Synthesis of lathyrane diterpenoid nitrogen-containing heterocyclic derivatives and evaluation of their anti-inflammatory activities

Wang Wang; Liangliang Xiong; Yutong Li; Zhuorui Song; Dejuan Sun; Hua Li; Lixia Chen

doi:10.1016/j.bmc.2022.116627

Synthesis of lathyrane diterpenoid nitrogen-containing heterocyclic derivatives and evaluation of their anti-inflammatory activities

Bioorg Med Chem. 2022 Feb 15:56:116627. doi: 10.1016/j.bmc.2022.116627. Epub 2022 Jan 14.

Authors

Wang Wang¹, Liangliang Xiong¹, Yutong Li¹, Zhuorui Song¹, Dejuan Sun², Hua Li³, Lixia Chen⁴

Affiliations

¹ Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
² Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: sywysdj@163.com.
³ Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China; Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Electronic address: li_hua@hust.edu.cn.
⁴ Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: syzyclx@163.com.

PMID: 35063896
DOI: 10.1016/j.bmc.2022.116627

Abstract

As our ongoing work on lathyrane diterpenoid derivatization, three series of lathyrane diterpenoid derivatives were designed and synthesized based combination principles, including pyrazole, thiazole and furoxan moieties. Biological evaluation indicated that compound 23d exhibited excellently inhibitory activity on LPS-induced NO production in RAW264.7 cells (IC₅₀ = 0.38 ± 0.18 μM). The preliminary structure-activity relationships (SARs) suggested that phenylsulfonyl substituted furoxan moiety had the strongest ability to improve anti-inflammatory activity of lathyrane diterpenoids. Furthermore, compound 23d significantly reduced the level of ROS. Its molecular mechanism was related to inhibiting the transcriptional activation of Nrf2/HO-1 pathway. Based on these considerations, 23d might be a promising anti-inflammatory agent, which is noteworthy for further exploration.

Keywords: Anti-inflammation; Furoxan; Lathyrane; Pyrazole; Structural modification; Thiazole.

Publication types

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

MeSH terms

Animals
Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis
Anti-Inflammatory Agents, Non-Steroidal / chemistry
Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
Diterpenes / chemical synthesis
Diterpenes / chemistry
Diterpenes / pharmacology*
Dose-Response Relationship, Drug
Heme Oxygenase-1 / antagonists & inhibitors
Heme Oxygenase-1 / metabolism
Heterocyclic Compounds / chemistry
Heterocyclic Compounds / pharmacology*
Lipopolysaccharides / antagonists & inhibitors
Lipopolysaccharides / pharmacology
Membrane Proteins / antagonists & inhibitors
Membrane Proteins / metabolism
Mice
Molecular Structure
NF-E2-Related Factor 2 / antagonists & inhibitors
NF-E2-Related Factor 2 / metabolism
Nitric Oxide / antagonists & inhibitors
Nitric Oxide / biosynthesis
Nitrogen Compounds / chemistry
Nitrogen Compounds / pharmacology*
RAW 264.7 Cells
Structure-Activity Relationship

Substances

Anti-Inflammatory Agents, Non-Steroidal
Diterpenes
Heterocyclic Compounds
Lipopolysaccharides
Membrane Proteins
NF-E2-Related Factor 2
Nfe2l2 protein, mouse
Nitrogen Compounds
lathyrane
Nitric Oxide
Heme Oxygenase-1
Hmox1 protein, mouse