Herein we report a mild, efficient, and epimerization‐free method for the synthesis of peptide‐derived 2‐thiazolines and 5,6‐dihydro‐4H‐1,3‐thiazines based on a cyclodesulfhydration of N‐thioacyl‐2‐mercaptoethylamine or N‐thioacyl‐3‐mercaptopropylamine derivatives. The described reaction can be easily carried out in aqueous solutions at room temperature and it is triggered by change of the pH, leading to complex thiazoline or dihydrothiazine derivatives without epimerization in excellent to quantitative yields. The new method was applied in the total synthesis of the marine metabolite mollamide F, resulting in the revision of its stereochemistry.
In diesem Bericht beschreiben wir eine milde, effiziente und epimerisierungsfreie Methode für die Synthese 2‐thiazolin‐ und 5,6‐dihydro‐4H‐1,3‐thiazinhaltiger Peptide durch Cyclodesulfhydrierung entsprechender N‐thioacylierter 2‐Mercaptoethylamin‐ oder 3‐Mercaptopropylaminderivate. Die beschriebene Reaktion wird durch eine Änderung des pH‐Wertes ausgelöst, kann in wässrigen Lösungen und bei Raumtemperatur durchgeführt werden und führt in hervorragenden bis quantitativen Ausbeuten zu komplexen Thiazolin‐ und Dihydrothiazinderivaten. Die neue Methode kam erfolgreich bei der Totalsynthese des marinen Naturstoffes Mollamid F zum Einsatz, was eine Revision seiner Stereochemie zur Folge hatte.
Biosensor techniques have become increasingly important for fragment-based drug discovery during the last years. Here, we describe a biolayer interferometry-based fragment screen targeting the AAA+ ATPase p97, an essential protein with key roles in protein homeostasis and a possible target for cancer chemotherapy. Currently available p97 inhibitors target its ATPase activity and globally impair p97-mediated processes. In contrast, inhibition of cofactor binding to the N-domain by a protein-protein-interaction inhibitor would enable the selective targeting of specific p97 functions. We demonstrate that a region known as SHP-motif binding site can be targeted with small molecules. Guided by molecular dynamics simulations, the binding sites of selected screening hits were postulated and experimentally validated using protein- and ligand-based NMR techniques, as well as X-ray crystallography, ultimately resulting in the first structure of a small molecule in complex with the N-domain of p97. The identified fragments provide insights into how this region could be targeted and present first chemical starting points for the development of a protein-protein interaction inhibitor preventing the binding of selected cofactors to p97.
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