Carbonic anhydrase inhibitors. Design of selective, membrane-impermeant inhibitors targeting the human tumor-associated isozyme IX.

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Casey JR, Morgan PE, Vullo D, Scozzafava A, Mastrolorenzo A, Supuran CT

Carbonic anhydrase inhibitors. Design of selective, membrane-impermeant inhibitors targeting the human tumor-associated isozyme IX.

J Med Chem. 2004 Apr 22;47(9):2337-47.

PubMed ID

15084132 [ View in PubMed

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Abstract

A series of positively charged sulfonamides were obtained by reaction of aminobenzolamide [5-(4-aminobenzenesulfonylamino)-1,3,4-thiadiazole-2-sulfonamide] with tri-/tetrasubstituted pyrilium salts possessing alkyl-, aryl- or combinations of alkyl and aryl groups at the pyridinium ring. The new compounds reported here were assayed for the inhibition of four physiologically relevant carbonic anhydrase (CA, EC 4.2.1.1) isozymes: the cytosolic hCA I and II, the membrane-anchored bCA IV, and the membrane-bound, tumor-associated isozyme hCA IX. They showed potent inhibitory activity against all investigated isozymes, although with different profiles. For CA I the new derivatives showed inhibition constants in the range of 3-12 nM, for CA II in the range of 0.20-5.96 nM, against CA IV in the range of 2.0-10.3 nM, and against CA IX in the range of 3-45 nM, respectively. These new compounds are membrane-impermeant due to their salt-like character. Some of these derivatives were also tested for their inhibitory activity against the Cl(-)/HCO(3)(-) anion exchanger AE1: two derivatives showed inhibitory activity in the low micromolar range, whereas one compound was inactive at these concentrations. The high affinity of these new derivatives for the tumor-associated isozyme CA IX and their membrane impermeability make this type of CA inhibitor interesting candidates for the selective inhibition of only the tumor-associated isozyme and not the cytosolic ones, for which they also show high potency. Furthermore, we prove here for the first time that the CA-AE metabolon can be inhibited by the same type of sulfonamide derivative.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Acetazolamide	Carbonic anhydrase 1	Ki (nM)	250	7.5	25	Details
Diclofenamide	Carbonic anhydrase 1	Ki (nM)	1200	7.5	25	Details
Methazolamide	Carbonic anhydrase 1	Ki (nM)	50	7.5	25	Details