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Issue 6, 2015
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Synthesis and biological evaluation of potential small moleculeinhibitors of tumor necrosis factor

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Abstract

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 TNFinhibitors. 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.

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

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Publication details

The article was received on 18 Jan 2015, accepted on 18 May 2015 and first published on 19 May 2015


Article type: Concise Article
DOI: 10.1039/C5MD00023H
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Med. Chem. Commun., 2015,6, 1196-1209

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    Synthesis and biological evaluation of potential small moleculeinhibitors of tumor necrosis factor

    C. Papaneophytou, P. Alexiou, A. Papakyriakou, E. Ntougkos, K. Tsiliouka, A. Maranti, F. Liepouri, A. Strongilos, A. Mettou, E. Couladouros, E. Eliopoulos, E. Douni, G. Kollias and G. Kontopidis, Med. Chem. Commun., 2015, 6, 1196
    DOI: 10.1039/C5MD00023H

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