, Inbred Lew

Substances

Analgesics
Anti-Inflammatory Agents, Non-Steroidal
Lactams
Limonins
deoxylimonin
Cyclooxygenase 2
Dinoprostone
limonin