title: Development of a novel furocoumarin derivative inhibiting NF-κB dependent biological functions: design, synthesis and biological effects.
abstract: Nuclear Factor kappaB (NF-κB) plays a very important role in the control of gene expression and is deeply involved in several human pathologies. Accordingly, molecules targeting NF-κB dependent biological functions are considered of great interest. Virtual screening of furocoumarin libraries against NF-κB p50 allowed to rank compounds in respect to their expected ability to bind NF-κB and the identified compound might be considered for the development of analogs to be tested for biological activity on inhibition of NF-κB/DNA complex formation. The data reported in the present paper suggest that, following this approach, the best ranked compounds identified by virtual screening (a) strongly bind in silico to NF-κB and (b) efficiently inhibit the molecular interactions between (32)P-labeled NF-κB double stranded DNA and p50 or p50/p65 complex. These data allowed to develop a novel lead of great interest for inhibiting NF-κB dependent biological functions. This novel molecule (compound 2), bearing a methyl group in the 9 position of the psoralen nucleus, exhibits high efficiency in inhibiting NF-κB/DNA interactions. In addition, we found that compound 2 is a potent inhibitor of IL-8 gene expression in TNF-α treated IB3-1 cystic fibrosis cells. Taken together, our data indicate that compound 2 might find an important place in the set of molecules of interest for the development of pharmaceutical strategies against the inflammatory phenotype of cystic fibrosis.
authors.affiliation: BioPharmaNet, Department of Biochemistry and Molecular Biology, Interdisciplinary Center for the Study of Inflammation, University of Ferrara, Via Fossato di Mortara 74, I-44100 Ferrara, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Borgatti
authors.forename: Adriana
authors.initials: A
authors.lastname: Chilin
authors.forename: Laura
authors.initials: L
authors.lastname: Piccagli
authors.forename: Ilaria
authors.initials: I
authors.lastname: Lampronti
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Bianchi
authors.forename: Irene
authors.initials: I
authors.lastname: Mancini
authors.forename: Giovanni
authors.initials: G
authors.lastname: Marzaro
authors.forename: Francesco
authors.initials: F
authors.lastname: dall'Acqua
authors.forename: Adriano
authors.initials: A
authors.lastname: Guiotto
authors.forename: Roberto
authors.initials: R
authors.lastname: Gambari
mesh_terms: D002460:Cell Line; D003550:Cystic Fibrosis / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004247:DNA / Q000378:metabolism*; D015195:Drug Design; D011564:Furocoumarins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics; D008958:Models, Molecular; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism*; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D011564:Furocoumarins; D016209:Interleukin-8; D016328:NF-kappa B; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D004247:DNA