Rationally designed less toxic SPD-304 analogs and preliminary evaluation of their TNF inhibitory effects

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

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

SPD-304 was discovered as a promising tumor necrosis factor alpha (TNF) antagonist that promotes dissociation of TNF trimers and therefore blocks the interaction of TNF and its receptor. However, SPD-304 contains a potentially toxic 3-alkylindole moiety, which can be bioactivated to a reactive electrophilic intermediate. A series of SPD-304 analogs was synthesized with the aim to diminish its toxicophore groups while maintaining the binding affinity for TNF. Incorporation of electron-withdrawing substituents at the indole moiety, in conjunction with elimination of the 6-methyl group of the 4-chromone moiety, led to a significantly less toxic and equally potent TNF inhibitor. A series of SPD-304 analogs was rationally designed aiming to diminish its toxicophore groups while maintaining its tumor necrosis factor alpha (TNF) inhibitory activity. Modification of the N-indole substituent with an aromatic deactivating group, in combination with elimination of the 6-methyl group of the 4-chromone of SPD-304, resulted in a significantly less toxic and equally potent TNF inhibitor (3c).

Original languageEnglish
Pages (from-to)798-805
Number of pages8
JournalArchiv der Pharmazie
Volume347
Issue number11
DOIs
Publication statusPublished - 1 Nov 2014

Keywords

  • Inhibitors
  • Rational drug design
  • Synthesis

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    Alexiou, P., Papakyriakou, A., Ntougkos, E., Papaneophytou, C. P., Liepouri, F., Mettou, A., Katsoulis, I., Maranti, A., Tsiliouka, K., Strongilos, A., Chaitidou, S., Douni, E., Kontopidis, G., Kollias, G., Couladouros, E., & Eliopoulos, E. (2014). Rationally designed less toxic SPD-304 analogs and preliminary evaluation of their TNF inhibitory effects. Archiv der Pharmazie, 347(11), 798-805. https://doi.org/10.1002/ardp.201400198