Synthesis and biological evaluation of pyrazole-fused oleanolic acid derivatives as novel inhibitors of inflammatory and osteoclast differentiation

Yuanyuan Yu; Wenlong Yuan; Jiaqi Yuan; Wenhui Wei; Qian He; Xiaofei Zhang; Shijun He; Chunhao Yang

doi:10.1016/j.bmc.2023.117177

Synthesis and biological evaluation of pyrazole-fused oleanolic acid derivatives as novel inhibitors of inflammatory and osteoclast differentiation

Bioorg Med Chem. 2023 Feb 15:80:117177. doi: 10.1016/j.bmc.2023.117177. Epub 2023 Jan 20.

Authors

Yuanyuan Yu¹, Wenlong Yuan², Jiaqi Yuan³, Wenhui Wei², Qian He⁴, Xiaofei Zhang⁴, Shijun He⁵, Chunhao Yang⁶

Affiliations

¹ School of Chinese Materia Medica, Nanjing University of Chinese Medicine, 138 Xianlin Avenue, Nanjing, Jiangsu Province 210023, China; State Key Laboratory of Drug Research, Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
² State Key Laboratory of Drug Research, Laboratory of Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China; School of Pharmacy, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
³ State Key Laboratory of Drug Research, Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China; School of Pharmacy, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
⁴ State Key Laboratory of Drug Research, Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
⁵ State Key Laboratory of Drug Research, Laboratory of Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China; School of Pharmacy, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China. Electronic address: heshijun@simm.ac.cn.
⁶ School of Chinese Materia Medica, Nanjing University of Chinese Medicine, 138 Xianlin Avenue, Nanjing, Jiangsu Province 210023, China; State Key Laboratory of Drug Research, Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China; School of Pharmacy, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China. Electronic address: chyang@simm.ac.cn.

PMID: 36701870
DOI: 10.1016/j.bmc.2023.117177

Abstract

A series of pyrazole-fused oleanolic acid derivatives were designed and synthesized. The modification of these analogues focused on the substituents screening on the pyrazole ring. The cytotoxicity of these compounds and their anti-inflammatory activities via inhibiting interleukin-1β (IL-1β) production were evaluated in RAW264.7 cells. Most of the derivatives showed significantly improved potency compared with oleanolic acid. Among them, compound 7n exhibited the most potent anti-inflammatory activity on decreasing IL-1β production with low cytotoxicity. Moreover, the further study found 7n could inhibit RANKL-induced osteoclast differentiation on bone marrow-derived macrophages (BMMs). These findings may provide a potential direction for the drug development of osteoarthritis.

Keywords: Anti-inflammatory; Antiosteoclastic activity; IL-1β inhibition; Oleanolic acid derivatives; Osteoarthritis.

Publication types

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

MeSH terms

Cell Differentiation
Macrophages
Oleanolic Acid*
Osteoclasts*
Pyrazoles / pharmacology
RANK Ligand / pharmacology

Substances

Oleanolic Acid
Pyrazoles
RANK Ligand