Abstract
Novel pyrrole and pyrrolopyrimidine scaffold-based sulfonamides were designed and synthesized. The carbonic anhydrase (CA) inhibition ability of all derivatives was assessed against the human (h) cytosolic isoforms hCA I and II and the transmembrane, tumor-associated isoforms hCA IX and XII. Some of these sulfonamides were 6-8 fold more potent than the reference drug acetazolamide (AZA, Ki = 5.7 nM)) against hCA XII showing subnanomolar activity. The in vitro cytotoxicity of these derivatives was evaluated against MCF-7, where some derivatives were more cytotoxic than doxorubicin (IC50 = 8.02 μM) displaying IC50 values between 6.46 and 7.56 μM. Docking of these sulfonamides with CA XII was performed and their binding modes were comparable with that of AZA.
Keywords:
Carbonic anhydrase; Cytotoxic activity; Pyrroles; Pyrrolopyrimidines; Sulfonamides.
Copyright © 2014 Elsevier Masson SAS. All rights reserved.
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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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / pharmacology
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Breast Neoplasms / drug therapy*
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Breast Neoplasms / metabolism
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Carbonic Anhydrase I / chemistry
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Carbonic Anhydrase II / chemistry
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Carbonic Anhydrase IX
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Carbonic Anhydrase Inhibitors / chemical synthesis*
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Carbonic Anhydrase Inhibitors / pharmacology*
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Carbonic Anhydrases / chemistry*
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Cell Proliferation / drug effects
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Drug Screening Assays, Antitumor
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Female
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Flow Cytometry
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Humans
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Models, Molecular
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Molecular Structure
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Pyrimidines / chemistry*
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Pyrroles / chemistry*
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Structure-Activity Relationship
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Sulfonamides / chemical synthesis*
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Sulfonamides / pharmacology*
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Tumor Cells, Cultured
Substances
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Antigens, Neoplasm
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Antineoplastic Agents
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Carbonic Anhydrase Inhibitors
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Pyrimidines
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Pyrroles
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Sulfonamides
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pyrrolopyrimidine
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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