Synthesis and biological evaluation of potential small molecule inhibitors of tumor necrosis factor

Christos Papaneophytou, Polyxeni Alexiou, Athanasios Papakyriakou, Evangelos Ntougkos, Katerina Tsiliouka, Anna Maranti, Fotini Liepouri, Alexandros Strongilos, Anthi Mettou, Elias Couladouros, Elias Eliopoulos, Eleni Douni, George Kollias, George Kontopidis

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9 Citations (Scopus)


Inhibition of tumor necrosis factor (TNF) production or function by small molecules has become a major focus in the pharmaceutical industry for the treatment of rheumatoid arthritis. In this study, a series of 39 novel SPD-304 analogs were designed, synthesized and evaluated as TNF inhibitors. Our results show that small structural changes produce ligands with similar binding affinities (Kd) for TNF, but significantly different potencies in a L929 cell-based assay. In addition, contrary to the high affinity of compounds 4e, 8c and 10e for TNF in vitro, the potency of these compounds was determined to be low. We propose that these differences can partly be explained by the physicochemical characteristics of the synthesized SPD-304 analogs. Our findings were supplemented by molecular docking studies on the TNF dimer. These synthesized analogs may serve as a starting point for developing novel TNF inhibitors.

Original languageEnglish
Pages (from-to)1196-1209
Number of pages14
Issue number6
Publication statusPublished - 1 Jun 2015

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