Abstract
Four generations of poly(amidoamine) (PAMAM) dendrimers decorated with benzenesulfonamide moieties were prepared by derivatizing the amino groups of the dendrimer with 4-carboxy-benzenesulfonamide functionalities. Compounds incorporating 4, 8, 16, and 32 sulfonamide moieties were thus obtained, which showed an increasing carbonic anhydrase (CA, EC 4.2.1.1) inhibitory action with the increase of the number of sulfamoyl groups in the dendrimer. Best inhibitory activity (in the low nanomolar-subnanomolar range) was observed for isoforms CA II and XII, involved among others in glaucoma. In an animal model of this disease, the chronic administration of such dendrimers for 5 days led to a much more efficient drop of intraocular pressure compared to the standard drug dorzolamide.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens, Neoplasm / metabolism
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Benzenesulfonamides
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Carbonic Anhydrase I / metabolism
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Carbonic Anhydrase II / metabolism
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Carbonic Anhydrase IX
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Carbonic Anhydrases / metabolism
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Dendrimers / chemical synthesis
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Dendrimers / chemistry*
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Dendrimers / pharmacology
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Glaucoma / drug therapy*
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Glaucoma / physiopathology
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Humans
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Intraocular Pressure / drug effects
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Isoenzymes / antagonists & inhibitors
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Isoenzymes / metabolism
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Male
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Polyamines / chemical synthesis
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Polyamines / chemistry*
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Polyamines / pharmacology
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Rabbits
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Structure-Activity Relationship
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Sulfonamides / chemical synthesis
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Sulfonamides / chemistry*
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Sulfonamides / pharmacology
Substances
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Antigens, Neoplasm
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Dendrimers
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Isoenzymes
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Poly(amidoamine)
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Polyamines
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Sulfonamides
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Carbonic Anhydrase I
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Carbonic Anhydrase II
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CA9 protein, human
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Carbonic Anhydrase IX
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Carbonic Anhydrases
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carbonic anhydrase XII