Carbonic anhydrase inhibitors. Synthesis and inhibition of cytosolic/tumor-associated carbonic anhydrase isozymes I, II, and IX with boron-containing sulfonamides, sulfamides, and sulfamates: toward agents for boron neutron capture therapy of hypoxic tumors.
A library of boron-containing carbonic anhydrase (CA, EC 4.2.1.1) inhibitors, including sulfonamides, sulfamides, and sulfamates is reported. The new compounds have been synthesized by derivatization reactions of 4-carboxy-/amino-/hydroxy-phenylboronic acid pinacol esters with amino/isothiocyanato-substituted aromatic/heteroaromatic sulfonamides or by sulfamoylation reactions with sulfamoyl chloride. The new derivatives have been assayed for the inhibition of three physiologically relevant CA isozymes, the cytosolic CA I and II, and the transmembrane, tumor-associated isozyme CA IX. Effective inhibitors were detected both among sulfonamides, sulfamates, and sulfamides. Against the human isozyme hCA I the new compounds showed inhibition constants in the range of 34-94nM, against hCA II in the range of 3.1-48nM, and against hCA IX in the range of 7.3-89nM, respectively. As hypoxic tumors highly overexpress CA IX, the design of boron-containing inhibitors with high affinity for the tumor-associated CA isozymes may lead to important advances in boron neutron capture therapy (BNCT) applications targeting such tumors, which are non-responsive to both classical chemo- and radiotherapy.
Winum
Jean-Yves
JY
Università degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino (Florence), Italy.
Cecchi
Alessandro
A
Montero
Jean-Louis
JL
Innocenti
Alessio
A
Scozzafava
Andrea
A
Supuran
Claudiu T
CT
D000951:Antigens, Neoplasm / Q000187:drug effects; D001896:Boron Compounds / Q000138:chemical synthesis*; D016754:Boron Neutron Capture Therapy; D024401:Carbonic Anhydrase I / Q000037:antagonists & inhibitors; D024402:Carbonic Anhydrase II / Q000037:antagonists & inhibitors; D000071231:Carbonic Anhydrase IX; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D002256:Carbonic Anhydrases / Q000187:drug effects; D006801:Humans; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis; D013451:Sulfonic Acids / Q000138:chemical synthesis
D000951:Antigens, Neoplasm; D001896:Boron Compounds; D002257:Carbonic Anhydrase Inhibitors; D013449:Sulfonamides; D013451:Sulfonic Acids; C005741:sulfamic acid; D024401:Carbonic Anhydrase I; D024402:Carbonic Anhydrase II; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases