Potent and Selective Carboxylic Acid Inhibitors of Tumor-Associated Carbonic Anhydrases IX and XII

Molecules. 2017 Dec 22;23(1):17. doi: 10.3390/molecules23010017.

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

  • Amino Acid Motifs
  • Antigens, Neoplasm / chemistry*
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry*
  • Carbonic Anhydrase IX / antagonists & inhibitors
  • Carbonic Anhydrase IX / chemistry*
  • Carbonic Anhydrase Inhibitors / chemical synthesis
  • Carbonic Anhydrase Inhibitors / chemistry*
  • Carbonic Anhydrases / chemistry*
  • Catalytic Domain
  • Dose-Response Relationship, Drug
  • Drug Design
  • Humans
  • Kinetics
  • Molecular Docking Simulation
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / chemistry*
  • Nitrobenzoates / chemical synthesis
  • Nitrobenzoates / chemistry*
  • Protein Binding
  • Protein Conformation, alpha-Helical
  • Protein Conformation, beta-Strand
  • Protein Interaction Domains and Motifs
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Structure-Activity Relationship
  • Thermodynamics

Substances

  • Antigens, Neoplasm
  • Antineoplastic Agents
  • Carbonic Anhydrase Inhibitors
  • Neoplasm Proteins
  • Nitrobenzoates
  • CA9 protein, human
  • Carbonic Anhydrase IX
  • Carbonic Anhydrases
  • carbonic anhydrase XII
  • 3-nitrobenzoic acid