Glucose-6-phosphatase inhibitors

Recently, two examples of the separation of enantiomers using CCC have been published (Fig. 1-2). The complete enantiomeric separation of commercial d,l-kynurenine (2) with bovine serum albumin (BSA) as a chiral selector in an aqueous-aqueous polymer phase system was achieved within 3.5 h [128]. Moreover, the chiral resolution of 100 mg of an estrogen receptor partial agonist (7-DMO, 3) was performed using a sulfated (3-cyclodextrin [129, 130], while previous attempts with unsubstituted cyclodextrin were not successful [124]. The same authors described the partial resolution of a glucose-6-phosphatase inhibitor (4) with a Whelk-0 derivative as chiral selector (5) [129]. 

Tsiani, E., E. Bogdanovic, A. Sorisky, L. Nagy, and I.G. Fantus. 1998. Tyrosine phosphatase inhibitors, vanadate and pervanadate, stimulate glucose transport and GLUT translocation in muscle cells by a mechanism independent of phosphatidyli-nositol 3-kinase and protein kinase C. Diabetes 47 1676-1686. 

Winter, C.L., J.S. Lange, M.G. Davis, G.S. Gerwe, T.R. Downs, K.G. Peters, and B. Kasibhatla. 2005. A nonspecific phosphotyrosine phosphatase inhibitor, bisfmalto-lato)oxovanadium(IV), improves glucose tolerance and prevents diabetes in Zucker diabetic fatty rats. Exp. Biol. Med. 230 207-16. 

We have developed two methods for the synthesis of natural and unnatural products from D-glucose. Enantio-and diastereo-switching method established a new strategy for the synthesis of four possible stereomers for natural products synthesis, and this powerful method was successfully applied to the synthesis of unnatural protein phosphatase inhibitors. The second synthetic method involved the preparation of the urea-glycosidic linkages for the synthesis of glycopeptide mimics. 

Corvera, S., Jaspers, S., and Pasceri, M., Acute inhibition of insulin-stimulated glucose transport by the phosphatase inhibitor, okadaic acid, J. Biol Chem., 266, 9271, 1991. 

Both phosphorylase a and phosphorylase kinase a are dephosphorylated and inactivated by protein phos-phatase-1. Protein phosphatase-1 is inhibited by a protein, inhibitor-1, which is active only after it has been phosphorylated by cAMP-dependent protein kinase. Thus, cAMP controls both the activation and inactivation of phosphorylase (Figure 18-6). Insulin reinforces this effect by inhibiting the activation of phosphorylase b. It does this indirectly by increasing uptake of glucose, leading to increased formation of glucose 6-phosphate, which is an inhibitor of phosphorylase kinase. 

Estrada O, Hasegawa M, Gonzalez-Mujica F, Motta N, Perdomo E, Solorzano A, Mendez J, Mendez B, Zea EG. (2005) Evaluation of flavonoids from Bauhinia megalandra leaves as inhibitors of glucose-6-phosphatase system. Phytother Res 19 859-863. 

Shaw (115) reported a 300-fold purification of enzyme from tobacco leaves. Activity of the enzyme was optimal at pH 5.5-5.7, and divalent cations were not required for activity. The enzyme possessed high activity toward ribonucleoside 2 - and 5 -monophosphates and glucose 1-phosphate. There was no activity toward RNA or phosphodiesters. Fluoride acts as a noncompetitive inhibitor for this enzyme. This behavior of fluoride is in contrast to the behavior with prostatic acid phosphatase where the inhibition is strictly competitive. 

Inhibitors of Hydrolase and Phosphotransferase Activities of Glucose-6-Phosphatase°... 

Fig. 8. Ionic species of some phosphate compounds serving as substrates and/or inhibitors of glucose-6-phosphatase (157). See Sections III,D,4 and 5 for details.

Herling AW, Burger HJ, Schwab D et al. (1998) Pharmacodynamic profile of a novel inhibitor of the hepatic glucose-6-phosphatase system. Am J Physiol 274 G1087-G1093... 

Vanadate (VOj or H2VO4 ) was first recognized in 1979 as having insulin mimetic properties [258]. Since then, vanadate and vanadyl (V ) have been shown to mimic most but not all biological actions of insulin in vitro and to lower blood glucose in streptozotocin-treated rats [259, 260]. Vanadate is a potent inhibitor of phosphotyrosine phosphatases, an interesting activity since the insulin receptor is a tyrosine kinase, and some of the actions of insulin have been proposed to take place via autophosphorylation of the insulin receptor and phosphorylation of cellular substrates on tyrosine residues [261]. Some recent developments on the mechanism and the in vivo activity of vanadate and its derivatives are presented here. 

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