TY - JOUR
T1 - Synthesis and biological evaluation of potential small molecule inhibitors of tumor necrosis factor
AU - Papaneophytou, Christos
AU - Alexiou, Polyxeni
AU - Papakyriakou, Athanasios
AU - Ntougkos, Evangelos
AU - Tsiliouka, Katerina
AU - Maranti, Anna
AU - Liepouri, Fotini
AU - Strongilos, Alexandros
AU - Mettou, Anthi
AU - Couladouros, Elias
AU - Eliopoulos, Elias
AU - Douni, Eleni
AU - Kollias, George
AU - Kontopidis, George
PY - 2015/6/1
Y1 - 2015/6/1
N2 - Inhibition of tumor necrosis factor (TNF) production or function by small molecules has become a major focus in the pharmaceutical industry for the treatment of rheumatoid arthritis. In this study, a series of 39 novel SPD-304 analogs were designed, synthesized and evaluated as TNF inhibitors. Our results show that small structural changes produce ligands with similar binding affinities (Kd) for TNF, but significantly different potencies in a L929 cell-based assay. In addition, contrary to the high affinity of compounds 4e, 8c and 10e for TNF in vitro, the potency of these compounds was determined to be low. We propose that these differences can partly be explained by the physicochemical characteristics of the synthesized SPD-304 analogs. Our findings were supplemented by molecular docking studies on the TNF dimer. These synthesized analogs may serve as a starting point for developing novel TNF inhibitors.
AB - Inhibition of tumor necrosis factor (TNF) production or function by small molecules has become a major focus in the pharmaceutical industry for the treatment of rheumatoid arthritis. In this study, a series of 39 novel SPD-304 analogs were designed, synthesized and evaluated as TNF inhibitors. Our results show that small structural changes produce ligands with similar binding affinities (Kd) for TNF, but significantly different potencies in a L929 cell-based assay. In addition, contrary to the high affinity of compounds 4e, 8c and 10e for TNF in vitro, the potency of these compounds was determined to be low. We propose that these differences can partly be explained by the physicochemical characteristics of the synthesized SPD-304 analogs. Our findings were supplemented by molecular docking studies on the TNF dimer. These synthesized analogs may serve as a starting point for developing novel TNF inhibitors.
UR - http://www.scopus.com/inward/record.url?scp=84935832409&partnerID=8YFLogxK
U2 - 10.1039/c5md00023h
DO - 10.1039/c5md00023h
M3 - Article
AN - SCOPUS:84935832409
SN - 2040-2503
VL - 6
SP - 1196
EP - 1209
JO - MedChemComm
JF - MedChemComm
IS - 6
ER -