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

Christos Papaneophytou,ab   Polyxeni Alexiou,c   Athanasios Papakyriakou,d   Evangelos Ntougkos,e   Katerina Tsiliouka,f   Anna Maranti,f   Fotini Liepouri,f   Alexandros Strongilos,f   Anthi Mettou,ab   Elias Couladouros,c   Elias Eliopoulos,d   Eleni Douni,de   George Kolliase  and  George Kontopidis*ab  
Author affiliations

* Corresponding authors

a Department of Biochemistry, Veterinary School, University of Thessaly, Trikalon 224, Karditsa 43100, Greece
E-mail: gkontopidis@vet.uth.gr
Fax: +30 24410 66041
Tel: +30 24410 66081

b Institute for Research and Technology of Thessaly (I.RE.TE.TH.), The Centre for Research & Technology Hellas (CE.R.TH.), Dimitriados 95 & Paulou Mela, Volos 38333, Greece

c Laboratory of General Chemistry, Department of Science, Agricultural University of Athens, Iera Odos 75, Athens 11855, Greece

d Laboratory of Genetics, Department of Biotechnology, Agricultural University of Athens, Iera Odos 75, Athens 11855, Greece

e Biomedical Sciences Research Center “Alexander Fleming”, Vari, Greece

f pro-ACTINA S.A., Archimidous Str. 59, P.O.Box 205, Koropi, Athens 19400, Greece

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
Author version
available: Download author version (PDF)
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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