title: New diphenylmethane derivatives as peroxisome proliferator-activated receptor alpha/gamma dual agonists endowed with anti-proliferative effects and mitochondrial activity.
abstract: We screened a short series of new chiral diphenylmethane derivatives and identified potent dual PPARα/γ partial agonists. As both enantiomers of the most active compound 1 displayed an unexpected similar transactivation activity, we performed docking experiments to provide a molecular understanding of their similar partial agonism. We also evaluated the ability of both enantiomers of 1 and racemic 2 to inhibit colorectal cancer cells proliferation: (S)-1 displayed a more robust activity due, at least in part, to a partial inhibition of the Wnt/β-catenin signalling pathway that is upregulated in the majority of colorectal cancers. Finally, we investigated the effects of (R)-1, (S)-1 and (R,S)-2 on mitochondrial function and demonstrated that they activate the carnitine shuttle system through upregulation of carnitine/acylcarnitine carrier (CAC) and carnitine-palmitoyl-transferase 1 (CPT1) genes. Consistent with the notion that these are PPARα target genes, we tested and found that PPARα itself is regulated by a positive loop. Moreover, these compounds induced a significant mitochondrial biogenesis. In conclusion, we identified a new series of dual PPARα/γ agonists endowed with novel anti-proliferative properties associated with a strong activation of mitochondrial functions and biogenesis, a potential therapeutic target of the treatment of insulin resistance.
authors.affiliation: Dipartimento Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", via Orabona 4, 70125 Bari, Italy; Istituto di Scienze delle Produzioni Alimentari, Consiglio Nazionale delle Ricerche, via Amendola 122/O, 70126 Bari, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Piemontese
authors.affiliation: Dipartimento di Farmacia, "Drug Discovery" Laboratory, Università degli Studi di Napoli "Federico II", via D. Montesano 49, 80131 Napoli, Italy.
authors.forename: Carmen
authors.initials: C
authors.lastname: Cerchia
authors.affiliation: Dipartimento Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", via Orabona 4, 70125 Bari, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Laghezza
authors.affiliation: Dipartimento di Scienze e Tecnologie, Università degli Studi del Sannio, via Port'Arsa 11, 82100 Benevento, Italy.
authors.forename: Pamela
authors.initials: P
authors.lastname: Ziccardi
authors.affiliation: Dipartimento Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", via Orabona 4, 70125 Bari, Italy.
authors.forename: Sabina
authors.initials: S
authors.lastname: Sblano
authors.affiliation: Dipartimento Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", via Orabona 4, 70125 Bari, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Tortorella
authors.affiliation: Dipartimento di Bioscienze, Biotecnologie e Biofarmaceutica, Laboratorio di Biochimica e Biologia Molecolare, Università degli Studi di Bari "Aldo Moro", via Orabona 4, 70125 Bari, Italy; Istituto di Biomembrane e Bioenergetica, Consiglio Nazionale delle Ricerche, via Orabona 4, 70125 Bari, Italy.
authors.forename: Vito
authors.initials: V
authors.lastname: Iacobazzi
authors.affiliation: Dipartimento di Bioscienze, Biotecnologie e Biofarmaceutica, Laboratorio di Biochimica e Biologia Molecolare, Università degli Studi di Bari "Aldo Moro", via Orabona 4, 70125 Bari, Italy; Dipartimento di Scienze, Università della Basilicata, viale dell'Ateneo Lucano 10, 85100 Potenza, Italy.
authors.forename: Vittoria
authors.initials: V
authors.lastname: Infantino
authors.affiliation: Dipartimento di Bioscienze, Biotecnologie e Biofarmaceutica, Laboratorio di Biochimica e Biologia Molecolare, Università degli Studi di Bari "Aldo Moro", via Orabona 4, 70125 Bari, Italy; Dipartimento di Scienze, Università della Basilicata, viale dell'Ateneo Lucano 10, 85100 Potenza, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Convertini
authors.affiliation: Dipartimento di Medicina e Chirurgia, Università di Salerno, via Giovanni Paolo II 132, 84084 Fisciano, SA, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Dal Piaz
authors.affiliation: Dipartimento di Scienze e Tecnologie, Università degli Studi del Sannio, via Port'Arsa 11, 82100 Benevento, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Lupo
authors.affiliation: Dipartimento di Scienze e Tecnologie, Università degli Studi del Sannio, via Port'Arsa 11, 82100 Benevento, Italy.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Colantuoni
authors.affiliation: Dipartimento di Farmacia, "Drug Discovery" Laboratory, Università degli Studi di Napoli "Federico II", via D. Montesano 49, 80131 Napoli, Italy. Electronic address: antonio.lavecchia@unina.it.
authors.forename: Antonio
authors.initials: A
authors.lastname: Lavecchia
authors.affiliation: Dipartimento Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", via Orabona 4, 70125 Bari, Italy. Electronic address: fulvio.loiodice@uniba.it.
authors.forename: Fulvio
authors.initials: F
authors.lastname: Loiodice
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D001559:Benzhydryl Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D002331:Carnitine / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D019073:HT29 Cells; D056945:Hep G2 Cells; D006801:Humans; D007333:Insulin Resistance; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D062105:Molecular Docking Simulation; D047493:PPAR alpha / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D015398:Signal Transduction / Q000187:drug effects; D051176:beta Catenin / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001559:Benzhydryl Compounds; D047493:PPAR alpha; D047495:PPAR gamma; D051176:beta Catenin; C010129:diphenylmethane; D002331:Carnitine
keywords: Anti-proliferative effects; Docking experiments; Gene expression analysis; Mitochondrial biogenesis; PPAR