ABSTRACT
A total synthesis of the mitochondrial complex I inhibitor piericidin A1 is described. It features a unique strategy for the key disconnection, highlighting a modified Negishi carboalumination/Ni-catalyzed cross-coupling on a polyenyne precursor.
Subject(s)
Aluminum Compounds/chemistry , Carbon/chemistry , Cross-Linking Reagents/chemistry , Nickel/chemistry , Pyridines/chemical synthesis , Catalysis , Chlorine Compounds/chemical synthesis , Chlorine Compounds/chemistry , Methylation , Molecular Structure , Picolines/chemical synthesis , Picolines/chemistry , Pyridines/chemistryABSTRACT
Treatment of beta,beta-disubstituted-alpha,beta-unsaturated ketones bearing a ketone residue with in situ generated, catalytic CuH ligated by a nonracemic ligand leads to three newly created adjacent chiral centers. Excellent de's and ee's are obtained for several examples studied.
Subject(s)
Alcohols/chemical synthesis , Cyclohexanes/chemical synthesis , Ketones/chemistry , Alcohols/chemistry , Catalysis , Copper/chemistry , Cyclization , Cyclohexanes/chemistry , Ketones/chemical synthesis , Oxidation-Reduction , StereoisomerismABSTRACT
Several C-1 homologated GlcNAc- and GalNAc-thiazolines, as well as a related GalNAc-thiazole, have been prepared. The compounds are analogues of GlcNAc-thiazoline, a potent transition-state-mimicking inhibitor of retaining beta-N-acetylglycosaminidases. Kinetic evaluation of these fused pyranose-heterocycles against the bacterial N-acetylhexosaminidase SpHex suggests active site steric restrictions around the substrate anomeric carbon.
Subject(s)
Enzyme Inhibitors/pharmacology , Galactose/pharmacology , Glucosamine/analogs & derivatives , Thiazoles/pharmacology , beta-N-Acetylhexosaminidases/antagonists & inhibitors , Binding Sites , Carbohydrate Sequence , Carbon/chemistry , Enzyme Inhibitors/chemical synthesis , Galactose/chemical synthesis , Glucosamine/chemical synthesis , Glucosamine/pharmacology , Kinetics , Models, Chemical , Molecular Sequence Data , Piperidines/chemistry , Piperidines/pharmacology , Substrate Specificity , Thiazoles/chemical synthesisABSTRACT
O-GlcNAcase (OGA) promotes O-GlcNAc removal, and thereby plays a key role in O-GlcNAc metabolism, a feature of a variety of vital cellular processes. Two splice transcripts of human OGA encode "long OGA", which contains a distinct N-terminal O-GlcNAcase domain and a C-terminal histoneacetylferase (HAT) domain, and "short OGA", which lacks the HAT domain. The functional roles of long OGA are only beginning to be unraveled, and the characteristics of short OGA remain almost unknown. We find that short OGA, which possesses O-GlcNAcase catalysis machinery like that of long OGA, exhibits comparative resistance to previously described potent inhibitors of long OGA and lysosomal hexosaminidases, including PUGNAc and NAG-thiazoline, suggesting a role for the HAT domain in O-GlcNAcase catalysis. We also find that alpha-GlcNAc thiolsulfonate (2) is the most potent inhibitor of short OGA yet described (Ki = 10 microM), and exhibits some degree of selectivity versus long OGA and lysosomal hexosaminidases. In contrast to its mode of inhibition of short OGA, 2 acts as a irreversible inhibitor of long OGA by covalently modifying the enzyme as an S-GlcNAc derivative. Covalent attachment of GlcNAc to the HAT domain of long OGA dramatically changes its properties with respect to enzymatic activity and caspase-3 cleavage.
Subject(s)
Enzyme Inhibitors/pharmacology , Thioglucosides/pharmacology , Tosyl Compounds/pharmacology , beta-N-Acetylhexosaminidases/antagonists & inhibitors , beta-N-Acetylhexosaminidases/metabolism , Enzyme Inhibitors/chemistry , Humans , Isoenzymes/antagonists & inhibitors , Isoenzymes/metabolism , Molecular Structure , Thioglucosides/chemistry , Tosyl Compounds/chemistryABSTRACT
The synthesis of a variety of new 1-thio-D-glucopyranose derivatives oxidized at the sulfur atom is described, including seven 1-C-sulfonic acids, three sulfonate esters, three sulfinate esters, an S,S'-diglycosyl thiolsulfonate and thiolsulfinate, four S-glycosyl sulfenamides, an S-glycosyl sulfinamide, and two S-glycosyl sulfonamides. These compounds possess unusual anomeric functionality that might be resistant or even inhibitory to normal enzymatic carbohydrate processing, and therefore, they may be of future use in studies of enzyme inhibition, structure, mechanism, and function.