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

Fabrizio Manetti (1, 2) , Elena Petricci (1, 2) , Annalisa Gabrielli (1, 2) , Andrè Mann (3) , Hélène Faure (4) , Tatiana Gorojankina (4) , Laurent Brasseur (4) , Lucile Hoch (4) , Martial Ruat (4) , Maurizio Taddei (1, 2)

1 Dipartimento di Biotecnologie, Chimica e Farmacia
2 UNISI - Università degli Studi di Siena = University of Siena
3 LIT - Laboratoire d'Innovation Thérapeutique
4 NeuroPSI - Institut des Neurosciences Paris-Saclay

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.

Domaines: Neurobiologie; Psychologie et comportements; Sciences cognitives

Fabrizio Manetti, Elena Petricci, Annalisa Gabrielli, Andrè Mann, Hélène Faure, et al.. Design, synthesis and biological characterization of a new class of osteogenic (1H)-quinolone derivatives. European Journal of Medicinal Chemistry, 2016, 121, pp.747-57. ⟨10.1016/j.ejmech.2016.05.062⟩. ⟨hal-01366729⟩