salacinol and Diabetes-Mellitus

During our studies characterizing functional substances from food resources for the prevention and treatment of lifestyle-related diseases, we isolated the active constituents, salacinol (1) and neokotalanol (4), and related thiosugar sulfoniums, from the roots and stems of the genus Salacia plants [Celastraceae (Hippocrateaceae)] such as Salacia reticulata Wight, S. oblonga Wall., and S. chinensis L., and observed their antidiabetic effects. These plant materials have been used traditionally in Ayurvedic medicine as a specific remedy at the early stage of diabetes, and have been extensively consumed in Japan, the United States, and other countries as a food supplement for the prevention of obesity and diabetes. Here, we review our studies on the antidiabetic effects of plants from the genus Salacia, from basic chemical and pharmacological research to their application and development as new functional food ingredients.

Topics: Animals; Diabetes Mellitus; Humans; Hypoglycemic Agents; Japan; Medicine, Ayurvedic; Molecular Structure; Obesity; Plant Roots; Plant Stems; Randomized Controlled Trials as Topic; Salacia; Sugar Alcohols; Sulfates; Thiosugars

Extracts of Salacia reticulata Wight (Hypocrataceae) roots, stems, and leaves have been used in Asia for hundreds of years for the folkloric treatment of diabetes and other health problems. Constituents that have been identified as exhibiting anti-diabetic effects include salacinol, kotalanol, ponkorinol, salaprinol, and their corresponding de-0-sulfonated compounds. Mangiferin, kotalagenin 16-acetate and various proanthocyanidin oligomers have also been isolated. Studies indicate that Salacia extracts modulate multiple targets that influence carbohydrate and lipid metabolism including α-glucosidase, aldose reductase, pancreatic lipase, peroxisomal proliferator-activated receptor-α, glucose transporter-4 mediated glucose uptake, and angiotensin II type 1 receptor. Furthermore, Salacia extracts exhibit free radical scavenging, antioxidant and hepatoprotectant activities. In human studies, Salacia extracts have been shown to decrease plasma glucose and insulin levels, decrease HbA1c, and modulate serum lipid levels with no adverse effects being reported. Similar results have been demonstrated in rat and mouse models as well as in vitro systems. Safety of S. reticulata and other Salacia species as S. oblonga and S. chinensis in rats and mice indicate that extracts are exceedingly safe. No clinical studies have examined the effects of Salacia extracts on human weight loss, although weight loss and decreases in weight gain have been demonstrated in animal models. Because of the large number of pharmacologically active compounds, it is difficult to establish standards for extracts.

Topics: Animals; Antioxidants; Carbohydrate Metabolism; Diabetes Mellitus; Humans; Hypolipidemic Agents; Lipid Metabolism; Mice; Monosaccharides; Plant Extracts; Plant Leaves; Plant Roots; Proanthocyanidins; Randomized Controlled Trials as Topic; Rats; Salacia; Sugar Alcohols; Sulfates; Triterpenes; Xanthones

The synthesis of aza- and thia-spiroheterocycles and the attempted synthesis of spiro sulfonium compounds related to salacinol are described. The binding of the nanomolar inhibitor swainsonine to Drosophila Golgi alpha-mannosidase II (dGMII) involves a large contribution of interactions between the six-membered ring of the inhibitor and the hydrophobic pocket within the enzyme active site. Salacinol, a naturally occurring sulfonium ion, is one of the active principles in the aqueous extracts of Salacia reticulata that are traditionally used in Sri Lanka and India for the treatment of diabetes. Spiro aza- and thia-heterocycles and a spiro analogue of salacinol were designed with the expectation that the hydrocarbon portions would make hydrophobic contributions to binding. The former sets of compounds were synthesized successfully but the salacinol analogue proved to be elusive. The stereochemistry of the final compounds was determined by means of 1D-NOESY experiments. The aza- and thia-heterocycles were not effective inhibitors of Golgi alpha-mannosidase II or human maltase glucoamylase.

Topics: alpha-Glucosidases; Animals; Carbohydrate Conformation; Diabetes Mellitus; Drosophila; Enzyme Inhibitors; Golgi Apparatus; Humans; Ketones; Mannosidases; Models, Molecular; Molecular Conformation; Sugar Alcohols; Sulfates; Sulfonium Compounds; Swainsonine

The syntheses of two nitrogen analogues (11 and 12) of the naturally occurring sulfonium ion, salacinol (7) are described. The latter compound is one of the active principles in the aqueous extracts of Salacia reticulata that are traditionally used in Sri Lanka and India for the treatment of diabetes. The synthetic strategy relies on the nucleophilic attack of a 1,4-dideoxy-1,4-imino-D- or L-arabinitol at the least hindered carbon of 2,4-O-benzylidene D- or L-erythritol-1,3-cyclic sulfate. The nitrogen analogues bear a permanent positive charge and serve as mimics of the sulfonium ion. We reasoned that these ammonium derivatives should function in a manner similar to that of known glycosidase inhibitors of the alkaloid class such as castanospermine (4) and deoxynojirimycin (5). Enzyme inhibition assays indicate that salacinol (7) is a weak (K(i) = 1.7 mM) inhibitor of glucoamylase, whereas compounds 11 and 12 inhibit glucoamylase with K(i) values in the range approximately 10-fold higher. The nitrogen analogues 11 and 12 showed no significant inhibitory effect of either barley alpha-amylase (AMY1) or porcine pancreatic alpha-amylase (PPA) at concentrations of 5 mM. In contrast, salacinol (7) inhibited AMY1 and PPA in the micromolar range, with K(i) values of 15 +/- 1 and 10 +/- 2 microM, respectively.

Topics: alpha-Amylases; Amylases; Animals; Arabinose; Carbohydrate Sequence; Diabetes Mellitus; Enzyme Inhibitors; Erythritol; Glucan 1,4-alpha-Glucosidase; Humans; Imino Furanoses; Indolizines; Isoenzymes; Magnetic Resonance Spectroscopy; Molecular Sequence Data; Molecular Structure; Monosaccharides; Plant Extracts; Quaternary Ammonium Compounds; Stereoisomerism; Sugar Alcohols; Sulfates; Swine