ABSTRACT
The synthesis, chemical derivatization, and investigation of the inhibitory properties of novel cyclitol derivatives on the phosphatidylinositol 4-kinase enzymes PI4K55 and PI4K230 involved in the phosphatidylinositol cycle are reported. Some of the prepared cyclitol derivatives (i.e. 9, 11, 12, and 14) proved to be very powerful and specific irreversible inhibitors of PI4K230 at or below a concentration of 1 mM.
Subject(s)
Cyclohexanones/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Phosphotransferases (Alcohol Group Acceptor)/antagonists & inhibitors , Sugar Alcohols/chemical synthesis , Animals , Cattle , Cyclohexanones/chemistry , Enzyme Inhibitors/chemistry , Isoenzymes/antagonists & inhibitors , Structure-Activity Relationship , Sugar Alcohols/chemistrySubject(s)
Anti-Bacterial Agents/chemical synthesis , Carbohydrates/chemistry , Amino Sugars/chemistry , Aminoglycosides , Anti-Bacterial Agents/pharmacology , Carbohydrate Sequence , Glycosylation , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Magnetic Resonance Spectroscopy , Microbial Sensitivity Tests , Molecular Sequence Data , Molecular StructureABSTRACT
Novel pseudodisaccharide-type aminocyclitol antibiotic models, built up from D-arabinose, D-ribose, D-glucosamine, L-ristosamine and L-acosamine have been synthesized by the glycosylation of suitably protected (azido)deoxyinosose aglycones derived by the Ferrier carbocyclic ring transformation of carbohydrate precursors. An alternative approach to related pseudodisaccharides, based on the Ferrier carbocyclization of reducing disaccharides, has also been elaborated. This latter method extends the scope of the Ferrier reaction, by demonstrating that acid-labile 2-deoxydisaccharides can also be readily transformed into the corresponding pseudodisaccharides under the slightly acidic conditions of this ring-transformation.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Disaccharides/chemical synthesis , Aminoglycosides , Anti-Bacterial Agents/chemistry , Disaccharides/chemistry , Molecular Structure , StereoisomerismABSTRACT
Proof is given by synthesis confirming the structure of ristobiose as 2-O-alpha-D-mannopyranosyl-D-glucose (IV) and ristotriose as O-alpha-L-rhamnopyranosyl (1 leads to 6)-O-[alpha-D-mannopyranosyl (1 leads to 2)]-D-glucose (X) which are obtained from ristomycin A upon mild acid hydrolysis. Both oligosaccharides, IV and X, have been detected for the first time as the components of an antibiotic.
