Abstract
A panel of compounds belonging to the underexposed sulfamate class of carbonic anhydrase (CA, EC 4.2.1.1) inhibitors was generated that displayed high specificity at nanomolar levels for the tumor-associated CA IX/XII isoforms. Three of the specific CA IX/XII inhibitors showed a positive response in in vitro assays for tumor cell migration and spreading. One of them, 4-(3'-(3″,5″-dimethylphenyl)ureido)phenyl sulfamate (S4), was taken forward into the orthotopic MDA-MB-231 (breast carcinoma) model in mice. Treatment with a 10 mg/kg maintenance dosage of S4 given daily on a "5 days on, 2 days off" regimen reduced metastatic tumor burden in the lung while not affecting primary tumor growth or mouse condition. CA inhibitors of the sulfamate class specifically targeting the tumor-associated isoforms are potential candidates in antimetastatic therapy.
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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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / therapeutic use
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Breast Neoplasms / drug therapy*
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Breast Neoplasms / pathology
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Carbonic Anhydrase IX
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Carbonic Anhydrase Inhibitors / chemical synthesis*
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Carbonic Anhydrase Inhibitors / chemistry
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Carbonic Anhydrase Inhibitors / therapeutic use
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Carbonic Anhydrases / metabolism*
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Cell Line, Tumor
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Cell Movement / drug effects
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Female
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Humans
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Lung Neoplasms / drug therapy*
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Lung Neoplasms / secondary
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Mice
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Neoplasm Transplantation
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Phenylurea Compounds / chemical synthesis*
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Phenylurea Compounds / chemistry
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Phenylurea Compounds / therapeutic use
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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 / therapeutic use
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Transplantation, Heterologous
Substances
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4-(3'-(3',5'-dimethylphenyl)ureido)phenyl sulfamate
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Antigens, Neoplasm
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Antineoplastic Agents
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Carbonic Anhydrase Inhibitors
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Phenylurea Compounds
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Sulfonamides
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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