2. Academic Validation
  3. Design, synthesis and biological characterization of a new class of osteogenic (1H)-quinolone derivatives

Design, synthesis and biological characterization of a new class of osteogenic (1H)-quinolone derivatives

  • Eur J Med Chem. 2016 Oct 4:121:747-757. doi: 10.1016/j.ejmech.2016.05.062.
Fabrizio Manetti 1,  Elena Petricci 2,  Annalisa Gabrielli 1,  Andrè Mann 3,  Hélène Faure 4,  Tatiana Gorojankina 4,  Laurent Brasseur 4,  Lucile Hoch 4,  Martial Ruat 4,  Maurizio Taddei 1
Affiliations

Affiliations

  • 1 Dipartimento di Biotecnologie, Chimica e Farmacia, Università di Siena, via Aldo Moro 2, I-53100, Siena, Italy.
  • 2 Dipartimento di Biotecnologie, Chimica e Farmacia, Università di Siena, via Aldo Moro 2, I-53100, Siena, Italy. Electronic address: elena.petricci@unisi.it.
  • 3 Laboratoire d'Innovation Thérapeutique CNRS, UMR-7200, Université de Strasbourg, F-67401, Illkirch, France.
  • 4 CNRS, UMR-9197, Neuroscience Paris-Saclay Institute, 1 Avenue de la Terrasse, F-91198, Gif-sur-Yvette, France.
PMID: 27429255 DOI: 10.1016/j.ejmech.2016.05.062
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.

Keywords

Hedgehog signaling pathway; Heterocycle; Osteogenic activity; Pharmacophore; Smoothened agonists; Stem cells; Structure-activity relationships; Synthesis.

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