Subject(s)
Enzyme Inhibitors/pharmacology , Trehalase/antagonists & inhibitors , Trehalase/chemistry , Catalysis , Colorimetry , Disaccharides/antagonists & inhibitors , Disaccharides/chemistry , Hydrogen Bonding , Inositol/analogs & derivatives , Inositol/antagonists & inhibitors , Inositol/chemistry , Protein ConformationABSTRACT
A new trehazolin analogue, 1-thiatrehazolin, has been synthesized from carbohydrate precursors by a highly efficient route based on our previously developed ketone/oxime ether reductive carbocyclization reaction for the construction of the cyclitol ring and an intramolecular nucleophilic displacement reaction for the construction of the thiazoline ring. 1-Thiatrehazolin is a very potent, slow, tight-binding trehalase inhibitor. A structural model for trehalase inhibition by trehazolin and its analogues, based on the experimental results and supported by theoretical calculations, is proposed.
Subject(s)
Disaccharides/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Monosaccharides/chemistry , Monosaccharides/pharmacology , Trehalase/antagonists & inhibitors , Animals , Disaccharides/chemistry , Enzyme Inhibitors/chemical synthesis , Kidney/enzymology , Models, Theoretical , Monosaccharides/chemical synthesis , Swine , Trehalase/chemistryABSTRACT
The first synthesis of the cyclopentitol units in bacterial hopanoids has been accomplished from D-glucosamine and the possible biological activity of the free cyclitols as glycosidase inhibitors has been studied.
Subject(s)
Amino Alcohols/chemical synthesis , Cyanobacteria/chemistry , Cyclopentanes/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Triterpenes/chemistry , Zymomonas/chemistry , Amino Alcohols/pharmacology , Cyclopentanes/pharmacology , Enzyme Inhibitors/pharmacology , Glucosidases/antagonists & inhibitors , Kinetics , Models, Chemical , StereoisomerismABSTRACT
Samarium(II) iodide was used to access eight- and nine-membered carbocycles via a domino reaction comprised of a Reformatsky reaction followed by a nucleophilic acyl substitution reaction. This method represents a general and efficient approach to a variety of highly functionalized, stereodefined carbocycles.
Subject(s)
Alkanes/chemistry , Iodides/chemistry , Ketones/chemistry , Samarium/chemistry , Alkylation , Catalysis , Cyclization , Molecular StructureABSTRACT
A short and very efficient synthesis of trehazolamine (3), the aglycon of the potent trehalase inhibitor trehazolin (2), has been achieved starting from D-glucose. The key transformation in this approach is a high-yielding two-step, one-pot sequence consisting of a Swern oxidation of a 1,5-diol followed by a reductive carbocyclization of the resultant 1,5-dicarbonyl compound promoted by samarium diiodide. The overall yield of 3 is 39% over nine steps from 2,3,4,6-tetra-O-benzyl-D-glucose (5). An even shorter synthesis of 30, a diastereoisomeric analogue of 3, is also described starting from 5. The key transformation in this second route is a highly stereoselective ketone oxime ether reductive carbocyclization promoted also by samarium diiodide. The overall yield of 30 is 57% over four steps from 5.