Synthesis of Thiohydantoin-Castanospermine Glycomimetics as Glycosidase Inhibitors

• Published in: Journal of organic chemistry 2009-05, Vol.74 (9), p.3595-3598
• Main Authors: Aguilar-Moncayo, Matilde, Mellet, Carmen Ortiz, García Fernández, José M, García-Moreno, M. Isabel
• Format: Article
• Language: English
• Subjects: Animals; Biomimetic Materials - chemical synthesis; Biomimetic Materials - chemistry; Biomimetic Materials - pharmacology; Carbohydrates - chemistry; Carbohydrates with 4, 5, 6, ... C atoms, dissacharides and oligosaccharides; Carbohydrates. Nucleosides and nucleotides; Cattle; Chemistry; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Exact sciences and technology; Glycoside Hydrolases - antagonists & inhibitors; Heterocyclic compounds; Heterocyclic compounds with only one n hetero atom and condensed derivatives; Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings; Indolizines - chemical synthesis; Indolizines - chemistry; Indolizines - pharmacology; Organic chemistry; Preparations and properties; Thiohydantoins - chemistry
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo900231b

The preparation of bicyclic carbohydrate mimics related to (+)-castanospermine incorporating a thiohydantoin moiety is reported. The synthetic approach is compatible with molecular diversity-oriented strategies and involves α-azidoesters, built at the C-5/C-6 segment in gluco- or galactofuranose scaffolds, as the key precursors. Reduction to the corresponding α-amino ester and in situ coupling with isothiocyanates afford thioureidoester intermediates that undergo spontaneous cyclization to the corresponding hydantoins, β-elimination, and furanose → indolizidine rearrangement in a tandem manner. Biological evaluation of the new sp2-iminosugar-type glycomimetics evidenced a strong influence of the nature of the substituents at the nitrogen or oxygen atoms on the glycosidase inhibitory properties.