title: Synthesis and structure-activity relationship study of triazine-based inhibitors of the DNA binding of NF-κB.
abstract: Nuclear transcription factor nuclear factor-kappa B (NF-κB) has diverse pathophysiological functions, and NF-κB inhibitors are considered to be candidates for multiple therapeutic applications. We previously reported a novel triazine-based NF-κB inhibitor, 2-anilino-4,6-dichloro-1,3,5-triazine (NI241), that directly inhibits DNA binding of NF-κB. Here, we report synthesis of a series of triazine derivatives and evaluation of their structure-activity relationships for NF-κB inhibition. We found that 2-amino-4,6-dichloro-1,3,5-triazine substructure is essential for the inhibitory activity of the lead compound NI241, and modification of NI241 by introduction of an m-methoxy substituent on the phenyl ring afforded the more potent derivative 28. The structure-activity relationships identified in this study suggested a possible mechanism of irreversible NF-κB inhibition by NI241, and should be helpful in the design of other NF-κB inhibitors.
authors.affiliation: Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University.
authors.forename: Shinya
authors.initials: S
authors.lastname: Fujii
authors.forename: Takanobu
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Aki
authors.initials: A
authors.lastname: Nakatsu
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Miyazawa
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kagechika
mesh_terms: D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D004926:Escherichia coli / Q000378:metabolism; D005456:Fluorescent Dyes / Q000737:chemistry; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism
chemical_list: D005456:Fluorescent Dyes; D016328:NF-kappa B; D011994:Recombinant Proteins; D014227:Triazines; D004247:DNA