Synthesis of novel psoralen derivatives as inhibitors of NF-kB dependent biological function

NF-kB is a transcription factor involved in the control of a large number of normal cellular and organism processes, such as immune and inflammatory responses, cellular growth and apoptosis. The dysregulation of NF-kB is associated with many disease states such as AIDS and viral infections, arthritis and inflammatory diseases, cancer and also genetic disorders. In this way, targeting NF-kB could be of great interest in order to find new therapeutic agents, mainly anticancer and/or antiinflammatory compounds. Recently, low-molecular-weight compounds able to interact with the DNA binding region of NFkB, thus inhibiting NF-kB\u2013DNA interactions and the related IL-8 gene expression, were identified by structured based virtual screening (VS) procedures. The most active compound selected through VS analysis showed furocoumarin structure, thus a focus library of differently substituted psoralens has been projected and synthesized to determine their activity on NF-kB/DNA interactions and TNF-alpha induced expression of IL-8. The title compounds present linear furocoumarin scaffold with methyl or tert-butyl substituent in the furan ring, an acetic or propionic residue in the 6 position and an aminoacid residue linked to the carboxylic function through amidic bond. The synthetic route was performed taking advantage of microwave assisted organic protocols, obtaining higher yield and reduced reaction times, if compared to previously reported methods.[3] EMSA evaluation of NF-kB/DNA interactions will be carried out to determine the biological activity of the synthesized compound. For the most promising ones, in-depth investigations will be performed to assess their antiinflammatory and/or antitumoral activity