Carbonic anhydrase inhibitors. Design of selective, membrane-impermeant inhibitors targeting the human tumor-associated isozyme IX.
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.
Casey
Joseph R
JR
Canadian Institutes of Health Research, Membrane Protein Research Group, Department of Physiology, University of Alberta, Edmonton, Alberta, Canada T6G 2H7.
Morgan
Patricio E
PE
Vullo
Daniela
D
Scozzafava
Andrea
A
Mastrolorenzo
Antonio
A
Supuran
Claudiu T
CT
D000951:Antigens, Neoplasm / Q000737:chemistry; D000071231:Carbonic Anhydrase IX; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D002256:Carbonic Anhydrases / Q000737:chemistry; D004910:Erythrocyte Membrane / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D010539:Permeability; D011726:Pyridinium Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry
D000951:Antigens, Neoplasm; D002257:Carbonic Anhydrase Inhibitors; D007527:Isoenzymes; D011726:Pyridinium Compounds; D013449:Sulfonamides; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases