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.

A Useful Route to Metal Complexes of Poorly Coordinating Sulfonamides

“…Many important catalysts [1][2][3] and drugs [4][5][6][7][8] contain sulfonamide groups. Among the different classes of sulfonamide drugs, those with nuclease and/or cytotoxic activity are receiving increasing attention in the search for anticancer chemotherapeutic strategies.…”

Identification of Potent and Selective Human Carbonic Anhydrase VII (hCA VII) Inhibitors

“…In fact, it is well known that the antiglaucoma agents target CA II, CA IV and CA XII, [6] the antiobesity agents inhibit CA VA and CA VB, [7,8] the anticonvulsant agents act against CA II, CA VII and CA XIV, [9] and the antitumor drugs target CA IX and CA XII. [2,[10][11][12][13] In previous works, we rationally designed, synthesized and evaluated isoquinoline-sulfonamides as CAIs, testing their affinity towards different human CA isoforms (hCA I, hCA II, hCA IX, and hCA XIV). [14, 15a-b] As a result of these studies, we identified some isoquinolines (1-10; Tables 1 and 2) that showed nanomolar binding affinities (K i values); these compounds were also characterized by significant selectivity for hCA IX and hCA XIV over ubiquitous cytosolic hCA II of up to approximately three orders of magnitude (i.e., compound 8).…”

Recent Advances on Radionuclide Labeled Hypoxia-Imaging Agents

“…In addition, copper complexes showed stronger inhibitory activity than the corresponding ligand sulfonamides. Incorporating a radioactive copper isotope, e.g., Cu-64, in this type of carbonic anhydrase (CA, EC 4.2.1.1) inhibitor may lead to the development of a novel PET hypoxia marker of tumors and eventually diagnostic or therapeutic applications for such compounds [65][66]. Recently a chimeric anti-CAIX antibody cG250 was labeled with iodine-124 and used to predict clear-cell renal carcinoma (ccRCC) through PET, because CA IX was overexpressed in clear-cell renal carcinoma.…”