{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T12:26:27Z","timestamp":1791116787198,"version":"4.1.0"},"reference-count":50,"publisher":"American Chemical Society (ACS)","issue":"20","license":[{"start":{"date-parts":[[2015,9,25]],"date-time":"2015-09-25T00:00:00Z","timestamp":1443139200000},"content-version":"vor","delay-in-days":365,"URL":"https:\/\/pubs.acs.org\/page\/policy\/authorchoice_termsofuse.html"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["CA165284"],"award-info":[{"award-number":["CA165284"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000780","name":"European Commission","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000923","name":"Australian Research Council","doi-asserted-by":"publisher","award":["DP110100071"],"award-info":[{"award-number":["DP110100071"]}],"id":[{"id":"10.13039\/501100000923","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000923","name":"Australian Research Council","doi-asserted-by":"publisher","award":["FT10100185"],"award-info":[{"award-number":["FT10100185"]}],"id":[{"id":"10.13039\/501100000923","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,10,23]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Carbonic anhydrase IX (CA IX) is an extracellular transmembrane homodimeric zinc metalloenzyme that has been validated as a prognostic marker and therapeutic target for several types of aggressive cancers. CA IX shares a close homology with other CA isoforms, making the design of CA IX isoform selective inhibitors challenging. In this paper, we describe the development of a new class of CA IX inhibitors that comprise a sulfamate as the zinc binding group, a variable linker, and a carbohydrate \u201ctail\u201d moiety. Seven compounds inhibited CA IX with low nM Ki values of 1\u20132 nM and also exhibited permeability profiles to preferentially target the binding of extracellular CA IX over cytosolic CAs. The crystal structures of two of these compounds in complex with a CA IX-mimic (a variant of CA II, with active site residues that mimic CA IX) and one compound in complex with CA II have been determined to 1.7 \u00c5 resolution or better and demonstrate a selective mechanism of binding between the hydrophilic and hydrophobic pockets of CA IX versus CA II. These compounds present promising candidates for anti-CA IX drugs and the treatment for several aggressive cancer types.<\/jats:p>","DOI":"10.1021\/jm5012935","type":"journal-article","created":{"date-parts":[[2014,9,25]],"date-time":"2014-09-25T11:48:07Z","timestamp":1411645687000},"page":"8635-8645","source":"Crossref","is-referenced-by-count":55,"title":["Structural Insights into Carbonic\nAnhydrase IX Isoform\nSpecificity of Carbohydrate-Based Sulfamates"],"prefix":"10.1021","volume":"57","author":[{"given":"Janina","family":"Moeker","sequence":"first","affiliation":[{"name":"Griffith University , , , ,","place":["Nathan, Queensland, Australia, 4111"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian P.","family":"Mahon","sequence":"additional","affiliation":[{"name":"University of Florida , , Box 100245, , ,","place":["Gainesville, Florida, United States, 32610"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurent F.","family":"Bornaghi","sequence":"additional","affiliation":[{"name":"Griffith University , , , ,","place":["Nathan, Queensland, Australia, 4111"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Vullo","sequence":"additional","affiliation":[{"name":"Universita\u0300 degli Studi di Firenze , , Via della Lastruccia 3, Rm. 188 , , ,","place":["Sesto Fiorentino, Florence, Italy, 50019"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudiu T.","family":"Supuran","sequence":"additional","affiliation":[{"name":"Universita\u0300 degli Studi di Firenze , , Via della Lastruccia 3, Rm. 188 , , ,","place":["Sesto Fiorentino, Florence, Italy, 50019"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"McKenna","sequence":"additional","affiliation":[{"name":"University of Florida , , Box 100245, , ,","place":["Gainesville, Florida, United States, 32610"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sally-Ann","family":"Poulsen","sequence":"additional","affiliation":[{"name":"Griffith University , , , ,","place":["Nathan, Queensland, Australia, 4111"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2014,9,25]]},"reference":[{"key":"2026090205581779800_cit1a","first-page":"7075","article-title":"Hypoxia-inducible\nexpression of tumor-associated carbonic\nanhydrases","volume":"60","author":"Wykoff","year":"2000","journal-title":"Cancer Res."},{"key":"2026090205581779800_cit1b","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1016\/j.febslet.2004.10.043","article-title":"Hypoxia activates\nthe capacity of tumor-associated carbonic anhydrase IX to acidify\nextracellular pH","volume":"577","author":"Svastova","year":"2004","journal-title":"FEBS Lett."},{"key":"2026090205581779800_cit1c","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.bbamcr.2010.09.018","article-title":"Role of hypoxia and EGF on expression,\nactivity, localization and phosphorylation of carbonic anhydrase IX\nin MDA-MB-231 breast cancer cells","volume":"1813","author":"Li","year":"2011","journal-title":"Biochim.\nBiophys. Acta"},{"key":"2026090205581779800_cit2a","first-page":"1","article-title":"Regulation and role of carbonic anhydrase\nIX and use as a biomarker and therapeutic target in cancer","volume":"15","author":"Mahon","year":"2013","journal-title":"Res. Trends Curr. Top. Biochem. Res."},{"key":"2026090205581779800_cit2b","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1038\/nrd3554","article-title":"Interfering\nwith pH regulation in tumours as a therapeutic strategy","volume":"10","author":"Neri","year":"2011","journal-title":"Nature Rev. Drug Discovery"},{"key":"2026090205581779800_cit2c","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1038\/nrd2467","article-title":"Carbonic\nanhydrases: novel therapeutic applications for inhibitors and activators","volume":"7","author":"Supuran","year":"2008","journal-title":"Nature Rev. Drug Discovery"},{"key":"2026090205581779800_cit3a","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1093\/jnci\/93.4.266","article-title":"Tumor hypoxia: Definitions\nand current clinical, biologic, and molecular aspects","volume":"93","author":"Ho\u0308ckel","year":"2001","journal-title":"J. Natl. Cancer Inst."},{"key":"2026090205581779800_cit3b","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1007\/BF00055376","article-title":"Tumor hypoxia:\nits impact on cancer therapy","volume":"5","author":"Moulder","year":"1987","journal-title":"Cancer Metastasis\nRev."},{"key":"2026090205581779800_cit4","doi-asserted-by":"crossref","first-page":"84","DOI":"10.18632\/oncotarget.422","article-title":"Recent developments\nin targeting carbonic anhydrase IX for cancer therapeutics","volume":"3","author":"McDonald","year":"2012","journal-title":"Oncotarget"},{"key":"2026090205581779800_cit5a","doi-asserted-by":"crossref","first-page":"6905","DOI":"10.1021\/jm200892s","article-title":"Targeting hypoxic tumor cell viability with carbohydrate-based\ncarbonic anhydrase IX and XII inhibitors","volume":"54","author":"Morris","year":"2011","journal-title":"J.\nMed. Chem."},{"key":"2026090205581779800_cit5b","doi-asserted-by":"crossref","first-page":"4231","DOI":"10.1002\/anie.201310709","article-title":"A small-molecule drug\nconjugate for the treatment of carbonic anhydrase IX expressing tumors","volume":"53","author":"Krall","year":"2014","journal-title":"Angew. Chem., Int. Ed. Engl."},{"key":"2026090205581779800_cit6a","doi-asserted-by":"crossref","first-page":"6539","DOI":"10.1021\/jm060967z","article-title":"A novel class of carbonic anhydrase\ninhibitors: glycoconjugate benzene sulfonamides prepared by \u201cclick-tailing\u201d","volume":"49","author":"Wilkinson","year":"2006","journal-title":"J. Med. Chem."},{"key":"2026090205581779800_cit6b","doi-asserted-by":"crossref","first-page":"1651","DOI":"10.1021\/jm061320h","article-title":"Carbonic anhydrase\ninhibitors: inhibition of isozymes I, II, and IX with triazole-linked O-glycosides of benzene sulfonamides","volume":"50","author":"Wilkinson","year":"2007","journal-title":"J. Med. Chem."},{"key":"2026090205581779800_cit6c","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1016\/j.bmcl.2006.11.046","article-title":"Inhibition of membrane-associated carbonic anhydrase\nisozymes IX, XII and XIV with a library of glycoconjugate benzenesulfonamides","volume":"17","author":"Wilkinson","year":"2007","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"2026090205581779800_cit6d","doi-asserted-by":"crossref","first-page":"1945","DOI":"10.1021\/jm701426t","article-title":"Inhibition\nof carbonic anhydrases with glycosyltriazole benzene sulfonamides","volume":"51","author":"Wilkinson","year":"2008","journal-title":"J. Med. Chem."},{"key":"2026090205581779800_cit6e","doi-asserted-by":"crossref","first-page":"2913","DOI":"10.1021\/jm901888x","article-title":"Sulfonamide linked neoglycoconjugates\u2500a\nnew class of inhibitors for cancer-associated carbonic anhydrases","volume":"53","author":"Lopez","year":"2010","journal-title":"J. Med. Chem."},{"key":"2026090205581779800_cit6f","doi-asserted-by":"crossref","first-page":"2273","DOI":"10.1016\/j.bmcl.2009.02.086","article-title":"Inhibition of carbonic\nanhydrase isozymes with benzene sulfonamides incorporating thio, sulfinyl\nand sulfonyl glycoside moieties","volume":"19","author":"Singer","year":"2009","journal-title":"Bioorg. Med.\nChem. Lett."},{"key":"2026090205581779800_cit7a","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1002\/med.20141","article-title":"Therapeutic applications\nof glycosidic carbonic anhydrase inhibitors","volume":"29","author":"Winum","year":"2009","journal-title":"Med. Res. Rev."},{"key":"2026090205581779800_cit7b","doi-asserted-by":"crossref","first-page":"1419","DOI":"10.1016\/j.bmc.2012.10.043","article-title":"Glycosidic carbonic anhydrase IX inhibitors: a sweet\napproach against cancer","volume":"21","author":"Winum","year":"2013","journal-title":"Bioorg. Med. Chem."},{"key":"2026090205581779800_cit8a","doi-asserted-by":"crossref","first-page":"7210","DOI":"10.1016\/j.bmc.2013.08.033","article-title":"Structural study of interaction between\nbrinzolamide\nand dorzolamide inhibition of human carbonic anhydrases","volume":"21","author":"Pinard","year":"2013","journal-title":"Bioorg. Med. Chem."},{"key":"2026090205581779800_cit8b","doi-asserted-by":"crossref","first-page":"4421","DOI":"10.1021\/cr200176r","article-title":"Multiple binding modes of inhibitors\nto carbonic anhydrases: how to design specific drugs targeting 15\ndifferent isoforms?","volume":"112","author":"Alterio","year":"2012","journal-title":"Chem. Rev."},{"key":"2026090205581779800_cit8c","doi-asserted-by":"crossref","first-page":"759","DOI":"10.3109\/14756366.2012.672983","article-title":"Structure-based drug discovery of carbonic anhydrase\ninhibitors","volume":"27","author":"Supuran","year":"2012","journal-title":"J. Enzyme Inhib. Med. Chem."},{"key":"2026090205581779800_cit8d","doi-asserted-by":"crossref","first-page":"291","DOI":"10.4155\/9781909453913","volume-title":"Carbonic\nAnhydrase: Mechanism, Regulation, Links to Disease, And Industrial\nApplications","author":"Supuran","year":"2014"},{"key":"2026090205581779800_cit9a","doi-asserted-by":"crossref","first-page":"1481","DOI":"10.1021\/jm101525j","article-title":"Design, synthesis,\nand biological evaluation of novel carbohydrate-based sulfamates as\ncarbonic anhydrase inhibitors","volume":"54","author":"Lopez","year":"2011","journal-title":"J. Med. Chem."},{"key":"2026090205581779800_cit9b","doi-asserted-by":"crossref","first-page":"18452","DOI":"10.1021\/ja207855c","article-title":"Promiscuity\nof carbonic anhydrase II. Unexpected ester hydrolysis of carbohydrate-based\nsulfamate inhibitors","volume":"133","author":"Lopez","year":"2011","journal-title":"J. Am. Chem. Soc."},{"key":"2026090205581779800_cit10","doi-asserted-by":"crossref","first-page":"2507","DOI":"10.1021\/cr400230c","article-title":"Sulfamic acid\nand its N- and O- substituted derivatives","volume":"114","author":"Spillane","year":"2014","journal-title":"Chem. Rev."},{"key":"2026090205581779800_cit11","doi-asserted-by":"crossref","first-page":"2965","DOI":"10.1021\/jo2001269","article-title":"Synthesis of sulfonamide-bridged\nglycomimetics","volume":"76","author":"Lopez","year":"2011","journal-title":"J. Org. Chem."},{"key":"2026090205581779800_cit12","first-page":"1254","article-title":"Degradation\nof the reducing bioses. I. Direct determination of the constitution\nof cellobiose","volume":"59","author":"Zemple\u0301n","year":"1926","journal-title":"Ber. Dtsch. Chem. Ges."},{"key":"2026090205581779800_cit13","doi-asserted-by":"crossref","first-page":"7783","DOI":"10.1016\/j.tet.2005.05.103","article-title":"Colorimetric calcium-response\nof b-lactosylated m-oxo-bis-[5,15-meso-diphenylporphyrinatoiron(III)]","author":"Hasegawa","year":"2005","journal-title":"Tetrahedron"},{"key":"2026090205581779800_cit14","first-page":"1527","article-title":"Mild and chemoselcective\ndeacetylation method using a catalytic amount of acetyl chloride in\nmethanol","volume":"10","author":"Yeom","year":"2005","journal-title":"Synlett"},{"key":"2026090205581779800_cit15","doi-asserted-by":"crossref","first-page":"3187","DOI":"10.1016\/S0040-4039(01)00406-3","article-title":"A facile chemoselective deacetylation\nin presence of\nbenzoyl and p-bromobenzoyl groups using p-toluenesulfonic acid","volume":"42","author":"Gonza\u0301lez","year":"2001","journal-title":"Tetrahedron Lett."},{"key":"2026090205581779800_cit16a","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1016\/j.bmcl.2012.11.056","article-title":"Synthesis\nof acylated glycoconjugates as templates to investigate in vitro biopharmaceutical\nproperties","volume":"23","author":"Carroux","year":"2013","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"2026090205581779800_cit16b","doi-asserted-by":"crossref","first-page":"9623","DOI":"10.1021\/jm401163e","article-title":"A prodrug approach toward cancer-related\ncarbonic anhydrase inhibition","volume":"56","author":"Carroux","year":"2013","journal-title":"J. Med. Chem."},{"key":"2026090205581779800_cit17","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1158\/0008-5472.CAN-08-2470","article-title":"Hypoxia-inducible carbonic anhydrase\nIX and XII promote tumor cell growth by counteracting acidosis through\nthe regulation of the intracellular pH","volume":"69","author":"Chiche","year":"2009","journal-title":"Cancer\nRes."},{"key":"2026090205581779800_cit18","doi-asserted-by":"crossref","first-page":"1526","DOI":"10.1016\/j.bmc.2012.08.019","article-title":"Insights towards\nsulfonamide drug\nspecificity in alpha carbonic anhydrases","volume":"21","author":"Aggarwal","year":"2013","journal-title":"Bioorg.\nMed. Chem."},{"key":"2026090205581779800_cit19","doi-asserted-by":"crossref","first-page":"7961","DOI":"10.1016\/j.tetlet.2003.08.120","article-title":"Reaction of 1,2-trans-glycosyl acetates with thiourea: a new entry to 1-thiosugars","volume":"44","author":"Ibatullin","year":"2003","journal-title":"Tetrahedron Lett."},{"key":"2026090205581779800_cit20a","doi-asserted-by":"crossref","first-page":"7047","DOI":"10.1016\/S0040-4039(00)01130-8","article-title":"Efficient\ngeneral method for sulfamoylation of a hydroxyl group","volume":"41","author":"Okada","year":"2000","journal-title":"Tetrahedron Lett."},{"key":"2026090205581779800_cit20b","doi-asserted-by":"crossref","first-page":"5349","DOI":"10.1021\/jm800567v","article-title":"Inhibition of siderophore biosynthesis in Mycobacterium tuberculosis with nucleoside bisubstrate\nanalogues: structure\u2013activity relationships of the nucleobase\ndomain of 5\u2032-O-[N-(salicyl)sulfamoyl]adenosine","volume":"51","author":"Neres","year":"2008","journal-title":"J. Med. Chem."},{"key":"2026090205581779800_cit21","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.carres.2013.08.017","article-title":"Synthesis of sulfonamide-conjugated\nglycosyl-amino acid building blocks","volume":"386","author":"Lopez","year":"2014","journal-title":"Carbohydr.\nRes."},{"key":"2026090205581779800_cit22","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":"2026090205581779800_cit23","doi-asserted-by":"crossref","DOI":"10.1016\/S0076-6879(97)76066-X","volume-title":"Processing of X-ray Diffraction\nData Collected in Oscillation Mode","author":"Otwinowski","year":"1997"},{"key":"2026090205581779800_cit24","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1021\/bi902007b","article-title":"A short, strong hydrogen bond in\nthe active site of human carbonic anhydrase II","volume":"49","author":"Avvaru","year":"2010","journal-title":"Biochemistry"},{"key":"2026090205581779800_cit25","doi-asserted-by":"crossref","first-page":"8933","DOI":"10.1021\/ja049297h","article-title":"A simple method\nfor improving protein solubility and long-term stability","volume":"126","author":"Golovanov","year":"2004","journal-title":"J. Am. Chem. Soc."},{"key":"2026090205581779800_cit26a","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1107\/S0907444912000200","article-title":"Handling ligands with\nCoot","volume":"68","author":"Debreczeni","year":"2012","journal-title":"Acta Crystallogr., Sect. D: Biol. Crystallogr."},{"key":"2026090205581779800_cit26b","doi-asserted-by":"crossref","first-page":"2126","DOI":"10.1107\/S0907444904019158","article-title":"Coot: Model-building tools for molecular\ngraphics","volume":"60","author":"Emsley","year":"2004","journal-title":"Acta Crystallogr., Sect. D: Biol.\nCrystallogr."},{"key":"2026090205581779800_cit27","unstructured":"The PyMOL Molecular\nGraphics System, version\n1.5.0.4; Schro\u0308dinger, LLC."},{"key":"2026090205581779800_cit28","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","volume":"246","author":"Khalifah","year":"1971","journal-title":"J. Biol. Chem."},{"key":"2026090205581779800_cit29","doi-asserted-by":"crossref","first-page":"2811","DOI":"10.1021\/jo9000367","article-title":"Synthesis of S-glycosyl primary sulfonamides","volume":"74","author":"Lopez","year":"2009","journal-title":"J.\nOrg. Chem."},{"key":"2026090205581779800_cit30a","doi-asserted-by":"crossref","first-page":"2197","DOI":"10.1021\/jm021124k","article-title":"Carbonic anhydrase\ninhibitors: inhibition of cytosolic isozymes I and II and the membrane-bound,\ntumor associated isozyme IX with sulfamates also acting as steroid\nsulfatase inhibitors","volume":"46","author":"Winum","year":"2003","journal-title":"J. Med. Chem."},{"key":"2026090205581779800_cit30b","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1016\/j.bmcl.2004.12.053","article-title":"Carbonic anhydrase inhibitors. Inhibition of the transmembrane\nisozyme XII with sulfonamides\u2500a new target for the design of\nantitumor and antiglaucoma drugs?","volume":"15","author":"Vullo","year":"2005","journal-title":"Bioorg. Med.\nChem. Lett."}],"container-title":["Journal of Medicinal Chemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/jm5012935","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/jmcmar\/article-pdf\/57\/20\/8635\/15130807\/jm5012935.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/jmcmar\/article-pdf\/57\/20\/8635\/15130807\/jm5012935.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T09:58:27Z","timestamp":1788343107000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/jmcmar\/article\/57\/20\/8635\/1436380\/Structural-Insights-into-Carbonic-Anhydrase-IX"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,9,25]]},"references-count":50,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2014,9,25]]},"published-print":{"date-parts":[[2014,10,23]]}},"URL":"https:\/\/doi.org\/10.1021\/jm5012935","relation":{},"ISSN":["0022-2623","1520-4804"],"issn-type":[{"value":"0022-2623","type":"print"},{"value":"1520-4804","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,9,25]]}}}