piperidines and castanospermine

We report the isolation and structural determination of fourteen iminosugars, containing five pyrrolizidines and five indolizidines, from Castanospermum australe. The structure of a new alkaloid was elucidated by spectroscopic methods as 6,8-diepi-castanospermine (13). Our side-by-side comparison between bicyclic and corresponding monocyclic iminosugars revealed that inhibition potency and spectrum against each enzyme are clearly changed by their core structures. Castanospermine (10) and 1-deoxynojirimycin (DNJ) have a common d-gluco configuration, and they showed the expected similar inhibition potency and spectrum. In sharp contrast, 6-epi-castanospermine (12) and 1-deoxymannojirimycin (manno-DNJ) both have the d-manno configuration but the α-mannosidase inhibition of 6-epi-castanospermine (12) was much better than that of manno-DNJ. 6,8-Diepi-castanospermine (13) could be regarded as a bicyclic derivative of talo-DNJ, but it showed a complete loss of α-galactosidase A inhibition. This behavior against α-galactosidase A is similar to that observed for 1-epi-australine (6) and altro-DMDP.

Topics: 1-Deoxynojirimycin; Alkaloids; Castanospermum; Enzyme Inhibitors; Glucosamine; Glycoside Hydrolases; Hypoglycemic Agents; Imino Sugars; Indolizines; Piperidines; Stereoisomerism; Structure-Activity Relationship

An asymmetric synthesis of (+)-castanospermine is presented in which enol ether metathesis-hydroboration/oxidation is used for stereoselective installation of the trans-trans hydroxyl groups on the piperidine ring of the alkaloid.

Topics: Alkaloids; Catalysis; Cyclization; Ether; Ethers; Indolizines; Oxidation-Reduction; Piperidines; Stereoisomerism

Inhibition of intestinal alpha-glucohydrolase activity is one approach for reducing the glycemic response from dietary carbohydrate and may prove useful for the treatment of diabetes mellitus. In this article, we describe the pharmacological properties of a time-dependent intestinal alpha-glucohydrolase inhibitor, MDL 73945. When preincubated 2 h with a rat intestinal mucosa preparation before substrate addition, MDL 73945 was a potent inhibitor of sucrase, maltase, glucoamylase, and isomaltase activities (MDL 73945 concentrations required to cause a 50% decrease in enzyme activity, 2 x 10(-7), 1 x 10(-6), 5 x 10(-6), and 8 x 10(-6) M, respectively); without preincubation, it was 10- to 500-fold less potent. In rats, a single oral dose of MDL 73945 administered simultaneously with 2 g/kg body wt sucrose resulted in a dose-dependent reduction in the area under the 0- to 3-h glycemic response curve, which was significant at 1 (45% reduction) and 3 (65% reduction) mg/kg. When administered 1 h before sucrose, the compound was more potent, with 0.3 mg/kg MDL 73945 significantly reducing the glycemic response to sucrose by 62%. A reduction in the glycemic response to sucrose was accompanied by reduced insulin secretion. MDL 73945 was slightly less effective against a starch load, with 3 and 10 mg/kg MDL 73945 administered 0.5 h before starch reducing the glycemic response by 39 and 52%, respectively. MDL 73945 was more effective against a sucrose load in streptozocin-administered rats than in control rats and was as effective after 16 daily doses as after a single dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood Glucose; Dietary Carbohydrates; Disaccharides; Glucosidases; Glycoside Hydrolase Inhibitors; Indolizines; Insulin; Intestinal Mucosa; Kinetics; Liver; Macaca fascicularis; Piperidines; Rats; Sucrose