title: Synthesis and biological evaluation of imidazo[1,2-a]pyrimidines and imidazo[1,2-a]pyridines as new inhibitors of the Wnt/β-catenin signaling.
abstract: Wnt/β-catenin signaling plays an important role in the regulation of embryonic development and tumorigenesis. Since its deregulation results in severe human diseases, especially cancer, the Wnt signaling pathway constitutes a promising platform for pharmacological targeting of cancer. In this study we synthesized a series of imidazo[1,2-a]pyrimidines and imidazo[1,2-a]pyridines and identified some derivatives that were able to inhibit the Wnt/β-catenin signaling pathway in a luciferase reporter assay and cell proliferation in selected cancer cell lines, endowed with APC or β-catenin gene mutations. The most active compounds significantly downregulate the expression of Wnt target genes such as c-myc and cyclin D1. Further studies indicated that these compounds function independently of GSK-3β activity. More importantly, in vivo experiments, carried out on a Wnt-reporter zebrafish model indicate, in particular for compounds 4c and 4i as the most active compounds, an activity comparable to that of the reference compound IWR1, suggesting their potential use not only as small molecule inhibitors of the Wnt/β-catenin signal in Wnt driven cancers, but also in other Wnt-related diseases.
authors.affiliation: Dipartimento di Farmacia, Università di Napoli Federico II, Via D. Montesano 49, 80131 Napoli, Italy. Electronic address: barbara.cosimelli@unina.it.
authors.forename: Barbara
authors.initials: B
authors.lastname: Cosimelli
authors.affiliation: Dipartimento di Farmacia, Università di Napoli Federico II, Via D. Montesano 49, 80131 Napoli, Italy.
authors.forename: Sonia
authors.initials: S
authors.lastname: Laneri
authors.affiliation: Dipartimento di Farmacia, Università di Napoli Federico II, Via D. Montesano 49, 80131 Napoli, Italy.
authors.forename: Carmine
authors.initials: C
authors.lastname: Ostacolo
authors.affiliation: Dipartimento di Farmacia, Università di Napoli Federico II, Via D. Montesano 49, 80131 Napoli, Italy.
authors.forename: Antonia
authors.initials: A
authors.lastname: Sacchi
authors.affiliation: Dipartimento di Farmacia, Università di Napoli Federico II, Via D. Montesano 49, 80131 Napoli, Italy.
authors.forename: Elda
authors.initials: E
authors.lastname: Severi
authors.affiliation: Dipartimento di Salute della Donna e del Bambino, Università di Padova, Via Giustiniani 3, 35128 Padova, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Porcù
authors.affiliation: Dipartimento di Salute della Donna e del Bambino, Università di Padova, Via Giustiniani 3, 35128 Padova, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Rampazzo
authors.affiliation: Dipartimento di Scienze Biomediche, Università di Padova, Viale G. Colombo 3, 35121 Padova, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Moro
authors.affiliation: Dipartimento di Salute della Donna e del Bambino, Università di Padova, Via Giustiniani 3, 35128 Padova, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Basso
authors.affiliation: Dipartimento di Salute della Donna e del Bambino, Università di Padova, Via Giustiniani 3, 35128 Padova, Italy. Electronic address: giampietro.viola.1@unipd.it.
authors.forename: Giampietro
authors.initials: G
authors.lastname: Viola
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D056744:Cyclin B1 / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D020128:Inhibitory Concentration 50; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D015027:Zebrafish; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D056744:Cyclin B1; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D011725:Pyridines; D011743:Pyrimidines; D051176:beta Catenin; D019938:Cyclin D1; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3
keywords: Colorectal cancer; Imidazo[1,2-a]pyridines; Imidazo[1,2-a]pyrimidines; Signal transduction; Wnt signaling; β-catenin