1-aza sugars, apparent transition state analogues of equatorial glycoside formation/cleavage

Triazole-carboxylic acids related to d -glucose and d -galactose may be prepared by intramolecular [1,3]-dipolar cycloadditions of azides to unsaturated esters, followed by bromine oxidation of the resulting triazoline. Such materials may provide a series of anionic mimics of carbohydrates.

Triazole carboxylic acids as anionic sugar mimics? Inhibition of glycogen phosphorylase by a d-glucotriazole carboxylate

UDP-glucose dehydrogenase catalyzes the NAD+-dependent 2-fold oxidation of UDP-glucose to give UDP-glucuronic acid. The putative aldehyde intermediate is not released from the active site and is presumably tightly bound. We have prepared UDP-7-deoxy-α-d-gluco-hept-6-ulopyranose, 5, that contains a methyl ketone at C-6 and cannot be further oxidized by the enzyme. Ketone 5 was found to be a competitive inhibitor of the dehydrogenase from Streptococcus pyogenes with a KI value of 6.7 μM. We have also prepared the secondary alcohols UDP-6S-6C-methylglucose, 4a, and UDP-6R-6C-methylglucose, 4b. Compound 4a, but not 4b, was found to be a slow substrate for the dehydrogenase and was converted into the ketone inhibitor 5. This is consistent with the notion that the pro-R hydride is transferred in the first oxidation step of the normal enzymatic reaction.

/pdf/udp-glucose-analogues-as-inhibitors-and-mechanistic-probes-y9juwhn9q8.pdf

UDP-Glucose Analogues as Inhibitors and Mechanistic Probes of UDP-Glucose Dehydrogenase

Much biological knowledge has been gained over the years as to the role of glucose-6-phosphatase, (G-6-pase), enzyme complex in glucose homeostasis and in Type 2 diabetes. Glucose-6-phosphatase is mainly located in the liver and catalyses the terminal step in both gluconeogenesis and glycogenolysis. Another interesting feature is that the enzyme activity is several fold higher in diabetic animals and probably also in diabetic humans and therefore could be an important key player in the elevated hepatic glucose production seen in Type 2 diabetes. During the last nine years substantial efforts have been made, primarily by scientists at Hoechst (now Aventis) and Novo Nordisk, in order to discover novel compounds which inhibit the glucose-6-phosphatase enzyme complex and could be applied therapeutically in the treatment of Type 2 diabetes. These compounds, as well as other compounds published with inhibitory action on glucose-6-phosphatase, are reviewed. No compounds yet have been reported to be in clinical d...

Glucose-6-phosphatase inhibitors for the treatment of Type 2 diabetes

Glucose-6-phosphatase catalytic enzyme inhibitors: synthesis and in vitro evaluation of novel 4,5,6,7-tetrahydrothieno[3,2-c]- and -[2,3-c]pyridines.

7-Carbon mimics of D-glucose and L-fucose: Activation by 6R-, and inactivation by 6S, -6C-methylglucose of glycogen synthase: Inhibition of glucokinase and/or glucose-6-phosphatase

The potential of carbohydrate mimics which incorporate an a-amino acid moiety at the anomeric position of the sugar is illustrated by the synthesis of both furanose and pyranose analogues of L-rhamnose in a study related to inhibition of the biosynthesis of mycobacterial cell walls. Some amino acid analogues of glucopyranose are inhibitors of glycogen phosphorylase wd may provide an approach to the treatment of late-onset diabetes; bicyclic lactone intermediates provide relatively easy access to both oper, chain and spiro derivatives of glucose in which both nitrogen and carbonyl functions are present at the anomeric position, and in which the anomeric configuration is defined. Other glucose analogues were found to be inhibitors of glucokinase and glucose-6-phosphatase; such materials may allow the investigation of metabolic control by the levels of sugar phosphates.

https://old.iupac.org/publications/pac/1998/pdf/7002x0279.pdf

Sugar mimics from sugar lactones

The First Example of a 6‐C‐Aryl‐D‐glucose: Inhibition of Glucokinase.

Short efficient syntheses of epimeric C6- C -methyl glucoses are described. One C-6 epimer activates glycogen synthase while the other epimer inactivates the enzyme; C6 R -C-methyl glucose 3 is the first example of a specific inhibitor of glucose-6-phosphatase and can increase the intracellular concentration of glucose-6-phosphate 20 times. C6 S -C-methyl glucose 2 inhibits glucokinase and glucose-6-phosphatase, but also has the potential to give easy access to α - C -glycosides of L-fucose. C -6-Alkyl carbohydrates may provide a new range of sugar mimics that control enzymes associated with formation, hydrolysis and other fates of sugar-6-phosphates.

7‐Carbon Mimics of D‐Glucose and L‐Fucose: Activation by 6R‐, and Inactivation by 6S, ‐6C‐Methylglucose of Glycogen Synthase: Inhibition of Glucokinase and/or Glucose‐6‐phosphatase.

W. Stalmans

Papers

7-Carbon mimics of D-glucose and L-fucose: Activation by 6R-, and inactivation by 6S, -6C-methylglucose of glycogen synthase: Inhibition of glucokinase and/or glucose-6-phosphatase

Sugar mimics from sugar lactones

The First Example of a 6‐C‐Aryl‐D‐glucose: Inhibition of Glucokinase.

7‐Carbon Mimics of D‐Glucose and L‐Fucose: Activation by 6R‐, and Inactivation by 6S, ‐6C‐Methylglucose of Glycogen Synthase: Inhibition of Glucokinase and/or Glucose‐6‐phosphatase.