Marouan Rami

Carbonic Anhydrase Inhibitor Coated Gold Nanoparticles Selectively Inhibit the Tumor-Associated Isoform IX over the Cytosolic Isozymes I and II

An approach for the synthesis of carbonic anhydrase (CA, EC 4.2.1.1) inhibitor coated gold nanoparticles is reported. This nanomaterial selectively inhibited the tumor-associated isoform CA IX overexpressed in hypoxic cancers over the ubiquitous, cytosolic housekeeping isozymes CA I and II and was membrane impermeant. As CA IX has an extracellular active site, the new nanomaterial which is confined to the extracellular space may be useful for imaging and treatment of hypoxic tumors.

Hypoxia-Targeting Carbonic Anhydrase IX Inhibitors by a New Series of Nitroimidazole-Sulfonamides/Sulfamides/Sulfamates

A series of nitroimidazoles incorporating sulfonamide/sulfamide/sulfamate moieties were designed and synthesized as radio/chemosensitizing agent targeting the tumor-associated carbonic anhydrase (CA) isoforms IX and XII. Most of the new compounds were nanomolar inhibitors of these isoforms. Crystallographic studies on the complex of hCA II with the lead sulfamide derivative of this series clarified the binding mode of this type of inhibitors in the enzyme active site cavity. Some of the best nitroimidazole CA IX inhibitors showed significant activity in vitro by reducing hypoxia-induced extracellular acidosis in HT-29 and HeLa cell lines. In vivo testing of the lead molecule in the sulfamide series, in cotreatment with doxorubicin, demonstrated a chemosensitization of CA IX containing tumors. Such CA inhibitors, specifically targeting the tumor-associated isoforms, are candidates for novel treatment strategies against hypoxic tumors overexpressing extracellular CA isozymes.

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

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.

Carbonic anhydrase inhibitors : 2-Substituted-1.3,4-thiadiazole-5-sulfamides act as powerful and selective inhibitors of the mitochondrial isozymes VA and VB over the cytosolic and membrane-associated carbonic anhydrases I, II and IV

A series of 2-substituted-1,3,4-thiadiazole-5-sulfamides was prepared and assayed as inhibitors of several carbonic anhydrase (CA, EC 4.2.1.1) isoforms, the cytosolic CA I and II, the membrane-associated CA IV and the mitochondrial CA VA and VB. The new compounds showed weak inhibitory activity against hCA I (K(I)s of 102 nM-7.42 microM), hCA II (K(I)s of 0.54-7.42 microM) and hCA IV (K(I)s of 4.32-10.05 microM) but were low nanomolar inhibitors of hCA VA and hCA VB, with inhibition constants in the range of 4.2-32 nM and 1.3-74 nM, respectively. Furthermore, the selectivity ratios for inhibiting the mitochondrial enzymes over CA II were in the range of 67.5-415, making these sulfamides the first selective CA VA/VB inhibitors.

Sulfonamides incorporating boroxazolidone moieties are potent inhibitors of the transmembrane, tumor-associated carbonic anhydrase isoforms IX and XII.

A new series of sulfonamides was synthesized by the reaction of the boroxazolidone complex of l-lysine with isothiocyanates incorporating sulfamoyl moieties and diverse organic scaffolds. The obtained thioureas have been investigated as inhibitors of four physiologically relevant human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms, hCA I, II, IX and XII. Inhibition between the low nanomolar to the micromolar range has been observed against them, with several low nanomolar and tumor-CA selective inhibitors detected. These boron-containing compounds might be useful for the management of hypoxic tumors overexpressing hCA IX/XII by means of boron neutron capture therapy, a technique not investigated so far with inhibitors of this enzyme.

Synthesis of rhodamine B-benzenesulfonamide conjugates and their inhibitory activity against human α- and bacterial/fungal β-carbonic anhydrases.

A series of fluorescent sulfonamide carbonic anhydrase (CA, EC 4.2.1.1) inhibitors were obtained by attaching rhodamine B moieties to the scaffold of benzenesulfonamides. The new compounds have been investigated for the inhibition of 12 human α-CA isoforms (hCA I-hCA XIV), three bacterial and one fungal β-class enzymes from the pathogens Mycobacterium tuberculosis and Candida albicans. All types of inhibitory activities have been detected, with several compounds showing low nanomolar inhibition against the transmembrane isoforms hCA IX, XII (cancer-associated) and XIV. The β-CAs were inhibited in the micromolar range by these compounds which may have applications for the imaging of hypoxic tumors or bacteria due to their fluorescent moieties.

Carbonic anhydrase inhibitors: Gd(III) complexes of DOTA- and TETA-sulfonamide conjugates targeting the tumor associated carbonic anhydrase isozymes IX and XII

Gd(III)-sulfonamide complexes incorporating macrocyclic rings of the DOTA/TETA type have been prepared and assayed for the inhibition of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). The cytosolic isoform, CA I, was poorly inhibited, whereas cytosolic CA II and transmembrane, tumor-associated CA IX and XII were inhibited in the low nanomolar range by the Gd(III) complexes. Magnetic susceptibility and relaxivity measurements proved that the Gd(III) complexes have comparable parameters to those of clinically used MRI contrast agents like Dotarem, Prohance and Omniscan in aqueous solution. Some Gd(III) complexes were investigated for the inhibition of extracellular tumor acidification in two cell lines overexpressing CA IX, the colorectal HT-29 cell line and the cervical HeLa carcinoma cell line. In both tumor types, a slight but significant reduction of tumor acidosis was detected. Gd(III)-sulfonamide conjugates may thus be of interest for developing imaging techniques or novel treatment strategies for the management of hypoxic tumors overexpressing extracellular CA isozymes such as CA IX and XII.