Carbonic anhydrase inhibitors: synthesis and inhibition of cytosolic/tumor-associated carbonic anhydrase isozymes I, II, and IX with sulfonamides incorporating thioureido-sulfanilyl scaffolds.

Article Details

Citation

Puccetti L, Fasolis G, Cecchi A, Winum JY, Gamberi A, Montero JL, Scozzafava A, Supuran CT

Carbonic anhydrase inhibitors: synthesis and inhibition of cytosolic/tumor-associated carbonic anhydrase isozymes I, II, and IX with sulfonamides incorporating thioureido-sulfanilyl scaffolds.

Bioorg Med Chem Lett. 2005 May 2;15(9):2359-64.

PubMed ID
15837325 [ View in PubMed
]
Abstract

The tumor-associated transmembrane carbonic anhydrase (CA, EC 4.2.1.1) isozyme IX (CA IX) is overexpressed in hypoxic tumors and appears to be involved in acidification of the tumor microenvironment, a process correlated with cancer progression and bad prognosis. The acidification may be reduced by inhibiting the enzyme with potent sulfonamide/sulfamate CA inhibitors. A series of such aromatic sulfonamides incorporating thioureido-sulfanilyl moieties has been prepared and investigated for its interaction with the catalytic domain of the human isozyme hCA IX. The key intermediates in the synthesis were obtained by reacting sulfanilamide, homosulfanilamide, or 4-aminoethylbenzenesulfonamide with 4-acetamido-benzenesulfonyl chloride followed by deacetylation and reaction with thiophosgene. The obtained isothiocyanato sulfonamides were reacted with aliphatic or aromatic primary amines or hydrazines, leading to the corresponding thioureas. Some of these compounds showed excellent inhibitory properties against isozymes I, II, and IX, with several inhibitors also presenting selectivity for the inhibition of CA IX over that of the ubiquitous isozyme CA II. Such sulfonamides may constitute interesting candidates for the development of novel antitumor therapies based on the inhibition of the CA isozymes overexpressed in hypoxic tumors. Due to the highest expression of CA IX in clear renal cell carcinoma and its chemo/radioresistance, our efforts are first of all directed to generate effective therapeutic strategies for the cure of this malignancy.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
4-(2-AMINOETHYL)BENZENESULFONAMIDECarbonic anhydrase 2Ki (nM)160000N/AN/ADetails
AcetazolamideCarbonic anhydrase 1Ki (nM)900000N/AN/ADetails
AcetazolamideCarbonic anhydrase 2Ki (nM)12000N/AN/ADetails
DiclofenamideCarbonic anhydrase 1Ki (nM)1200000N/AN/ADetails
DiclofenamideCarbonic anhydrase 2Ki (nM)38000N/AN/ADetails
EthoxzolamideCarbonic anhydrase 1Ki (nM)25000N/AN/ADetails
EthoxzolamideCarbonic anhydrase 2Ki (nM)8000N/AN/ADetails