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.

Sulfonimide and Amide Derivatives as Novel PPARα Antagonists: Synthesis, Antiproliferative Activity, and Docking Studies

Ammazzalorso, Alessandra
;
Bruno, Isabella;Florio, Rosalba;De Lellis, Laura;De Filippis, Barbara;Fantacuzzi, Marialuigia;Giampietro, Letizia;Maccallini, Cristina;Tortorella, Paolo;Veschi, Serena;Loiodice, Fulvio;Cama, Alessandro;Amoroso, Rosa
2020

Abstract

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.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11564/718022
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