title: Synthesis, in vitro evaluation, and molecular modeling investigation of benzenesulfonimide peroxisome proliferator-activated receptors α antagonists.
abstract: Recent evidences suggest a moderate activation of Peroxisome Proliferator-Activated Receptors (PPARs) could be favorable in metabolic diseases, reducing side effects given from full agonists. PPAR partial agonists and antagonists represent, to date, interesting tools to better elucidate biological processes modulated by these receptors. In this work are reported new benzenesulfonimide compounds able to block PPARα, synthesized and tested by transactivation assays and gene expression analysis. Some of these compounds showed a dose-dependent antagonistic behavior on PPARα, submicromolar potency, different profiles of selectivity versus PPARγ, and a repressive effect on CPT1A expression. Dockings and molecular dynamics on properly selected benzenesulfonimide derivatives furnished fresh insights into the molecular determinant most likely responsible for PPARα antagonism.
authors.affiliation: Unità di Chimica Farmaceutica, Dipartimento di Farmacia, Università"G. d'Annunzio", Chieti, Italy. Electronic address: aammazzalorso@unich.it.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Ammazzalorso
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università di Bari, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Carrieri
authors.affiliation: Unità di Patologia Generale, Dipartimento di Farmacia, Università "G. d'Annunzio", Chieti, Italy; Aging Research Center (Ce.S.I.), Università "G. d'Annunzio", Chieti, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Verginelli
authors.affiliation: Unità di Chimica Farmaceutica, Dipartimento di Farmacia, Università"G. d'Annunzio", Chieti, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Bruno
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università di Bari, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Carbonara
authors.affiliation: Unità di Chimica Farmaceutica, Dipartimento di Farmacia, Università"G. d'Annunzio", Chieti, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: D'Angelo
authors.affiliation: Unità di Chimica Farmaceutica, Dipartimento di Farmacia, Università"G. d'Annunzio", Chieti, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: De Filippis
authors.affiliation: Unità di Chimica Farmaceutica, Dipartimento di Farmacia, Università"G. d'Annunzio", Chieti, Italy.
authors.forename: Marialuigia
authors.initials: M
authors.lastname: Fantacuzzi
authors.affiliation: Unità di Patologia Generale, Dipartimento di Farmacia, Università "G. d'Annunzio", Chieti, Italy; Aging Research Center (Ce.S.I.), Università "G. d'Annunzio", Chieti, Italy.
authors.forename: Rosalba
authors.initials: R
authors.lastname: Florio
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università di Bari, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Fracchiolla
authors.affiliation: Unità di Chimica Farmaceutica, Dipartimento di Farmacia, Università"G. d'Annunzio", Chieti, Italy.
authors.forename: Letizia
authors.initials: L
authors.lastname: Giampietro
authors.affiliation: Unità di Chimica Farmaceutica, Dipartimento di Farmacia, Università"G. d'Annunzio", Chieti, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Giancristofaro
authors.affiliation: Unità di Chimica Farmaceutica, Dipartimento di Farmacia, Università"G. d'Annunzio", Chieti, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Maccallini
authors.affiliation: Unità di Patologia Generale, Dipartimento di Farmacia, Università "G. d'Annunzio", Chieti, Italy; Aging Research Center (Ce.S.I.), Università "G. d'Annunzio", Chieti, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Cama
authors.affiliation: Unità di Chimica Farmaceutica, Dipartimento di Farmacia, Università"G. d'Annunzio", Chieti, Italy. Electronic address: ramoroso@unich.it.
authors.forename: Rosa
authors.initials: R
authors.lastname: Amoroso
mesh_terms: D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D047492:Peroxisome Proliferator-Activated Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000187:drug effects / Q000235:genetics / Q000302:isolation & purification; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D047492:Peroxisome Proliferator-Activated Receptors; D012334:RNA, Neoplasm; D013449:Sulfonamides
keywords: Benzenesulfonimides; CPT1A; Docking; Fibrates; Molecular dynamic; PPAR antagonist; PPARs; Transactivation assay