posted on 2020-03-16, 12:04authored byAlessandra Ammazzalorso, Isabella Bruno, Rosalba Florio, Laura De Lellis, Antonio Laghezza, Carmen Cerchia, Barbara De Filippis, Marialuigia Fantacuzzi, Letizia Giampietro, Cristina Maccallini, Paolo Tortorella, Serena Veschi, Fulvio Loiodice, Antonio Lavecchia, Alessandro Cama, Rosa Amoroso
An
agonist–antagonist switching strategy was performed to
discover novel PPARα antagonists. Phenyldiazenyl derivatives
of fibrates were developed, bearing sulfonimide or amide functional
groups. A second series of compounds was synthesized, replacing the
phenyldiazenyl moiety with amide or urea portions. Final compounds
were screened by transactivation assay, showing good PPARα antagonism
and selectivity at submicromolar concentrations. When tested in cancer
cell models expressing PPARα, selected derivatives induced marked
effects on cell viability. Notably, 3c, 3d, and 10e displayed remarkable antiproliferative effects
in two paraganglioma cell lines, with CC50 lower than commercial
PPARα antagonist GW6471 and a negligible toxicity on normal
fibroblast cells. Docking studies were also performed to elucidate
the binding mode of these compounds and to help interpretation of
SAR data.