2 research outputs found
Design, Palladium-Catalyzed Synthesis, and Biological Investigation of 2‑Substituted 3‑Aroylquinolin-4(1<i>H</i>)‑ones as Inhibitors of the Hedgehog Signaling Pathway
2-Substituted
3-aroylquinolin-4Â(1<i>H</i>)-ones, prepared through a palladium-catalyzed
carbonylative cyclization of <i>N</i>-(2-iodoaryl)Âenaminones,
proved to inhibit efficiently the Hedgehog pathway through direct
antagonism of the wild-type and drug-resistant form of the Smoothened
receptor. Notably, these compounds repressed the Hh-dependent growth
events and the proliferation of tumor cells with aberrant activation
of the Hh pathway, which plays a crucial role in development and tumorigenesis
Chemical, computational and functional insights into the chemical stability of the Hedgehog pathway inhibitor GANT61
<p>This work aims at elucidating the mechanism and kinetics of hydrolysis of GANT61, the first and most-widely used inhibitor of the Hedgehog (Hh) signalling pathway that targets Glioma-associated oncogene homologue (Gli) proteins, and at confirming the chemical nature of its bioactive form. GANT61 is poorly stable under physiological conditions and rapidly hydrolyses into an aldehyde species (GANT61-A), which is devoid of the biological activity against Hh signalling, and a diamine derivative (GANT61-D), which has shown inhibition of Gli-mediated transcription. Here, we combined chemical synthesis, NMR spectroscopy, analytical studies, molecular modelling and functional cell assays to characterise the GANT61 hydrolysis pathway. Our results show that GANT61-D is the bioactive form of GANT61 in NIH3T3 Shh-Light II cells and SuFu<sup>−/−</sup> mouse embryonic fibroblasts, and clarify the structural requirements for GANT61-D binding to Gli1. This study paves the way to the design of GANT61 derivatives with improved potency and chemical stability.</p