Synthesis and Biological Evaluations of Betulinic Acid Derivatives With Inhibitory Activity on Hyaluronidase and Anti-Inflammatory Effects Against Hyaluronic Acid Fragment Induced Inflammation

Zhujun Luo; Hao He; Tiantian Tang; Jun Zhou; Huifang Li; Navindra P Seeram; Dongli Li; Kun Zhang; Hang Ma; Panpan Wu

doi:10.3389/fchem.2022.892554

Synthesis and Biological Evaluations of Betulinic Acid Derivatives With Inhibitory Activity on Hyaluronidase and Anti-Inflammatory Effects Against Hyaluronic Acid Fragment Induced Inflammation

Front Chem. 2022 May 4:10:892554. doi: 10.3389/fchem.2022.892554. eCollection 2022.

Authors

Zhujun Luo^{1

2}, Hao He^{1

2

3

4}, Tiantian Tang^{5

6

7}, Jun Zhou^{1

2}, Huifang Li^{1

2

3}, Navindra P Seeram³, Dongli Li^{1

2}, Kun Zhang^{1

2}, Hang Ma^{1

2

3}, Panpan Wu^{1

2}

Affiliations

¹ School of Biotechnology and Health Sciences, Wuyi University, Jiangmen, China.
² International Healthcare Innovation Institute, Jiangmen, China.
³ Bioactive Botanical Research Laboratory, Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, NY, United States.
⁴ School of Chemical Engineering, Shanxi Institute of Science and Technology, Jincheng, China.
⁵ Laboratory of Nutrition and Development, Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing, China.
⁶ Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, Beijing, China.
⁷ National Center for Children's Health, Beijing, China.

Abstract

We previously reported that the structural modifications of pentacyclic triterpenoids including oleanolic acid resulted in enhanced hyaluronidase inhibitory activity but whether this applies to other pentacyclic triterpenoids such as betulinic acid (BA) is unknown. Herein, we synthesized BA derivatives with an α,β-unsaturated ketene moiety and evaluated for their: 1) hyaluronidase inhibitory activity and, 2) anti-inflammatory effects against lipopolysaccharides (LPS) induced inflammation. Compared to BA, the BA derivatives exerted improved anti-hyaluronidase activity (26.3%-72.8% vs. 22.6%) and anti-inflammatory effects by reducing nitrite production in BV2 cells (3.9%-46.8% vs. 3.4%) and RAW264.7 cells (22.7%-49.2% vs. 20.4%). BA derivatives inhibited LPS-induced production of pro-inflammatory cytokines in THP-1 cells (15.2%-22.4%). BA derivatives also exerted promising anti-inflammatory effects against hyaluronic acid fragment induced nitrite production (8.6%-35.6%) in THP-1 cells. BA derivatives showed augmented anti-hyaluronidase and anti-inflammatory effects but further biological evaluations using in vivo models are warranted to confirm their efficacy.

Keywords: anti-inflammatory; betulinic acid; derivative; hyaluronidase; α,β-unsaturated ketene.