ao-128 and salacinol

Four chain-extended analogs (12a-12d) and two related de-O-sulfonated analogs (13a and 13c) by introducing alkyl groups (a: R = C

Topics: alpha-Glucosidases; Animals; Dose-Response Relationship, Drug; Glycoside Hydrolase Inhibitors; Humans; Intestines; Medicine, Ayurvedic; Molecular Conformation; Rats; Salacia; Structure-Activity Relationship; Sugar Alcohols; Sulfates

Using an in silico method, seven analogs bearing hydrophobic substituents (8a: Me, 8b: Et, 8c: n-Pent, 8d: n-Hept, 8e: n-Tridec, 8f: isoBu and 8g: neoPent) at the 3'-O-position in salacinol (1), a highly potent natural α-glucosidase inhibitor from Ayurvedic traditional medicine 'Salacia', were designed and synthesized. In order to verify the computational SAR assessments, their α-glucosidase inhibitory activities were evaluated in vitro. All analogs (8a-8g) exhibited an equal or considerably higher level of inhibitory activity against rat small intestinal α-glucosidases compared with the original sulfonate (1), and were as potent as or higher in potency than the clinically used anti-diabetics, voglibose, acarbose or miglitol. Their activities against human maltase exhibited good relationships to the results obtained with enzymes of rat origin. Among the designed compounds, the one with a 3'-O-neopentyl moiety (8g) was most potent, with an approximately ten fold increase in activity against human maltase compared to 1.

Topics: Animals; Glycoside Hydrolase Inhibitors; Humans; Hydrophobic and Hydrophilic Interactions; Intestine, Small; Medicine, Ayurvedic; Microsomes; Rats; Structure-Activity Relationship; Sugar Alcohols; Sulfates

Four analogs with 3'-O-alkyl groups (9a: CH(3), 9b: C(2)H(5), 9c: C(13)H(27) or 9d: CH(2)Ph) instead of the 3'-O-sulfate anion in salacinol (1), a naturally occurring potent α-glucosidase inhibitor, were synthesized by the coupling reaction of 1,4-dideoxy-1,4-epithio-d-arabinitols (18a and 18b) with appropriate epoxides (10a-10d). These analogs showed equal or considerably higher inhibitory activity against rat small intestinal α-glucosidases than the original sulfate (1), and one of them (9d) was found more potent than currently used α-glucosidase inhibitors as antidiabetics. Thus, introduction of a hydrophobic moiety at the C3' position of this new class of inhibitor was found beneficial for onset of stronger inhibition against these enzymes.

Topics: Enzyme Activation; Enzyme Inhibitors; Glycoside Hydrolase Inhibitors; Hydrophobic and Hydrophilic Interactions; Magnetic Resonance Spectroscopy; Molecular Structure; Sugar Alcohols; Sulfates