title: Design, synthesis and biological characterization of a new class of osteogenic (1H)-quinolone derivatives.
abstract: Smoothened (Smo) is the signal transducer of the Hedgehog (Hh) pathway and its stimulation is considered a potential powerful tool in regenerative medicine to treat severe tissue injuries. Starting from GSA-10, a recently reported Hh activator acting on Smo, we have designed and synthesized a new class of quinolone-based compounds. Modification and decoration of three different portions of the original scaffold led to compounds able to induce differentiation of multipotent mesenchymal cells into osteoblasts. The submicromolar activity of several of these new quinolones (0.4-0.9 μM) is comparable to or better than that of SAG and purmorphamine, two reference Smo agonists. Structure-activity relationships allow identification of several molecular determinants important for the activity of these compounds.
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia, Università di Siena, via Aldo Moro 2, I-53100, Siena, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Manetti
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia, Università di Siena, via Aldo Moro 2, I-53100, Siena, Italy. Electronic address: elena.petricci@unisi.it.
authors.forename: Elena
authors.initials: E
authors.lastname: Petricci
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia, Università di Siena, via Aldo Moro 2, I-53100, Siena, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Gabrielli
authors.affiliation: Laboratoire d'Innovation Thérapeutique CNRS, UMR-7200, Université de Strasbourg, F-67401, Illkirch, France.
authors.forename: Andrè
authors.initials: A
authors.lastname: Mann
authors.affiliation: CNRS, UMR-9197, Neuroscience Paris-Saclay Institute, 1 Avenue de la Terrasse, F-91198, Gif-sur-Yvette, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Faure
authors.affiliation: CNRS, UMR-9197, Neuroscience Paris-Saclay Institute, 1 Avenue de la Terrasse, F-91198, Gif-sur-Yvette, France.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Gorojankina
authors.affiliation: CNRS, UMR-9197, Neuroscience Paris-Saclay Institute, 1 Avenue de la Terrasse, F-91198, Gif-sur-Yvette, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Brasseur
authors.affiliation: CNRS, UMR-9197, Neuroscience Paris-Saclay Institute, 1 Avenue de la Terrasse, F-91198, Gif-sur-Yvette, France.
authors.forename: Lucile
authors.initials: L
authors.lastname: Hoch
authors.affiliation: CNRS, UMR-9197, Neuroscience Paris-Saclay Institute, 1 Avenue de la Terrasse, F-91198, Gif-sur-Yvette, France.
authors.forename: Martial
authors.initials: M
authors.lastname: Ruat
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia, Università di Siena, via Aldo Moro 2, I-53100, Siena, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Taddei
mesh_terms: D000818:Animals; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D053823:Hedgehog Proteins / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D041681:NIH 3T3 Cells; D010012:Osteogenesis / Q000187:drug effects*; D015363:Quinolones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D053823:Hedgehog Proteins; D015363:Quinolones
keywords: Hedgehog signaling pathway; Heterocycle; Osteogenic activity; Pharmacophore; Smoothened agonists; Stem cells; Structure-activity relationships; Synthesis