title: Synthesis of 6-tetrazolyl-substituted sulfocoumarins acting as highly potent and selective inhibitors of the tumor-associated carbonic anhydrase isoforms IX and XII.
abstract: A series of 6-substituted sulfocoumarins incorporating substituted-1,2,3,4-tetrazol-5-yl moieties were synthesized by reaction of 6-iodo-sulfocoumarin and the corresponding tetrazole via the CH activation reaction. The new sulfocoumarins incorporating alkyl and substituted aryl moieties at the 1-position of the tetrazole, were investigated for the inhibition of four human (h) carbonic anhydrase (hCA, EC 4.2.1.1) isoforms, the cytosolic hCA I and II; and the transmembrane, tumor-associated hCA IX and XII. The tetrazole-substituted sulfocoumarins did not inhibit the ubiquitous, off-target cytosolic isoforms (KIs >10 μM) but showed effective inhibition against the two transmembrane CAs, with KIs ranging from 6.5 to 68.6 nM against hCA IX, and between 4.3 and 59.8 nM against hCA XII. As hCA IX and XII are validated anti-tumor targets, such prodrug, isoform-selective inhibitors as the sulfocoumarins reported here, may be useful for identifying suitable drug candidates for clinical trials.
authors: Latvian Institute of Organic Synthesis, Aizkraukles 21, LV-1006 Riga, Latvia.
authors: Aiga
authors: A
authors: Grandane
authors: Università degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino (Florence), Italy; Università degli Studi di Firenze, NEUROFARBA Department, Section of Pharmaceutical Chemistry, Via Ugo Schiff 6, 50019 Sesto Fiorentino (Florence), Italy.
authors: Muhammet
authors: M
authors: Tanc
authors: Latvian Institute of Organic Synthesis, Aizkraukles 21, LV-1006 Riga, Latvia. Electronic address: raivis@osi.lv.
authors: Raivis
authors: R
authors: Zalubovskis
authors: Università degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino (Florence), Italy; Università degli Studi di Firenze, NEUROFARBA Department, Section of Pharmaceutical Chemistry, Via Ugo Schiff 6, 50019 Sesto Fiorentino (Florence), Italy. Electronic address: claudiu.supuran@unifi.it.
authors: Claudiu T
authors: CT
authors: Supuran
mesh_terms: D000951:Antigens, Neoplasm; D024401:Carbonic Anhydrase I / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D024402:Carbonic Anhydrase II / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002256:Carbonic Anhydrases / Q000737:chemistry* / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D009369:Neoplasms / Q000201:enzymology / Q000473:pathology; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000494:pharmacology*; D014230:Triazoles / Q000737:chemistry*
chemical_list: D000951:Antigens, Neoplasm; D002257:Carbonic Anhydrase Inhibitors; D013449:Sulfonamides; D014230:Triazoles; D024401:Carbonic Anhydrase I; D024402:Carbonic Anhydrase II; D002256:Carbonic Anhydrases
keywords: Carbonic anhydrase; Inhibitor; Sulfocoumarin; Tetrazole; Tumor-associated isoform IX, XII