title: Synthetic, enzyme kinetic, and protein crystallographic studies of C-β-d-glucopyranosyl pyrroles and imidazoles reveal and explain low nanomolar inhibition of human liver glycogen phosphorylase.
abstract: 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.
authors: Department of Biochemistry and Biotechnology, University of Thessaly, 26 Ploutonos Str. 41221, Larissa, Greece.
authors: Anastassia L
authors: AL
authors: Kantsadi
authors: Department of Organic Chemistry, University of Debrecen, POB 400, H-4002, Debrecen, Hungary.
authors: Éva
authors: É
authors: Bokor
authors: Department of Organic Chemistry, University of Debrecen, POB 400, H-4002, Debrecen, Hungary.
authors: Sándor
authors: S
authors: Kun
authors: Department of Biochemistry and Biotechnology, University of Thessaly, 26 Ploutonos Str. 41221, Larissa, Greece.
authors: George A
authors: GA
authors: Stravodimos
authors: Department of Biochemistry and Biotechnology, University of Thessaly, 26 Ploutonos Str. 41221, Larissa, Greece.
authors: Demetra S M
authors: DSM
authors: Chatzileontiadou
authors: Department of Biochemistry and Biotechnology, University of Thessaly, 26 Ploutonos Str. 41221, Larissa, Greece. Electronic address: ddleonidas@bio.uth.gr.
authors: Demetres D
authors: DD
authors: Leonidas
authors: Department of Organic Chemistry, University of Debrecen, POB 400, H-4002, Debrecen, Hungary.
authors: Éva
authors: É
authors: Juhász-Tóth
authors: Department of Organic Chemistry, University of Debrecen, POB 400, H-4002, Debrecen, Hungary.
authors: Andrea
authors: A
authors: Szakács
authors: Department of Organic Chemistry, University of Debrecen, POB 400, H-4002, Debrecen, Hungary.
authors: Gyula
authors: G
authors: Batta
authors: Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Egyetem tér 1, H-4032, Debrecen, Hungary.
authors: Tibor
authors: T
authors: Docsa
authors: Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Egyetem tér 1, H-4032, Debrecen, Hungary.
authors: Pál
authors: P
authors: Gergely
authors: Department of Organic Chemistry, University of Debrecen, POB 400, H-4002, Debrecen, Hungary. Electronic address: somsak.laszlo@science.unideb.hu.
authors: László
authors: L
authors: Somsák
mesh_terms: D000818:Animals; D060326:Chemistry Techniques, Synthetic; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D024981:Glycogen Phosphorylase / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000737:chemistry* / Q000494:pharmacology*; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D008958:Models, Molecular; D011487:Protein Conformation; D011758:Pyrroles / Q000737:chemistry* / Q000494:pharmacology*; D011817:Rabbits; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D007093:Imidazoles; D011758:Pyrroles; D024981:Glycogen Phosphorylase
keywords: C-Glucopyranosyl derivative; Diabetes type 2; Glycogen phosphorylase inhibitor; Imidazole; Indole; Pyrrole