Abstract
The natural product primary sulfonamide, psammaplin C (1), when used in combination with clinically used chemotherapeutic drugs, including temozolomide, reverses multidrug resistance and increases survival in glioblastoma, a highly aggressive primary brain tumor. We showed previously that the mechanism of action of 1 is novel, acting to indirectly interfere with P-glycoprotein drug efflux activity as a consequence of carbonic anhydrase XII (CA XII) inhibition. To build structure-activity relationships, 45 derivatives of 1 were designed, synthesized, and evaluated against a panel of CA isoforms. Compound 55 was identified as a potent inhibitor of CA XII ( Ki = 0.56 nM) and was investigated in vitro and in vivo using samples from glioblastoma patients. The results strengthen the possibility that co-therapy of temozolomide with a CA XII inhibitor may more effectively treat glioblastoma by suppressing an important temozolomide resistance mechanism.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Antineoplastic Agents / therapeutic use
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Brain Neoplasms / drug therapy
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Brain Neoplasms / pathology
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Carbonic Anhydrase Inhibitors / chemical synthesis
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Carbonic Anhydrase Inhibitors / chemistry*
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Carbonic Anhydrase Inhibitors / pharmacology
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Carbonic Anhydrase Inhibitors / therapeutic use
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Carbonic Anhydrases / chemistry*
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Carbonic Anhydrases / metabolism
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Cell Survival / drug effects
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Drug Design
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Drug Resistance, Neoplasm / drug effects*
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Female
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Glioblastoma / drug therapy
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Glioblastoma / pathology
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Humans
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Mice
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Mice, Nude
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Protein Isoforms / antagonists & inhibitors
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Protein Isoforms / metabolism
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Structure-Activity Relationship
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Temozolomide / therapeutic use
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Transplantation, Heterologous
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Tumor Cells, Cultured
Substances
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Antineoplastic Agents
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Carbonic Anhydrase Inhibitors
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Protein Isoforms
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Carbonic Anhydrases
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carbonic anhydrase XII
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Temozolomide