A New Application of Parallel Synthesis Strategy for Discovery of Amide-Linked Small Molecules as Potent Chondroprotective Agents in TNF-α-Stimulated Chondrocytes

• Published in: PloS one 2016-03, Vol.11 (3), p.e0149317-e0149317
• Main Authors: Lee, Chia-Chung, Lo, Yang, Ho, Ling-Jun, Lai, Jenn-Haung, Lien, Shiu-Bii, Lin, Leou-Chyr, Chen, Chun-Liang, Chen, Tsung-Chih, Liu, Feng-Cheng, Huang, Hsu-Shan
• Format: Article
• Language: English
• Subjects: Amides - chemical synthesis; Amides - chemistry; Amides - pharmacology; Animals; Anti-inflammatory agents; Arthritis; Benzamides - pharmacology; Biocompatibility; Biological effects; Biology; Biology and Life Sciences; Biomedical materials; Cancer; Cell Survival - drug effects; Chemical synthesis; Chemistry; Chondrocytes; Chondrocytes - cytology; Chondrocytes - drug effects; Chondrocytes - metabolism; Collagenase 3; Crystallography, X-Ray; Cytokines; Cytoprotection - drug effects; Hospitals; Humans; Immunology; Inflammation; Matrix Metalloproteinase 13 - metabolism; Matrix metalloproteinases; Medical treatment; Medicine and Health Sciences; Models, Biological; NF-kappa B - metabolism; NF-κB protein; Nitric oxide; Nitric Oxide - biosynthesis; Nitric Oxide Synthase Type II - metabolism; Nitric-oxide synthase; NMR; Nuclear magnetic resonance; Osteoarthritis; Pathogenesis; Pharmacy; Physical Sciences; Research and analysis methods; Rheumatology; Rodents; Science; Small Molecule Libraries - chemical synthesis; Small Molecule Libraries - chemistry; Stat3 protein; STAT3 Transcription Factor - metabolism; Studies; Sus scrofa; Transcription factors; Tumor Necrosis Factor-alpha - pharmacology; Tumor necrosis factor-TNF; Tumor necrosis factor-α
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0149317

As part of an effort to profile potential therapeutics for the treatment of inflammation-related diseases, a diversity of amide-linked small molecules was synthesized by using parallel synthesis strategy. Moreover, these new compounds were also evaluated for their inhibitory effects on nitric oxide (NO) by using tumor necrosis factor alpha (TNF-α)-induced inflammatory responses in chondrocytes. Among the tested compounds, N-(3-chloro-4-fluorophenyl)-2-hydroxybenzamide (HS-Ck) was the most potent inhibitor of NO production and inducible nitric oxide synthase (iNOS) expression in TNF-α-stimulated chondrocytes. In addition, our biological results indicated that HS-Ck might suppress the expression levels of iNOS and matrix metalloproteinases-13 (MMP-13) activities through downregulating the activation of nuclear factor kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT-3) transcriptional factors. Therefore, the parallel synthesis was successful used to develop a new class of potential anti-inflammatory agents as chondroprotective candidates for the treatment of osteoarthritis.