title: A New Application of Parallel Synthesis Strategy for Discovery of Amide-Linked Small Molecules as Potent Chondroprotective Agents in TNF-α-Stimulated Chondrocytes.
abstract: 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.
authors.affiliation: Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.|School of Pharmacy, National Defense Medical Center, Taipei, Taiwan.|Graduate Institute of Medical Science, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Chia-Chung
authors.initials: CC
authors.lastname: Lee
authors.affiliation: School of Pharmacy, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Yang
authors.initials: Y
authors.lastname: Lo
authors.affiliation: Institute of Cellular and System Medicine, National Health Research Institute, Zhunan, Taiwan.
authors.forename: Ling-Jun
authors.initials: LJ
authors.lastname: Ho
authors.affiliation: Division of Allergy, Immunology and Rheumatology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, Tao-Yuan, Taiwan.
authors.forename: Jenn-Haung
authors.initials: JH
authors.lastname: Lai
authors.affiliation: Department of Orthopaedics, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Shiu-Bii
authors.initials: SB
authors.lastname: Lien
authors.affiliation: Department of Orthopaedics, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Leou-Chyr
authors.initials: LC
authors.lastname: Lin
authors.affiliation: Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.|School of Pharmacy, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Chun-Liang
authors.initials: CL
authors.lastname: Chen
authors.affiliation: Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.|School of Pharmacy, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Tsung-Chih
authors.initials: TC
authors.lastname: Chen
authors.affiliation: Graduate Institute of Medical Science, National Defense Medical Center, Taipei, Taiwan.|Rheumatology/Immunology/Allergy, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Feng-Cheng
authors.initials: FC
authors.lastname: Liu
authors.affiliation: Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.|School of Pharmacy, National Defense Medical Center, Taipei, Taiwan.|Graduate Institute of Medical Science, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Hsu-Shan
authors.initials: HS
authors.lastname: Huang
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D019902:Chondrocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D018360:Crystallography, X-Ray; D019610:Cytoprotection / Q000187:drug effects*; D006801:Humans; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D054852:Small Molecule Libraries / Q000138:chemical synthesis* / Q000737:chemistry; D034421:Sus scrofa; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D000577:Amides; D001549:Benzamides; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; D054852:Small Molecule Libraries; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D053509:Matrix Metalloproteinase 13