Carbonic anhydrase inhibitors: design of spin-labeled sulfonamides incorporating TEMPO moieties as probes for cytosolic or transmembrane isozymes.
A series of spin-labeled sulfonamides incorporating TEMPO moieties were synthesized by a procedure involving the formation of a thiourea functionality between the benzenesulfonamide and free radical fragment of the molecules. The new compounds were tested as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) and showed efficient inhibition of the physiologically relevant isozymes hCA II and hCA IX (hCA IX being predominantly found in tumors) and moderate to weak inhibitory activity against hCA I. Some derivatives were also selective for inhibiting the tumor-associated isoform over the cytosolic one CA II, and presented significant changes in their ESR signals when complexed to the enzyme active site, being interesting candidates for the investigation of hypoxic tumors overexpressing CA IX by ESR techniques, as well as for imaging/treatment purposes.
Cecchi
Alessandro
A
Università degli Studi di Firenze, Laboratorio di Chimica Bioinorganica, Room 188, Via della Lastruccia 3, I-50019 Sesto Fiorentino, Firenze, Italy.
Ciani
Laura
L
Winum
Jean-Yves
JY
Montero
Jean-Louis
JL
Scozzafava
Andrea
A
Ristori
Sandra
S
Supuran
Claudiu T
CT
D000951:Antigens, Neoplasm / Q000737:chemistry / Q000187:drug effects; D024402:Carbonic Anhydrase II / Q000037:antagonists & inhibitors / Q000737:chemistry; D000071231:Carbonic Anhydrase IX; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000737:chemistry / Q000187:drug effects*; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology; D003497:Cyclic N-Oxides / Q000737:chemistry*; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D005609:Free Radicals / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry; D015394:Molecular Structure; D011994:Recombinant Proteins / Q000187:drug effects; D013113:Spin Labels; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
D000951:Antigens, Neoplasm; D002257:Carbonic Anhydrase Inhibitors; D003497:Cyclic N-Oxides; D005609:Free Radicals; D007527:Isoenzymes; D011994:Recombinant Proteins; D013113:Spin Labels; D013449:Sulfonamides; D024402:Carbonic Anhydrase II; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases; C003959:TEMPO