C-branched iminosugars: α-glucosidase inhibition by enantiomers of isoDMDP, isoDGDP, and isoDAB-L-isoDMDP compared to miglitol and miglustat.

The Ho crossed aldol condensation provides access to a series of carbon branched iminosugars as exemplified by the synthesis of enantiomeric pairs of isoDMDP, isoDGDP, and isoDAB, allowing comparison of their biological activities with three linear isomeric natural products DMDP, DGDP, and DAB and their enantiomers. L-IsoDMDP [(2S,3S,4R)-2,4-bis(hydroxymethyl)pyrrolidine-3,4-diol], prepared in 11 steps in an overall yield of 45% from d-lyxonolactone, is a potent specific competitive inhibitor of gut disaccharidases [K(i) 0.081 µM for rat intestinal maltase] and is more effective in the suppression of hyperglycaemia in a maltose loading test than miglitol, a drug presently used in the treatment of late onset diabetes. The partial rescue of the defective F508del-CFTR function in CF-KM4 cells by L-isoDMDP is compared with miglustat and isoLAB in an approach to the treatment of cystic fibrosis.

Protective effects of dietary 1,5-anhydro-D-glucitol as a blood glucose regulator in diabetes and metabolic syndrome.

1,5-Anhydro-D-glucitol (1,5-AG) is fairly widespread in food products. It is also one of the major polyols in the human body, and its concentration is homeostatically regulated. We report here on the beneficial effects of 1,5-AG in preventing hyperglycemia and its role in improving metabolic syndrome. The findings revealed that it does not affect blood glucose levels itself under normal conditions but clearly has a suppressive effect on the levels of dietary sugars, such as glucose, maltose, and sucrose. A long-term administration study revealed that feeding db/db diabetic mice 3% 1,5-AG for 8 weeks significantly decreased blood glucose levels compared to untreated mice (339 ± 30 versus 438 ± 34 mg/dL; p < 0.05). Furthermore, this treatment also significantly suppressed serum cholesterol levels (110.2 ± 18.0 versus 168.4 ± 9.8 mg/dL; p < 0.01). 1,5-AG did not inhibit intestinal α-glucosidase activities but regulated liver glucose levels via affecting both the glycogenolysis and gluconeogenesis pathways. Furthermore, the oral administration of 1,5-AG significantly increased urinary glucose excretion in hyperglycemic conditions. These results clearly suggest that dietary 1,5-AG acts as a modulator of glucose levels in hyperglycemia. 1,5-AG therefore represents a new class of promising functional sweeteners, where the daily consumption of 1,5-AG with meals could inhibit the progress of hyperglycemia and metabolic syndrome.