Claire J. F. Bichard

Potent inhibition of glycogen phosphorylase by a spirohydantoin of glucopyranose: First pyranose analogues of hydantocidin

Abstract The synthesis of two epimeric spirohydantoins of glucopyranose provides the first examples of pyranose analogues of hydantocidin: molecular modelling correctly predicted that one of the epimers would be a potent inhibitor of glycogen phosphorylase. This is the first example of specific enzyme inhibition by a spirohydantoin at the anomeric position of a sugar.

Glucose analogue inhibitors of glycogen phosphorylase: from crystallographic analysis to drug prediction using GRID force-field and GOLPE variable selection.

Several inhibitors of the large regulatory enzyme glycogen phosphorylase (GP) have been studied in crystallographic and kinetic experiments. GP catalyses the first step in the phosphorylysis of glycogen to glucose-l-phosphate, which is utilized via glycolysis to provide energy to sustain muscle contraction and in the liver is converted to glucose. alpha-D-Glucose is a weak inhibitor of glycogen phosphorylase form b (GPb, K(i) = 1.7 mM) and acts as a physiological regulator of hepatic glycogen metabolism. Glucose binds to phosphorylase at the catalytic site and results in a conformational change that stabilizes the inactive T state of the enzyme, promoting the action of protein phosphatase 1 and stimulating glycogen synthase. It has been suggested that in the liver, glucose analogues with greater affinity for glycogen phosphorylase may result in a more effective regulatory agent. Several N-acetyl glucopyranosylamine derivatives have been synthesized and tested in a series of crystallographic and kinetic binding studies with GPb. The structural results of the bound enzyme-ligand complexes have been analysed together with the resulting affinities in an effort to understand and exploit the molecular interactions that might give rise to a better inhibitor. Comparison of the N-methylacetyl glucopyranosylamine (N-methylamide, K(i) = 0.032 mM) with the analogous beta-methylamide derivative (C-methylamide, K(i) = 0.16 mM) illustrate the importance of forming good hydrogen bonds and obtaining complementarity of van der Waals interactions. These studies also have shown that the binding modes can be unpredictable but may be rationalized with the benefit of structural data and that a buried and mixed polar/non-polar catalytic site poses problems for the systematic addition of functional groups. Together with previous studies of glucose analogue inhibitors of GPb, this work forms the basis of a training set suitable for three-dimensional quantitative structure-activity relationship studies. The molecules in the training set are void of problems and potential errors arising from the alignment and bound conformations of each of the ligands since the coordinates were those determined experimentally from the X-ray crystallographic refined ligand-enzyme complexes. The computational procedure described in this work involves the use of the program GRID to describe the molecular structures and the progam GOLPE to obtain the partial least squares regression model with the highest prediction ability. The GRID/GOLPE procedure performed using 51 glucose analogue inhibitors of GPb has good overall predictivity [standard deviation of error predictions (SDEP) = 0.98 and Q(2) = 0.76] and has shown good agreement with the crystallographic and kinetic results by reliably selecting regions that are known to affect the binding affinity.

The ring contraction of δ-lactones with leaving group α-substituents: a strategy for the synthesis of 2,5-disubstituted highly functionalised homochiral tetrahydrofurans

Treatment of derivatives of δ-lactones having a leaving group at C-2 with methanol in the presence of base gives methyl tetrahydrofuran-α-carboxylates in good to excellent yield with a high degree of stereocontrol of the carbon substituents at C-2 and C-5.

Acetonides of heptonolactones: Kiliani ascension of 3-O-benzyl-D-glucose and 3-O-benzyl-D-allose

Abstract The preparation of the δ-heptonolactones, 4- O -benzyl- D - glycero - D - D - gulo -heptono-1,5-lactoneand 4- O -benzyl- D - glycero - D - allo -heptono-1,5-lactone, by Kiliani reactions on 3- O -benzylglucose and 3- O -benzylallose are reported; acetonides of the two lactones are described.

The design of potential antidiabetic drugs: experimental investigation of a number of β-D-glucose analogue inhibitors of glycogen phosphorylase

Summaryα-D-glucose is a weak inhibitor (Ki=1.7 mM) of glycogen phosphorylase (GP) and acts as physiological regulator of hepatic glycogen metabolism; it binds to GP at the catalytic site and stabilizes the inactive T state of the enzyme promoting the action of protein phosphatase 1 and stimulating glycogen synthase. The three-dimensional structures of T state rabbit muscle GPb and the GPb-α-D-glucose complex have been exploited in the design of better regulators of GP that could shift the balance between glycogen synthesis and glycogen degradation in favour of the former. Close examination of the catalytic site with α-D-glucose bound shows that there is an empty pocket adjacent to the β-1-C position. β-D-glucose is a poorer inhibitor (Ki=7.4 mM) than α-D-glucose, but mutarotaion has prevented the binding of β-D-glucose in T state GP crystals. A series of β-D-glucose analogues has been designed and tested in kinetic and crystallographic experiments. Several compounds have been discovered that have an increased affinity for GP than the parent compound.

Acid-catalysed transformation of α-trifluoromethanesulfonates of γ- and δ-lactones into 2,5-disubstituted homochiral tetrahydrofurans

Excellent yields of methyl tetrahydrofuran-α-carboxylates are obtained by treatment of 2-O-trifluoromethanesulfonates (triflates) of either 1,4-or 1,5-lactones with acid in methanol; in some cases, very different tetrahydrofurans may result from acid or base treatment of a methanolic solution of the same starting material.

Acetonides of α-hydroxy-δ-altronolactones

Abstract The preparation and characterisation of some derivatives of α-hydroxy-δ-lactones, in which the δ-carbon substituent on the lactone ring is trans to an adjacent isopropylidene protected diol, are described; the X-ray crystal structures of 3,4-O-isopropylidene-D-altrono-1,5-lactone and of 3,4:6,7-di-O-isopropylidene-D-glycero-D-altro-heptono-1,5-lactone are reported.

Benzylidene acetals of heptonolactones

Abstract The preparation of 3,5-(R)-O-benzylidene-D-glycero-D-gulo-heptono-1,4-lactone, a readily available and powerful chiron, is described; other benzylidene derivatives of heptono-1,4-lactones are characterised. The X-ray crystal structure of 3,5(R):6,7(R)-di-O-benzylidene-D-glycero-D-gulo-heptono-1,4-lactone is reported.

X-Ray crystallographic analysis of 2,6-anhydro-N-methyl-D-glycero-D-ido-heptonamide: the first example of a simple glucose analogue with a skew boat structure

Single crystal X-ray crystallographic analysis of 2,6-anhydro-N-methyl-D-glycero-D-ido-heptonamide and a crystallographic binding study with glycogen phosphorylase show an unexpected skew boat conformation for the glucose analogue.

Complex tetrahydrofurans from carbohydrate lactones: easy access to epimeric C-glycosides of glucofuranose from D-glycero-D-gulo-heptono-1,4-lactone

A practical synthesis of epimeric C-glycosides of glucofuranose from the cheap gluco-heptono-1,4-lactone is reported; the ring contractions of 2-O-triflates of protected gluco-heptono-1,5-lactones are discussed. No tetrahydropyrancarboxylates were isolated from any of the reactions.