2. Academic Validation
  3. Discovery of novel 3-hydroxyandrosta-5,7-Diene-17-Carboxylic acid derivatives as anti-inflammatory bowel diseases (IBD) agents

Discovery of novel 3-hydroxyandrosta-5,7-Diene-17-Carboxylic acid derivatives as anti-inflammatory bowel diseases (IBD) agents

  • Eur J Med Chem. 2021 Aug 5:220:113468. doi: 10.1016/j.ejmech.2021.113468.
Jingxuan Chen 1,  Ling Li 1,  Jin Liu 1,  Sijie Yuan 2,  Wenzhen Liao 2,  Andrzej T Slominski 3,  Wei Li 4,  Michał A Żmijewski 5,  Jianjun Chen 6
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou, 510515, China.
  • 2 Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, China.
  • 3 Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
  • 4 Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN, 38163, USA.
  • 5 Department of Histology, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland.
  • 6 School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou, 510515, China. Electronic address: jchen21@smu.edu.cn.
PMID: 33933753 DOI: 10.1016/j.ejmech.2021.113468
Abstract

A series of steroidal compounds based on 3-hydroxyandrosta-5,7-diene-17-carboxylic acid core structure were designed, synthesized and bio-evaluated for their anti-inflammatory potency. Among them, compound 5c, 6f, and 6q effectively inhibited the production of nitric oxide (NO) in lipopolysaccharide (LPS) stimulated RAW 264.7 macrophages. They inhibited the expression of inducible NO Synthase (iNOS) and prostaglandin synthase-2 (COX-2) at mRNA level. Compound 6q displayed inhibitory effects on both iNOS and COX-2 expression in a concentration-dependent manner. Furthermore, 6q was found to effectively decrease the mRNA and protein levels of interleukin 6 (IL-6). Mechanically, 6q could potently downregulate NF-κB signaling via suppression of the Akt/PI3K pathway. Moreover, 6q demonstrated high in vivo anti-inflammatory activities in a mouse colitis model induced by dextran sulfate sodium (DSS). Taken together, these data indicate that 6q represents a novel and promising anti-inflammatory bowel diseases (IBD) agent worthy of further investigation.

Keywords

Anti-inflammatory bowel diseases; DSS-Induced mouse colitis; NF-κB signaling; Steroidal compounds.

Figures