Synthesis and evaluation of novel D-ring substituted steroidal pyrazolines as potential anti-inflammatory agents
| Autor: | Yicun Chen, Zhiwei Zheng, Huide Zhu, Zhiwei Zhu, De Cai, Shulin Zhao, Jinhong Zheng, Duncan Wei, Xiaorui Cai |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Cell Survival
Clinical Biochemistry Anti-Inflammatory Agents Nitric Oxide Synthase Type II 030209 endocrinology & metabolism Pyrazoline Chemistry Techniques Synthetic Pyrazole Nitric Oxide Biochemistry Dinoprostone Gene Expression Regulation Enzymologic Nitric oxide Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Endocrinology medicine Animals Cytotoxicity Molecular Biology RAW 264.7 Cells Pharmacology Nucleophilic addition biology Interleukin-6 Tumor Necrosis Factor-alpha Chemistry Organic Chemistry Combinatorial chemistry Nitric oxide synthase Cyclooxygenase 2 030220 oncology & carcinogenesis biology.protein Pregnenolone Pyrazoles Steroids medicine.drug |
| Zdroj: | Steroids. 146:70-78 |
| ISSN: | 0039-128X |
| DOI: | 10.1016/j.steroids.2019.03.012 |
| Popis: | To identify new potential anti-inflammatory agents, a number of novel steroidal derivatives with nitrogen heterocyclic side chains 4a-4l were synthesized and evaluated for their anti-inflammatory effects in activated RAW 264.7 macrophage cells. The synthesis scheme involves two steps, Claisen-Schmidt condensation with the corresponding pregnenolone and aromatic aldehydes as the first step followed by nucleophilic addition of thiosemicarbazide across an α, β-unsaturated carbonyl as a later step. Compound structures were confirmed by 1H NMR, 13C NMR, HRMS, and IR. The compounds were assayed to test their anti-inflammatory effects in activated RAW 264.7 cells. Compound 4g, 3β-hydroxy-pregn-5-en-17β-yl-5′-(m-fluorophenyl)-4′, 5′-dihydro-1′-carbothioic acid amido pyrazole, was identified as the most potent anti-inflammatory agent of the analysed compounds, with an IC50 value of 0.86 µM on nitric oxide (NO) production in lipopolysaccharide (LPS)-induced RAW 264.7 cells for 24 h compared to dexamethasone (IC50 = 0.62 µM) and low cytotoxicity against RAW 264.7 cells. Compound 4g significantly inhibited NO produced by LPS-induced RAW 264.7 cells. Further studies showed that compound 4g markedly inhibited the expression of pro-inflammatory factors, including inducible nitric oxide synthase (iNOS), interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α), and cyclooxygenase-2 (COX-2) in LPS-induced RAW 264.7 cells. These results indicate that derivatives bearing pyrazoline structure might be considered for further research and scaffold optimization in designing anti-inflammatory drugs and compound 4g might be a promising therapeutic anti-inflammatory drug candidate. |
| Databáze: | OpenAIRE |
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