Synthetic, enzyme kinetic, and protein crystallographic studies of C-[béta]-D-glucopyranosyl pyrroles and imidazoles reveal and explain low nanomolar inhibition of human liver glycogen phosphorylase
| Autor: | Demetra S.M. Chatzileontiadou, Anastassia L. Kantsadi, George A. Stravodimos, Pál Gergely, Éva Bokor, Tibor Docsa, Andrea Szakács, Gyula Batta, Demetres D. Leonidas, Sándor Kun, László Somsák, Éva Juhász-Tóth |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
Models
Molecular Protein Conformation Stereochemistry Chemistry Techniques Synthetic Crystallography X-Ray 010402 general chemistry 01 natural sciences Structure-Activity Relationship chemistry.chemical_compound Glycogen phosphorylase Drug Discovery Animals Humans Imidazole Structure–activity relationship Transferase Pyrroles Elméleti orvostudományok Enzyme Inhibitors Pyrrole Pharmacology chemistry.chemical_classification Indole test biology 010405 organic chemistry Artificial enzyme Glycogen Phosphorylase Organic Chemistry Imidazoles General Medicine Orvostudományok 0104 chemical sciences carbohydrates (lipids) Kinetics Crystallography Enzyme Liver chemistry biology.protein Rabbits |
| Popis: | C-β-d-Glucopyranosyl pyrrole derivatives were prepared in the reactions of pyrrole, 2-, and 3-aryl-pyrroles with O-peracetylated β-d-glucopyranosyl trichloroacetimidate, while 2-(β-d-glucopyranosyl) indole was obtained by a cross coupling of O-perbenzylated β-d-glucopyranosyl acetylene with N-tosyl-2-iodoaniline followed by spontaneous ring closure. An improved synthesis of O-perbenzoylated 2-(β-d-glucopyranosyl) imidazoles was achieved by reacting C-glucopyranosyl formimidates with α-aminoketones. The deprotected compounds were assayed with isoforms of glycogen phosphorylase (GP) to show no activity of the pyrroles against rabbit muscle GPb. The imidazoles proved to be the best known glucose derived inhibitors of not only the muscle enzymes (both a and b) but also of the pharmacologically relevant human liver GPa (Ki = 156 and 26 nM for the 4(5)-phenyl and -(2-naphthyl) derivatives, respectively). An X-ray crystallographic study of the rmGPb-imidazole complexes revealed structural features of the strong binding, and also allowed to explain the absence of inhibition for the pyrrole derivatives. |
| Databáze: | OpenAIRE |
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