2. Academic Validation
  3. Rationally designed less toxic SPD-304 analogs and preliminary evaluation of their TNF inhibitory effects

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

  • Arch Pharm (Weinheim). 2014 Nov;347(11):798-805. doi: 10.1002/ardp.201400198.
Polyxeni Alexiou 1,  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
Affiliations

Affiliation

  • 1 Laboratory of General Chemistry, Department of Science, Agricultural University of Athens, Athens, Greece.
PMID: 25160057 DOI: 10.1002/ardp.201400198
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.

Keywords

Inhibitors; Rational drug design; Synthesis.

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