Abstract
Multifunctional silica nanoparticles decorated with fluorescent and sulfonamide carbonic anhydrase (CA) inhibitors were prepared and investigated as multivalent enzyme inhibitors against the cytosolic isoforms hCA I and II and the transmembrane tumor-associated ones hCA IX and XII. Excellent inhibitory effects were observed with these nanoparticles, with KI values in the low nanomolar range (6.2-0.67 nM) against all tested isozymes. A significant multivalency effect was seen for the inhibition of the monomeric enzymes hCA I and II compared to the dimeric hCA IX and hCA XII isoforms, where no multivalent effect was observed, suggesting that the multivalent binding is occurring through enzyme clustering.
Keywords:
carbonic anhydrase; inhibitors; multivalency; nanoparticles; sulfonamide.
© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antigens, Neoplasm / chemistry*
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Antigens, Neoplasm / metabolism
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Antineoplastic Agents / chemistry*
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Antineoplastic Agents / pharmacology
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Carbonic Anhydrase I / antagonists & inhibitors*
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Carbonic Anhydrase I / chemistry
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Carbonic Anhydrase I / metabolism
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Carbonic Anhydrase II / antagonists & inhibitors*
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Carbonic Anhydrase II / chemistry
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Carbonic Anhydrase II / metabolism
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Carbonic Anhydrase Inhibitors / chemistry*
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Carbonic Anhydrase Inhibitors / pharmacology*
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Carbonic Anhydrases / metabolism
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Cell Line, Tumor
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Cytosol / chemistry
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Cytosol / drug effects*
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Cytosol / enzymology
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Dose-Response Relationship, Drug
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / pharmacology*
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Humans
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Isoenzymes / antagonists & inhibitors*
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Isoenzymes / chemistry
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Isoenzymes / metabolism*
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Molecular Structure
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Nanoparticles / chemistry*
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Neoplasms / chemistry*
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Neoplasms / drug therapy*
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Neoplasms / enzymology
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Silicon Dioxide / chemistry*
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Structure-Activity Relationship
Substances
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Antigens, Neoplasm
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Antineoplastic Agents
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Carbonic Anhydrase Inhibitors
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Enzyme Inhibitors
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Isoenzymes
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Silicon Dioxide
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Carbonic Anhydrase I
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Carbonic Anhydrase II
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Carbonic Anhydrases