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Rationally Designed Less Toxic SPD‐304 Analogs and Preliminary Evaluation of Their TNF Inhibitory Effects
Author(s) -
Alexiou Polyxeni,
Papakyriakou Athanasios,
Ntougkos Evangelos,
Papaneophytou Christos P.,
Liepouri Fotini,
Mettou Anthi,
Katsoulis Ioannis,
Maranti Anna,
Tsiliouka Katerina,
Strongilos Alexandros,
Chaitidou Sotiria,
Douni Eleni,
Kontopidis George,
Kollias George,
Couladouros Elias,
Eliopoulos Elias
Publication year - 2014
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.201400198
Subject(s) - moiety , chemistry , tumor necrosis factor alpha , stereochemistry , chromone , electrophile , antagonist , indole test , receptor , pharmacology , biochemistry , immunology , medicine , catalysis
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.