ABSTRACT
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
Functionalized derivatives of the saddle-shaped molecule tetrabenzo[8]circulene were successfully synthesized through a Diels-Alder/oxidative cyclodehydrogenation approach. This methodology improves on our previously reported synthesis, affording products containing both electron-rich and electron-poor functional groups from readily available starting materials in a more efficient manner. The optoelectronic effects that result from the introduction of this functionality are presented and briefly discussed.
