ABSTRACT
Aromatic platforms are ubiquitous recognition motifs occurring in protein carbohydrate- binding domains (CBDs), RNA receptors and enzymes. They stabilize the glycoside/ receptor complexes by participating in stacking CH/π interactions with either the α- or ß- face of the corresponding pyranose units. In addition, the role played by aromatic units in the stabilization of glycoside cationic transition states has started being recognized in recent years. Extensive studies carried out during the last decade have allowed the dissection of the main contributing forces that stabilize the carbohydrate/aromatic complexes, while helping delineate not only the standing relationship between the glycoside/ aromatic chemical structures and the strength of this interaction but also their potential influence on glycoside reactivity.
Subject(s)
Carbohydrates , Glycosides , Carbohydrates/chemistry , Catalysis , Cations/chemistry , Humans , Models, MolecularABSTRACT
Glycosidase inhibitors have shown great potential as pharmacological chaperones for lysosomal storage diseases. In light of this, a series of new cyclopentanoid ß-galactosidase inhibitors were prepared and their inhibitory and pharmacological chaperoning activities determined and compared with those of lipophilic analogs of the potent ß-d-galactosidase inhibitor 4-epi-isofagomine. Structure-activity relationships were investigated by X-ray crystallography as well as by alterations in the cyclopentane moiety such as deoxygenation and replacement by fluorine of a "strategic" hydroxyl group. New compounds have revealed highly promising activities with a range of ß-galactosidase-compromised human cell lines and may serve as leads towards new pharmacological chaperones for GM1-gangliosidosis and Morquio B disease.
Subject(s)
Cyclopentanes/pharmacology , Galactosidases/metabolism , Imino Pyranoses/pharmacology , Lysosomes/enzymology , Molecular Chaperones/metabolism , Crystallization , Cyclopentanes/chemical synthesis , Cyclopentanes/chemistry , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Galactosidases/antagonists & inhibitors , Humans , Imino Pyranoses/chemical synthesis , Imino Pyranoses/chemistry , Ligands , Lysosomes/drug effects , Molecular Conformation , Mutant Proteins/metabolismABSTRACT
From an easily available partially protected formal derivative of 1-deoxymannojirimycin, by hydroxymethyl chain-branching and further elaboration, lipophilic analogs of the powerful ß-d-galactosidase inhibitor 4-epi-isofagomine have become available. New compounds exhibit improved inhibitory activities comparable to benchmark compound NOEV (N-octyl-epi-valienamine) and may serve as leads towards improved and more selective pharmacological chaperones for GM1-gangliosidosis.
