Synthesis of a Double-Spanned Resorc[4]arene via Ring-Closing Metathesis and Calculation of Aggregation Propensity

Ring-closing metathesis (RCM) catalyzed by a second-generation Grubbs catalyst has been used to synthesize resorc[4]­arenes <b>2b</b>–<b>5b</b> starting from undecenyl resorc[4]­arene <b>1b</b> fixed in the cone conformation. X-ray diffraction analysis of the major metathesis product, <b>3b</b> (50% yield), revealed a cavity-shaped architecture resembling a basket, endowed with a large intramolecular space (∼10 Å) and a strong propensity to self-assemble as a supramolecular trio of heterochiral dimers. This prompted us to investigate the aggregation propensity of basket <b>3b</b> in THF/water solution by UV–visible spectroscopy. The cavitation Gibbs free-energy change (ΔΔ<i>G</i>_cav = 4.78 kcal mol^–1) associated with the self-assembly of macrocycle <b>3b</b> was calculated as a measure of the solvophobic interactions involved in the process

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^−/− 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