{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T21:39:33Z","timestamp":1791322773147,"version":"4.3.1"},"reference-count":49,"publisher":"American Chemical Society (ACS)","issue":"1","license":[{"start":{"date-parts":[[2012,12,17]],"date-time":"2012-12-17T00:00:00Z","timestamp":1355702400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2012,12,17]],"date-time":"2012-12-17T00:00:00Z","timestamp":1355702400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2012,12,17]],"date-time":"2012-12-17T00:00:00Z","timestamp":1355702400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2013,1,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Coumarins were recently shown to constitute a novel class of mechanism-based carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. We demonstrate that sulfocoumarins (1,2-benzoxathiine 2,2-dioxides) possess a similar mechanism of action, acting as effective CA inhibitors. The sulfocoumarins were hydrolyzed by the esterase CA activity to 2-hydroxyphenyl-vinylsulfonic acids, which thereafter bind to the enzyme in a region rarely occupied by other classes of inhibitors. The X-ray structure of one of these compounds in adduct with a modified CA II enzyme possessing two amino acid residues from the CA IX active site, allowed us to decipher the inhibition mechanism. The sulfonic acid was observed anchored to the zinc-coordinated water molecule, making favorable interactions with Thr200 and Pro201. Some other sulfocoumarins incorporating substituted-1,2,3-triazole moieties were prepared by using click chemistry and showed low nanomolar inhibitory action against the tumor-associated isoforms CA IX and XII, being less effective against the cytosolic CA I and II.<\/jats:p>","DOI":"10.1021\/jm301625s","type":"journal-article","created":{"date-parts":[[2012,12,17]],"date-time":"2012-12-17T05:07:14Z","timestamp":1355720834000},"page":"293-300","source":"Crossref","is-referenced-by-count":214,"title":["Sulfocoumarins (1,2-Benzoxathiine-2,2-dioxides):\nA\nClass of Potent and Isoform-Selective Inhibitors of Tumor-Associated\nCarbonic Anhydrases"],"prefix":"10.1021","volume":"56","author":[{"given":"Kaspars","family":"Tars","sequence":"first","affiliation":[{"name":"Biomedical Research and Study Center, Ratsupites 1, LV 1067, Riga, Latvia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Vullo","sequence":"additional","affiliation":[{"name":"Universita\u0300 degli Studi di Firenze, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, I-50019 Sesto Fiorentino (Firenze), Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andris","family":"Kazaks","sequence":"additional","affiliation":[{"name":"Biomedical Research and Study Center, Ratsupites 1, LV 1067, Riga, Latvia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janis","family":"Leitans","sequence":"additional","affiliation":[{"name":"Biomedical Research and Study Center, Ratsupites 1, LV 1067, Riga, Latvia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alons","family":"Lends","sequence":"additional","affiliation":[{"name":"Latvian Institute of Organic Synthesis, Aizkraukles 21, LV-1006, Riga, Latvia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aiga","family":"Grandane","sequence":"additional","affiliation":[{"name":"Latvian Institute of Organic Synthesis, Aizkraukles 21, LV-1006, Riga, Latvia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raivis","family":"Zalubovskis","sequence":"additional","affiliation":[{"name":"Latvian Institute of Organic Synthesis, Aizkraukles 21, LV-1006, Riga, Latvia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Scozzafava","sequence":"additional","affiliation":[{"name":"Universita\u0300 degli Studi di Firenze, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, I-50019 Sesto Fiorentino (Firenze), Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudiu T.","family":"Supuran","sequence":"additional","affiliation":[{"name":"Universita\u0300 degli Studi di Firenze, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, I-50019 Sesto Fiorentino (Firenze), Italy"},{"name":"Universita\u0300 degli Studi di Firenze, Dipartimento di Scienze Farmaceutiche, Via Ugo Schiff 6, I-50019 Sesto Fiorentino (Firenze), Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2012,12,17]]},"reference":[{"key":"2026081706081528000_cit1a","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1177\/1087057108315739","article-title":"Direct screening\nof natural product extracts using mass spectrometry","volume":"13","author":"Vu","year":"2008","journal-title":"J. Biomol. Screening"},{"key":"2026081706081528000_cit1b","doi-asserted-by":"crossref","first-page":"3057","DOI":"10.1021\/ja809683v","article-title":"Non-zinc mediated inhibition of carbonic\nanhydrases: coumarins are a new class of suicide inhibitors","volume":"131","author":"Maresca","year":"2009","journal-title":"J. Am. Chem. Soc."},{"key":"2026081706081528000_cit2","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1021\/jm901287j","article-title":"Deciphering the mechanism of carbonic anhydrase inhibition\nwith coumarins and thiocoumarins","volume":"53","author":"Maresca","year":"2010","journal-title":"J. Med. Chem."},{"key":"2026081706081528000_cit3a","doi-asserted-by":"crossref","first-page":"4511","DOI":"10.1016\/j.bmcl.2010.06.040","article-title":"Coumarins incorporating\nhydroxy-\nand chloro- moieties selectively inhibit the transmembrane, tumor-associated\ncarbonic anhydrase isoforms IX and XII over the cytosolic ones I and\nII","volume":"20","author":"Maresca","year":"2010","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"2026081706081528000_cit3b","doi-asserted-by":"crossref","first-page":"7255","DOI":"10.1016\/j.bmcl.2010.10.094","article-title":"7,8-Disubstituted- but not 6,7-disubstituted\ncoumarins selectively inhibit the transmembrane, tumor-associated\ncarbonic anhydrase isoforms IX and XII over the cytosolic ones I and\nII in the low nanomolar\/subnanomolar range","volume":"20","author":"Maresca","year":"2010","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"2026081706081528000_cit4a","doi-asserted-by":"crossref","first-page":"3364","DOI":"10.1158\/0008-5472.CAN-10-4261","article-title":"Targeting Tumor Hypoxia: Suppression\nof Breast Tumor Growth and Metastasis by Novel Carbonic Anhydrase\nIX Inhibitors","volume":"71","author":"Lou","year":"2011","journal-title":"Cancer Res."},{"key":"2026081706081528000_cit4b","doi-asserted-by":"crossref","first-page":"8271","DOI":"10.1021\/jm200983e","article-title":"Glycosyl coumarin\ncarbonic anhydrase IX and XII inhibitors strongly attenuate the growth\nof primary breast tumors","volume":"54","author":"Touisni","year":"2011","journal-title":"J. Med. Chem."},{"key":"2026081706081528000_cit5","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2012.07.021","article-title":"Natural product\ncoumarins that inhibit human carbonic anhydrases","author":"Davis","year":"2012","journal-title":"Bioorg. Med. 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Pat."},{"key":"2026081706081528000_cit8","doi-asserted-by":"crossref","first-page":"4421","DOI":"10.1021\/cr200176r","article-title":"Multiple binding\nmodes of inhibitors to carbonic anhydrases: how to design specific\ndrugs targeting 15 different isoforms?","volume":"112","author":"Alterio","year":"2012","journal-title":"Chem.\nRev."},{"key":"2026081706081528000_cit9a","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1038\/nrd2467","article-title":"Carbonic\nanhydrases: novel therapeutic applications\nfor inhibitors and activators","volume":"7","author":"Supuran","year":"2008","journal-title":"Nature Rev. Drug\nDiscovery"},{"key":"2026081706081528000_cit9b","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1038\/nrd3554","article-title":"Interfering with\npH regulation in tumours as a therapeutic strategy","volume":"10","author":"Neri","year":"2011","journal-title":"Nature Rev. 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Rev."},{"key":"2026081706081528000_cit11a","doi-asserted-by":"crossref","first-page":"14726","DOI":"10.1021\/ja3068098","article-title":"Neutron Diffraction of Acetazolamide-Bound\nHuman Carbonic Anhydrase II Reveals Atomic Details of Drug Binding","volume":"134","author":"Fisher","year":"2012","journal-title":"J. Am. Chem. Soc."},{"key":"2026081706081528000_cit11b","doi-asserted-by":"crossref","first-page":"8329","DOI":"10.1021\/ja061574s","article-title":"Carbonic anhydrase\ninhibitors: X-ray and molecular modeling study for the interaction\nof a fluorescent antitumor sulfonamide with isozyme II and IX","volume":"128","author":"Alterio","year":"2006","journal-title":"J. Am. Chem. Soc."},{"key":"2026081706081528000_cit11c","doi-asserted-by":"crossref","first-page":"7697","DOI":"10.1002\/anie.200701189","article-title":"Saccharin inhibits\ncarbonic anhydrases: possible explanation for its unpleasant metallic\naftertaste","volume":"46","author":"Ko\u0308hler","year":"2007","journal-title":"Angew. Chem., Int. Ed. Engl."},{"key":"2026081706081528000_cit12a","doi-asserted-by":"crossref","first-page":"3659","DOI":"10.1021\/ja00087a086","article-title":"Two-site\nbinding of phenol in the active site of human carbonic anhydrase II:\nstructural implications for substrate association","volume":"116","author":"Nair","year":"1994","journal-title":"J. Am. Chem. Soc."},{"key":"2026081706081528000_cit12b","doi-asserted-by":"crossref","first-page":"1583","DOI":"10.1016\/j.bmcl.2008.01.077","article-title":"Carbonic anhydrase inhibitors: interactions\nof phenols with the 12 catalytically active mammalian isoforms (CA\nI\u2013XIV)","volume":"18","author":"Innocenti","year":"2008","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"2026081706081528000_cit12c","doi-asserted-by":"crossref","first-page":"3593","DOI":"10.1016\/j.bmcl.2008.04.077","article-title":"Carbonic anhydrase inhibitors: inhibition\nof the new membrane-associated isoform XV with phenols","volume":"18","author":"Innocenti","year":"2008","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"2026081706081528000_cit13a","first-page":"317","article-title":"Carbonic anhydrase activators","volume-title":"Carbonic\nAnhydrase\ue5f8Its Inhibitors and Activators","author":"Ilies","year":"2004"},{"key":"2026081706081528000_cit13b","doi-asserted-by":"crossref","first-page":"10384","DOI":"10.1021\/bi970760v","article-title":"Carbonic anhydrase activators: X-ray\ncrystallographic and spectroscopic investigations for the interaction\nof isozymes I and II with histamine","volume":"36","author":"Briganti","year":"1997","journal-title":"Biochemistry"},{"key":"2026081706081528000_cit13c","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1021\/jm010958k","article-title":"Carbonic anhydrase activators: high\naffinity isozymes I, II and IV activators, incorporating a \u03b2-alanyl-histidine\nscaffold","volume":"45","author":"Scozzafava","year":"2002","journal-title":"J. Med. Chem."},{"key":"2026081706081528000_cit14","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1002\/med.20068","article-title":"Therapeutic\nPotential\nof Sulfamides as Enzyme Inhibitors","volume":"26","author":"Winum","year":"2006","journal-title":"Med. Res.\nRev."},{"key":"2026081706081528000_cit15a","doi-asserted-by":"crossref","first-page":"1868","DOI":"10.1039\/c2cc16395k","article-title":"Dithiocarbamates:\na new class of carbonic anhydrase inhibitors. Crystallographic and\nkinetic investigations","volume":"48","author":"Carta","year":"2012","journal-title":"Chem. Commun."},{"key":"2026081706081528000_cit15b","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1016\/j.bmcl.2011.12.033","article-title":"Dithiocarbamates strongly inhibit the beta-class fungal\ncarbonic anhydrases from Cryptococcus neoformans, Candida albicans, and Candida glabrata","volume":"22","author":"Monti","year":"2012","journal-title":"Bioorg. Med.\nChem. Lett."},{"key":"2026081706081528000_cit15c","doi-asserted-by":"crossref","first-page":"1721","DOI":"10.1021\/jm300031j","article-title":"Dithiocarbamates\nstrongly inhibit carbonic anhydrases and show antiglaucoma action\nin vivo","volume":"55","author":"Carta","year":"2012","journal-title":"J. Med. Chem."},{"key":"2026081706081528000_cit16","doi-asserted-by":"crossref","first-page":"2266","DOI":"10.1016\/j.bmc.2012.02.014","article-title":"Novel coumarins\nand 2-thioxo-coumarins as inhibitors of the tumor-associated carbonic\nanhydrases IX and XII","volume":"20","author":"Carta","year":"2012","journal-title":"Bioorg. Med. Chem."},{"key":"2026081706081528000_cit17","doi-asserted-by":"crossref","first-page":"2182","DOI":"10.1016\/j.bmcl.2012.01.129","article-title":"New chemotypes acting as isozyme-selective\ncarbonic\nanhydrase inhibitors with low affinity for the offtarget cytosolic\nisoform II","volume":"22","author":"Carta","year":"2012","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"2026081706081528000_cit18","doi-asserted-by":"crossref","first-page":"5541","DOI":"10.1016\/j.tet.2012.04.080","article-title":"Facile synthesis\nof coumarin bioisosteres\ue5f81,2-benzoxathiine 2,2-dioxides","volume":"68","author":"Grandane","year":"2012","journal-title":"Tetrahedron"},{"key":"2026081706081528000_cit19a","doi-asserted-by":"crossref","first-page":"4851","DOI":"10.1016\/j.bmcl.2009.06.022","article-title":"In vivo targeting of tumor-associated\ncarbonic anhydrases using acetazolamide derivatives","volume":"19","author":"Ahlskog","year":"2009","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"2026081706081528000_cit19b","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1021\/cb1003477","article-title":"Selection of Carbonic Anhydrase IX\nInhibitors from One Million DNA-Encoded Compounds","volume":"6","author":"Buller","year":"2011","journal-title":"ACS Chem. Biol."},{"key":"2026081706081528000_cit20a","doi-asserted-by":"crossref","first-page":"2379","DOI":"10.1039\/B517529A","article-title":"Carbohydrate triazoles\nand isoxazoles as inhibitors of galectins-1 and -3","author":"Gigue\u0300re","year":"2006","journal-title":"Chem. Commun."},{"key":"2026081706081528000_cit20b","doi-asserted-by":"crossref","first-page":"4145","DOI":"10.1021\/ol061782p","article-title":"One-pot synthesis\nof macrocycles by a tandem three-component reaction and intramolecular\n[3 + 2] cycloaddition","volume":"8","author":"Pirali","year":"2006","journal-title":"Org. Lett."},{"key":"2026081706081528000_cit21","doi-asserted-by":"crossref","first-page":"1322","DOI":"10.1021\/bi802035f","article-title":"Design of a carbonic\nanhydrase IX active-site mimic to screen inhibitors for possible anticancer\nproperties","volume":"48","author":"Genis","year":"2009","journal-title":"Biochemistry"},{"key":"2026081706081528000_cit22","doi-asserted-by":"crossref","first-page":"16233","DOI":"10.1073\/pnas.0908301106","article-title":"Crystal structure\nof the extracellular catalytic domain of the tumor-associated human\ncarbonic anhydrase IX","volume":"106","author":"Alterio","year":"2009","journal-title":"Proc. Natl. Acad. Sci.\nU. S. A."},{"key":"2026081706081528000_cit23","doi-asserted-by":"crossref","first-page":"2561","DOI":"10.1016\/S0021-9258(18)62326-9","article-title":"The carbon\ndioxide hydration activity of carbonic anhydrase. I. Stop-flow kinetic\nstudies on the native human isoenzymes B and C","volume":"246","author":"Khalifah","year":"1971","journal-title":"J. Biol. Chem."},{"key":"2026081706081528000_cit24","doi-asserted-by":"crossref","first-page":"5511","DOI":"10.1021\/jm1003667","article-title":"Polyamines inhibit carbonic anhydrases\nby anchoring to the zinc-coordinated water molecule","volume":"53","author":"Carta","year":"2010","journal-title":"J. Med. Chem."},{"key":"2026081706081528000_cit25","doi-asserted-by":"crossref","first-page":"1682","DOI":"10.1021\/jm1013242","article-title":"Natural\nProduct-Based Phenols as Novel Probes for Mycobacterial and Fungal\nCarbonic Anhydrases","volume":"54","author":"Davis","year":"2011","journal-title":"J. Med. Chem."},{"key":"2026081706081528000_cit26","doi-asserted-by":"crossref","first-page":"5259","DOI":"10.1039\/c2cc32013d","article-title":"Nucleophile recognition\nas an alternative inhibition\nmode for benzoic acid based carbonic anhydrase inhibitors","volume":"48","author":"Martin","year":"2012","journal-title":"Chem. Commun."},{"key":"2026081706081528000_cit27","unstructured":"DeLano\n              W. L.\n            \n          \n          The PyMOL\nMolecular Graphics System; DeLano Scientific: San Carlos, CA, 2002."},{"key":"2026081706081528000_cit28","unstructured":"Leslie\n              A. G. W.\n            \n          \n          Joint CCP4 ESF-EAMCB\nNewsletter on Protein\nCrystallography; Daresbury Laboratory: Warrington, UK, 1992; Vol. 26, pp 24\u201328."},{"key":"2026081706081528000_cit29","unstructured":"Evans\n              P. R.\n            \n          \n          SCALA. 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Crystallogr."},{"key":"2026081706081528000_cit33","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.1016\/S0969-2126(96)00147-5","article-title":"Phi\/psi-chology: Ramachandran revisited","volume":"4","author":"Kleywegt","year":"1996","journal-title":"Structure"}],"container-title":["Journal of Medicinal Chemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/jm301625s","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/jmcmar\/article-pdf\/56\/1\/293\/16876224\/jm301625s.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/jmcmar\/article-pdf\/56\/1\/293\/16876224\/jm301625s.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T10:22:38Z","timestamp":1786962158000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/jmcmar\/article\/56\/1\/293\/1590239\/Sulfocoumarins-1-2-Benzoxathiine-2-2-dioxides-A"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,12,17]]},"references-count":49,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2012,12,17]]},"published-print":{"date-parts":[[2013,1,10]]}},"URL":"https:\/\/doi.org\/10.1021\/jm301625s","relation":{},"ISSN":["0022-2623","1520-4804"],"issn-type":[{"value":"0022-2623","type":"print"},{"value":"1520-4804","type":"electronic"}],"subject":[],"published":{"date-parts":[[2012,12,17]]}}}