Abstract
Refining the chemical structure of functionalized pyrrolidine-based inhibitors of Golgi alpha-mannosidase II (GMII) to optimize binding affinity provided a lead molecule that demonstrated nanomolar competitive inhibition of alpha-mannosidases II and an optimal fit in the active site of Drosophila GMII by X-ray crystallography. Esters of this lead compound also inhibited the growth of human glioblastoma and brain-derived endothelial cells more than the growth of non-tumoral human fibroblasts, suggesting their potential for anti-cancer therapy.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Antineoplastic Agents / chemistry*
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Antineoplastic Agents / pharmacology*
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Binding Sites
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Cell Line, Tumor
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Drosophila / enzymology
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Endothelial Cells / drug effects
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Fabaceae / enzymology
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Glioblastoma
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Humans
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Models, Molecular
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Molecular Structure
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Pyrrolidines / chemistry*
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Pyrrolidines / pharmacology*
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Structure-Activity Relationship
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alpha-Mannosidase / antagonists & inhibitors*
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alpha-Mannosidase / classification*
Substances
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Antineoplastic Agents
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Pyrrolidines
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alpha-Mannosidase