Abstract
Selective inhibition of tumor-associated carbonic anhydrase (CA; EC 4.2.1.1) isoforms IX and XII is a crucial prerequisite to develop successful anticancer therapeutics. Herein, we confirmed the efficacy of the 3-nitrobenzoic acid substructure in the design of potent and selective carboxylic acid derivatives as CAs inhibitors. Compound 10 emerged as the most potent inhibitor of the tumor-associated hCA IX and XII (Ki = 16 and 82.1 nM, respectively) with a significant selectivity with respect to the wide spread hCA II. Other 3-nitrobenzoic acid derivatives showed a peculiar CA inhibition profile with a notable potency towards hCA IX.
Keywords:
carbonic anhydrase inhibitors (CAIs); carboxylic acid; isoform selectivity; molecular modeling; tumor-associated isoforms.
MeSH terms
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Amino Acid Motifs
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Antigens, Neoplasm / chemistry*
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry*
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Carbonic Anhydrase IX / antagonists & inhibitors
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Carbonic Anhydrase IX / chemistry*
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Carbonic Anhydrase Inhibitors / chemical synthesis
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Carbonic Anhydrase Inhibitors / chemistry*
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Carbonic Anhydrases / chemistry*
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Catalytic Domain
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Dose-Response Relationship, Drug
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Drug Design
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Humans
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Kinetics
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Molecular Docking Simulation
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Neoplasm Proteins / antagonists & inhibitors
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Neoplasm Proteins / chemistry*
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Nitrobenzoates / chemical synthesis
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Nitrobenzoates / chemistry*
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Protein Binding
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Protein Conformation, alpha-Helical
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Protein Conformation, beta-Strand
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Protein Interaction Domains and Motifs
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Sequence Alignment
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Sequence Homology, Amino Acid
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Structure-Activity Relationship
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Thermodynamics
Substances
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Antigens, Neoplasm
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Antineoplastic Agents
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Carbonic Anhydrase Inhibitors
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Neoplasm Proteins
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Nitrobenzoates
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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
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3-nitrobenzoic acid