Aldose reductase and

The complex thioamide lolrestat (8) is an inhibitor of aldose reductase. This enzyme catalyzes the reduction of glucose to sorbitol. The enzyme is not very active, but in diabetic individuals where blood glucose levels can. spike to quite high levels in tissues where insulin is not required for glucose uptake (nerve, kidney, retina and lens) sorbitol is formed by the action of aldose reductase and contributes to diabetic complications very prominent among which are eye problems (diabetic retinopathy). Tolrestat is intended for oral administration to prevent this. One of its syntheses proceeds by conversion of 6-methoxy-5-(trifluoroniethyl)naphthalene-l-carboxyl-ic acid (6) to its acid chloride followed by carboxamide formation (7) with methyl N-methyl sarcosinate. Reaction of amide 7 with phosphorous pentasulfide produces the methyl ester thioamide which, on treatment with KOH, hydrolyzes to tolrestat (8) 2[. 

Reactions are catalysed by aldose reductase and iditol dehydrogenase. (For details, see Appendix 6.6). 

Yoshikawa M, Shimada H, Nishida N, Li Y, Toguchida I, Yamahara J, Matsuda H. (1998) Antidiabetic principles of natural medicines. II. Aldose reductase and a-glucosidase inhibitors from Brazilian natural medicine, the leaves of Myrcia multiflora DC. (Myrtacae) Structures of myrciacitrins I and II and myrciaphenones A and B. Chem Pharm Bull 46 113-119. 

Wirasathien L, Pengsuparp T, Suttisri R, Ueda H, Moriyasu M, Kawanishi K. (2007) Inhibitors of aldose reductase and advanced glycation end-products formation from the leaves of Stelechocarpus cauliflorus R.E. Er. Phytomedicine 14 546-550. 

Lee YS, Lee S, Lee HS, Kim B-K, Ohuchi K, Shin KH. (2005) Inhibitory effects of isorhamnetin-3-O-P-D-glucoside from Salicornia herbacea on rat lens aldose reductase and sorbitol accumulation in streptozotocin-induced diabetic rat tissues. Biol Pharm Bull 28 916-918. 

Jung SH, Lee JM, Lee HJ, Kim CY, Lee EH, Urn BH. (2007) Aldose reductase and advanced glycation endproducts inhibitory effect of Phyllostachys nigra. Biol Pharm Bull 30 1569-1572. 

Lee EH, Song DG, Lee JY, Pan CH, Um BH, Jung SH. (2008) Inhibitory effect of the compounds isolated from Rhus verniciflua on aldose reductase and advanced glycation end products. Biol Pharm Bull 31 1626-1630. 

I.L. Kwee, H. Igarashi, T. Nakada, Aldose reductase and sorbitol dehydrogenase activities in diabetic brain In vivo kinetic studies using F-19 3-FDG NMR in rats, Neuroreport 7 (1996) 726-728. 

Several fluorine-containing drugs are currently in development for the treatment of diabetes. These are peroxisome proliferator-activated nuclear receptor (PPAR) agonists, aldose reductase, and dipeptidylpeptidase IV (DPP-IV) inhibitors. 

Yoshikawa, M. et al.. New flavonol oligoglycosides and polyacylated sucroses with inhibitory effects on aldose reductase and platelet aggregation from flowers of Prunus mume, J. Nat. Prod., 65, 1151, 2002. 

Adult male albino rats received 0, 500 or 1000 mg/kg di(2-ethylhexyl) phthalate by gavage for 15 days and were killed 24 h later (Siddiqui Srivastava, 1992). Relative testis weight and epididymal sperm counts were reduced at the highest dose, as was the activity of several enzymes relevant to spermatogenesis (aldose reductase and sorbitol dehydrogenase). The activity of testicular lactate dehydrogenase was increased at this dose. 

Srivastava SK, Ramana KV, Bhatnagar A. Role of aldose reductase and oxidative damage in diabetes and the consequent potential for therapeutic options. Endocr Rev. 2005 26 380-392. 

Potassium cyanide and ammonium carbonate react with 1-alkyl377 or 1-alkenylisatins363 generating. s/ /7 ohydantoins. These compounds are inhibitors of the enzyme aldose reductase, and have potential use as hypoglycemic agents (Scheme 92). 

Table 14.5 Aldose reductase and aldehyde reductase inhibitors...

Excess glucose can enter the polyol pathway, where it is reduced to sorbitol (by aldose reductase and the reductant NADPH). Sorbitol dehydrogenase will oxidise sorbitol to fructose, which also produces NADH from NAD+. Hexokinase will return fructose to the glycolysis pathway by phosphorylating it to fructose-6-phosphate. However, in uncontrolled diabetics with high blood glucose, the production of sorbitol is favoured. 

Loss of mural cells (pericytes) in the retinal microcapillaries is a typical event in diabetic retinopathy. These mural cells contain aldose reductase and accumulate sorbitol in experimental hyperglycaemia (Buzney et al., 1977), leading to degenerative changes implying participation of the polyol pathway in cell death. 

Fig. 37 Inhibitory prenylated flavonoids from Sophora flavescens against aldose reductase and generation of advanced glycation endproducts...

Stevens MJ, Dananberg J, Eeldman EL, Lattimer S A. Kamijo M, Thomas TP, et al. The linked role of nitric oxide, aldose reductase and, (Na+.K-i-)-ATPase in the slowing of nerve conduction in the streptozotocin diabetic rat. J Clin Invests 1994 94 853-859. 

Stefanic-Petek, A., Krbavcic, A. and Solmajer, T. (2002) QSAR of flavonoids. 4. Differential inhibition of aldose reductase and p56 protein tyrosine kinase. Croat. Chem. Acta, 75, 517-529. 

Hydrogen peroxide is not merely dismutated by catalase, but used as substrate in a second enzyme cascade reaction producing propylene oxide [123 1251. In an alternative process 1261 the reduction step was performed enzymatically using aldose reductase and formate dehydrogenase for NADH regeneration. Thus, essentially glucose free D-fructose was obtained. 

CURRENT STATUS OF THE CHEMISTRY AND SYNTHESIS OF NATURAL ANTIMALARIAL COMPOUNDS AND NATURAL SUBSTANCES USED TO ALLEVIATE SYMPTOMS OF DIABETES (ALDOSE REDUCTASE AND A-GLUCOSIDASE INHIBITORS)... 

Tetroses and Pentoses - 4-0- -Butyldimethylsilyl-2,3-0-isopropylidene-L-threose (1) has been prepared in seven efficient steps from o-xylose. 3,4-0-Isopropylidene-D-eythrulose (4) has been synthesized from the known tetritol derivative 2 by primary protection as the silyl ether 3, followed by Dess-Martin oxidation and desilylation. Compound 2 was derived from D-isoascorbic acid (see Vol. 22, p. 178, refs. 9,10). In a similar reaction sequence, the enantiomer 5 has been obtained from L-ascorbic acid. The dehomologation of several di-0-isopropylidenehexofuranoses e.g., 6- 7) has been carried out in two steps without intermediate purification, by successive treatment with periodic acid in ethyl acetate, followed by sodium borohydride in ethanol. Selective reduction of 3-deoxy-D-g/jcero-pentos-2-ulose (8) to 3-deoxy-D-g/> cero-pent-2-ose (9) has been achieved enzymically with aldose reductase and NADPH." 4-Isopropyl-2-oxazolin-5-one (10) is a masked formaldehyde equivalent that is easily converted to an anion and demasked by mild acid hydrolysis. One of the three examples of its use in the synthesis of monosaccharides is shown in Scheme 1. ... 

Jatrorrhizine (69) and palmatine (78) are active against Plasmodium falciparum. Jatrorrhizine inhibits butyrylchol-inesterase (Wink, 1993). Palmatine inhibits reverse transcriptase, aldose reductase, and acetylcholinesterase (Wink, 1993). 

In these coupled reactions, the overall transformation of glucose to fructose is accompanied by a transfer of hydrogen from NADPH to NAD. Studies on the activity of aldose reductase and sorbitol dehydrogenase as well as the presence of sorbitol in seminal vesicles of several species and rat coagulating gland are consistent with the operation of the sorbitol pathway as a major determinant of seminal fructose biosynthesis (248, 252-260). Nonphosphorylative conversion of glucose to sorbitol has also been demonstrated in placenta (258, 261, 262), smooth muscle of the aorta (263), the lens of the eye (264, 265), erythrocytes (266) and hepatoma-derived (HTC) cells in culture (267), and possibly normal liver cells (267, 268). 

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