title: Synthesis, characterization and biological evaluation of ureidofibrate-like derivatives endowed with peroxisome proliferator-activated receptor activity.
abstract: A series of ureidofibrate-like derivatives was prepared and assayed for their PPAR functional activity. A calorimetric approach was used to characterize PPARγ-ligand interactions, and docking experiments and X-ray studies were performed to explain the observed potency and efficacy. R-1 and S-1 were selected to evaluate several aspects of their biological activity. In an adipogenic assay, both enantiomers increased the expression of PPARγ target genes and promoted the differentiation of 3T3-L1 fibroblasts to adipocytes. In vivo administration of these compounds to insulin resistant C57Bl/6J mice fed a high fat diet reduced visceral fat content and body weight. Examination of different metabolic parameters showed that R-1 and S-1 are insulin sensitizers. Notably, they also enhanced the expression of hepatic PPARα target genes indicating that their in vivo effects stemmed from an activation of both PPARα and γ. Finally, the capability of R-1 and S-1 to inhibit cellular proliferation in colon cancer cell lines was also evaluated.
authors.affiliation: Laboratorio di Oncologia Sperimentale Clinica, Istituto Tumori "Giovanni Paolo II", 70124 Bari, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Porcelli
authors.forename: F
authors.initials: F
authors.lastname: Gilardi
authors.forename: A
authors.initials: A
authors.lastname: Laghezza
authors.forename: L
authors.initials: L
authors.lastname: Piemontese
authors.forename: N
authors.initials: N
authors.lastname: Mitro
authors.forename: A
authors.initials: A
authors.lastname: Azzariti
authors.forename: F
authors.initials: F
authors.lastname: Altieri
authors.forename: L
authors.initials: L
authors.lastname: Cervoni
authors.forename: G
authors.initials: G
authors.lastname: Fracchiolla
authors.forename: M
authors.initials: M
authors.lastname: Giudici
authors.forename: U
authors.initials: U
authors.lastname: Guerrini
authors.forename: A
authors.initials: A
authors.lastname: Lavecchia
authors.forename: R
authors.initials: R
authors.lastname: Montanari
authors.forename: C
authors.initials: C
authors.lastname: Di Giovanni
authors.forename: A
authors.initials: A
authors.lastname: Paradiso
authors.forename: G
authors.initials: G
authors.lastname: Pochetti
authors.forename: G M
authors.initials: GM
authors.lastname: Simone
authors.forename: P
authors.initials: P
authors.lastname: Tortorella
authors.forename: M
authors.initials: M
authors.lastname: Crestani
authors.forename: F
authors.initials: F
authors.lastname: Loiodice
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001583:Benzoxazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects; D002151:Calorimetry; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D054333:Drug Partial Agonism; D004354:Drug Screening Assays, Antitumor; D058607:Fibric Acids / Q000737:chemistry*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D007333:Insulin Resistance; D050152:Intra-Abdominal Fat / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D047493:PPAR alpha / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D047495:PPAR gamma / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D011422:Propionates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014508:Urea / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D001583:Benzoxazoles; D058607:Fibric Acids; D047493:PPAR alpha; D047495:PPAR gamma; D011422:Propionates; D014508:Urea