Carbonic anhydrase inhibitors: design of membrane-impermeant copper(II) complexes of DTPA-, DOTA-, and TETA-tailed sulfonamides targeting the tumor-associated transmembrane isoform IX.

Abstract

The synthesis and carbonic anhydrase (CA, EC 4.2.1.1) inhibitory activity of two series of aromatic sulfonamides and their Cu(II) 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 Cu(II) 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 (K(I) values in the range of 66-2130 nM), were better CA II inhibitors (K(I) values in the range of 21-360 nM), and excellent inhibitors of the tumor-associated isoform CA IX (K(I) 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.

• Authors: Marouan Rami, Alessandro Cecchi, Jean-Louis Montero, Alessio Innocenti, Daniela Vullo, Andrea Scozzafava, Jean-Yves Winum, Claudiu T Supuran
• Journal: ChemMedChem (ChemMedChem) Vol. 3 Issue 11 Pg. 1780-8 (Nov 2008) ISSN: 1860-7187 [Electronic] Germany
• PMID: 18956406 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Neoplasm
• Carbonic Anhydrase Inhibitors
• Enzyme Inhibitors
• Heterocyclic Compounds, 1-Ring
• Protein Isoforms
• Sulfonamides
• 1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid
• Copper
• Pentetic Acid
• CA9 protein, human
• Carbonic Anhydrase IX
• Carbonic Anhydrases

Topics

• Antigens, Neoplasm (chemistry)
• Carbonic Anhydrase IX
• Carbonic Anhydrase Inhibitors (chemical synthesis, pharmacology)
• Carbonic Anhydrases (chemistry)
• Cell Membrane (drug effects)
• Chemistry, Pharmaceutical (methods)
• Copper (chemistry)
• Cytosol (metabolism)
• Drug Design
• Enzyme Inhibitors (pharmacology)
• Heterocyclic Compounds, 1-Ring (chemistry)
• Humans
• Pentetic Acid (chemistry)
• Positron-Emission Tomography (methods)
• Protein Isoforms
• Sulfonamides (chemical synthesis, chemistry)