Carbonic Anhydrase Inhibitors: Design of Membrane-Impermeant Copper(II) Complexes of DTPA-, DOTA-, and TETA-Tailed Sulfonamides Targeting the Tumor-Associated Transmembrane Isoform IX

• Published in: ChemMedChem 2008-11, Vol.3 (11), p.1780-1788
• Main Authors: Rami, Marouan, Cecchi, Alessandro, Montero, Jean-Louis, Innocenti, Alessio, Vullo, Daniela, Scozzafava, Andrea, Winum, Jean-Yves, Supuran, Claudiu T.
• Format: Article
• Language: English
• Subjects: Antigens, Neoplasm - chemistry; carbonic anhydrase; Carbonic Anhydrase Inhibitors - chemical synthesis; Carbonic Anhydrase Inhibitors - pharmacology; Carbonic Anhydrase IX; Carbonic Anhydrases - chemistry; Cell Membrane - drug effects; Chemistry, Pharmaceutical - methods; Copper - chemistry; Cytosol - metabolism; Drug Design; Enzyme Inhibitors - pharmacology; enzymes; Heterocyclic Compounds, 1-Ring - chemistry; Humans; inhibitors; Pentetic Acid - chemistry; positron emission tomography; Positron-Emission Tomography - methods; Protein Isoforms; Sulfonamides - chemical synthesis; Sulfonamides - chemistry
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.200800267

The synthesis and carbonic anhydrase (CA, EC 4.2.1.1) inhibitory activity of two series of aromatic sulfonamides and their CuII derivatives, incorporating metal‐complexing moieties of the DTPA, DOTA, and TETA type are reported. The new compounds were designed in such a way as to possess high affinity for CuII ions, exploiting four pendant carboxylate moieties in the DTPA derivatives, as well as the cyclen/cyclam macrocyles, and three pendant acetate moieties in the DOTA and TETA derivatives. The new derivatives showed modest inhibition of the cytosolic isoform CA I (KI values in the range of 66–2130 nM), were better CA II inhibitors (KI values in the range of 21–360 nM), and excellent inhibitors of the tumor‐associated isoform CA IX (KI values in the range of 4.1–110 nM), with selectivity ratios for the inhibition of the tumor (CA IX) over the cytosolic (CA II) isozyme in the range of 10.74–20.88 for the best derivatives. Copper complexes were more inhibitory than the corresponding ligand sulfonamides, and showed membrane impermeability, thus, having the possibility to specifically target the transmembrane CA IX that has an extracellular active site. Incorporation of radioactive copper isotopes in this type of CA inhibitor may lead to interesting diagnostic/therapeutic applications for such compounds. Copper carbonic anhydrase inhibitors: The synthesis of carbonic anhydrase inhibitors incorporating metal‐complexing moieties was carried out. Complexation with copper gave impermeable inhibitors, which can target the transmembrane tumor associated CA IX. Incorporation of radioactive copper isotopes may lead to interesting diagnostic/therapeutic applications.