TY - JOUR
T1 - Rationally designed less toxic SPD-304 analogs and preliminary evaluation of their TNF inhibitory effects
AU - Alexiou, Polyxeni
AU - Papakyriakou, Athanasios
AU - Ntougkos, Evangelos
AU - Papaneophytou, Christos P.
AU - Liepouri, Fotini
AU - Mettou, Anthi
AU - Katsoulis, Ioannis
AU - Maranti, Anna
AU - Tsiliouka, Katerina
AU - Strongilos, Alexandros
AU - Chaitidou, Sotiria
AU - Douni, Eleni
AU - Kontopidis, George
AU - Kollias, George
AU - Couladouros, Elias
AU - Eliopoulos, Elias
PY - 2014/11/1
Y1 - 2014/11/1
N2 - 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).
AB - 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).
KW - Inhibitors
KW - Rational drug design
KW - Synthesis
UR - http://www.scopus.com/inward/record.url?scp=84927130984&partnerID=8YFLogxK
U2 - 10.1002/ardp.201400198
DO - 10.1002/ardp.201400198
M3 - Article
C2 - 25160057
AN - SCOPUS:84927130984
SN - 0365-6233
VL - 347
SP - 798
EP - 805
JO - Archiv der Pharmazie
JF - Archiv der Pharmazie
IS - 11
ER -