Development of a novel furocoumarin derivative inhibiting NF-kappa B dependent biological functions: Design, synthesis and biological effects

作者：Borgatti Monica; Chilin Adriana; Piccagli Laura; Lampronti Ilaria; Bianchi Nicoletta; Mancini Irene; Marzaro Giovanni; dall'Acqua Francesco; Guiotto Adriano; Gambari Roberto^*

来源：European Journal of Medicinal Chemistry, 2011, 46(10): 4870-4877.

DOI：10.1016/j.ejmech.2011.07.032

• Furocoumarin
• Virtual screening
• Docking
• Cystic fibrosis
• Interleukin-8
• TNF-alpha

Nuclear Factor kappaB (NF-kappa B) plays a very important role in the control of gene expression and is deeply involved in several human pathologies. Accordingly, molecules targeting NF-kappa B dependent biological functions are considered of great interest. Virtual screening of furocoumarin libraries against NF-kappa B p50 allowed to rank compounds in respect to their expected ability to bind NF-kappa B and the identified compound might be considered for the development of analogs to be tested for biological activity on inhibition of NF-kappa B/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 silica to NF-kappa B and (b) efficiently inhibit the molecular interactions between P-32-labeled NF-kappa B double stranded DNA and p50 or p50/p65 complex. These data allowed to develop a novel lead of great interest for inhibiting NF-kappa B 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-kappa B/DNA interactions. In addition, we found that compound 2 is a potent inhibitor of IL-8 gene expression in TNF-alpha 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.

• 出版日期2011-10