ABSTRACT
[structure: see text]. Tallysomycins are glycopeptide antibiotics that were first isolated from fermentation broths of Streptoalloteichus hindustanus. They are structurally related to the bleomycins but contain an additional talose sugar attached via a unique glycosylcarbinolamide linkage. Herein we report the synthesis of a key tallysomycin intermediate that incorporates the glycosylcarbinolamide moiety unique to the tallysomycins.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Bleomycin/analogs & derivatives , Bleomycin/chemical synthesis , Thiazoles/chemical synthesis , Anti-Bacterial Agents/chemistry , Bleomycin/chemistry , Thiazoles/chemistryABSTRACT
The peroxisome proliferator-activated receptors (PPARs) are dietary lipid sensors that regulate fatty acid and carbohydrate metabolism. The hypolipidemic effects of the fibrate drugs and the antidiabetic effects of the glitazone drugs in humans are due to activation of the alpha (NR1C1) and gamma (NR1C3) subtypes, respectively. By contrast, the therapeutic potential of the delta (NR1C2) subtype is unknown, due in part to the lack of selective ligands. We have used combinatorial chemistry and structure-based drug design to develop a potent and subtype-selective PPARdelta agonist, GW501516. In macrophages, fibroblasts, and intestinal cells, GW501516 increases expression of the reverse cholesterol transporter ATP-binding cassette A1 and induces apolipoprotein A1-specific cholesterol efflux. When dosed to insulin-resistant middle-aged obese rhesus monkeys, GW501516 causes a dramatic dose-dependent rise in serum high density lipoprotein cholesterol while lowering the levels of small-dense low density lipoprotein, fasting triglycerides, and fasting insulin. Our results suggest that PPARdelta agonists may be effective drugs to increase reverse cholesterol transport and decrease cardiovascular disease associated with the metabolic syndrome X.
Subject(s)
ATP-Binding Cassette Transporters/metabolism , Cholesterol/metabolism , Receptors, Cytoplasmic and Nuclear/agonists , Transcription Factors/agonists , ATP Binding Cassette Transporter 1 , ATP-Binding Cassette Transporters/genetics , Animals , Apolipoprotein A-I/metabolism , Biological Transport/drug effects , Blood Glucose/analysis , Cell Line , Cholesterol/blood , Cholesterol, HDL/blood , Drug Design , Fasting , Fibroblasts/drug effects , Fibroblasts/metabolism , Humans , Hyperinsulinism/blood , Hyperinsulinism/drug therapy , Hyperinsulinism/metabolism , Insulin/blood , Insulin Resistance , Intestinal Mucosa/metabolism , Intestines/cytology , Intestines/drug effects , Macaca mulatta , Macrophages/drug effects , Macrophages/metabolism , Male , Metabolic Diseases/blood , Metabolic Diseases/drug therapy , Metabolic Diseases/metabolism , Obesity/blood , Obesity/drug therapy , Obesity/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptors, Cytoplasmic and Nuclear/metabolism , Substrate Specificity , Thiazoles/pharmacology , Thiazoles/therapeutic use , Transcription Factors/metabolism , Triglycerides/bloodABSTRACT
Phosphonate acyclic derivates of guanines, pyrazolo[3,4-d]pyrimidines, and triazolo[4,5-d]-pyrimidines (8-azaguanines) are inhibitors of the enzyme purine nucleoside phosphorylase (PNPase) with Ki' values ranging from 0.05 to 1.6 microM. These compounds are enzymatically stable congeners of the potent PNPase inhibitor acyclovir diphosphate (53).
Subject(s)
Azaguanine/analogs & derivatives , Azaguanine/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Guanine/analogs & derivatives , Guanine/chemical synthesis , Organophosphonates/chemical synthesis , Pteridines/chemical synthesis , Purine-Nucleoside Phosphorylase/antagonists & inhibitors , Azaguanine/chemistry , Azaguanine/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Erythrocytes/enzymology , Guanine/pharmacology , Humans , Kinetics , Magnetic Resonance Spectroscopy , Molecular Structure , Organophosphonates/chemistry , Organophosphonates/pharmacology , Pteridines/chemistry , Pteridines/pharmacology , Purine-Nucleoside Phosphorylase/blood , Purine-Nucleoside Phosphorylase/isolation & purification , Structure-Activity RelationshipABSTRACT
Daunosamine, as its 4-O-acetyl-3-N-trifluoroacetyl glycosyl chloride derivative (1b), has been coupled alpha-L-glycosidically to the 3- and 4-mono-O-acetyl derivatives of L-rhamnal to afford disaccharide glycal derivatives, whose conversion into the corresponding 2-deoxyglycosides by sequential alkoxyiodination-tributylstannane reduction has been evaluated. The sequence successfully demonstrated with the methyl glycosides was successfully extended with daunomycinone as the aglycon, providing a preparative route to 7-O-[3-O-(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)- 2,6-dideoxy-alpha-L-arabino-hexopyranosyl]daunomycinone hydrochloride (15), an analogue of natural anthracycline antibiotics containing daunosamine and a 2,6-dideoxy-L-hexose.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Antibiotics, Antineoplastic/chemical synthesis , Antineoplastic Agents/chemical synthesis , Hexosamines/chemistry , Aminoglycosides , Anti-Bacterial Agents/pharmacology , Antibiotics, Antineoplastic/pharmacology , Antineoplastic Agents/pharmacology , Carbohydrate Sequence , Humans , Molecular Sequence Data , Tumor Cells, Cultured/drug effectsABSTRACT
A convenient preparative route is described for 3-deoxyaldulosonic acids. Glycal precursors are oxidatively converted into 2-deoxyaldonolactones, which react with 1,3-dithian-2-yl anion to afford 1,3-propanediyl dithioacetals of higher 3-deoxyaldosuloses. Deprotection with mercuric salts in wet or dry alcohols gave high yields of the corresponding alkyl aldulosonates. Preparative reaction conditions were optimized and the anomeric configurations of the ketopyranose products were established by 13C NMR.
