Rationally Designed Less Toxic SPD-304 Analogs and Preliminary Evaluation of Their TNF Inhibitory Effects
AuthorAlexiou, 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.
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.