{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,21]],"date-time":"2026-02-21T05:19:56Z","timestamp":1771651196346,"version":"3.50.1"},"reference-count":48,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2022,6,24]],"date-time":"2022-06-24T00:00:00Z","timestamp":1656028800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Ministry for University and Research (MIUR)","award":["prot. 2017XYBP2R"],"award-info":[{"award-number":["prot. 2017XYBP2R"]}]},{"name":"Italian Ministry for University and Research (MIUR)","award":["CRF2020.1395.(CTS)"],"award-info":[{"award-number":["CRF2020.1395.(CTS)"]}]},{"name":"Fondazione Cassa di Risparmio di Firenze","award":["prot. 2017XYBP2R"],"award-info":[{"award-number":["prot. 2017XYBP2R"]}]},{"name":"Fondazione Cassa di Risparmio di Firenze","award":["CRF2020.1395.(CTS)"],"award-info":[{"award-number":["CRF2020.1395.(CTS)"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>A series of new 3- and 7-substituted sulfocoumarins was obtained by several cyclization reactions and subsequent derivatization for screening as prodrug inhibitors of the human (h) cancer-associated carbonic anhydrases (CAs) IX and XII. All products were ineffective inhibitors against the off-target hCA I and II, whilst hCAs IX and XII were inhibited with inhibition constants (KIs) spanning from low nanomolar to the high micromolar range, according to the sulfocoumarin derivatization pattern. In particular, sulfocoumarin 15 turned out to be the most potent and selective inhibitor herein reported (hCA I and II: KI &gt; 100 \u00b5M; hCA IX: KI = 22.9 nM; hCA XII: KI = 19.2 nM). Considering that hCA IX and XII 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.<\/jats:p>","DOI":"10.3390\/molecules27134076","type":"journal-article","created":{"date-parts":[[2022,6,26]],"date-time":"2022-06-26T21:01:41Z","timestamp":1656277301000},"page":"4076","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Continued Structural Exploration of Sulfocoumarin as Selective Inhibitor of Tumor-Associated Human Carbonic Anhydrases IX and XII"],"prefix":"10.3390","volume":"27","author":[{"given":"Simone","family":"Giovannuzzi","sequence":"first","affiliation":[{"name":"Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, Sesto Fiorentino, 50019 Firenze, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3314-2411","authenticated-orcid":false,"given":"Clemente","family":"Capasso","sequence":"additional","affiliation":[{"name":"Istituto di Bioscienze e Biorisorse, CNR, Via Pietro Castellino 111, 80131 Napoli, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3342-702X","authenticated-orcid":false,"given":"Alessio","family":"Nocentini","sequence":"additional","affiliation":[{"name":"Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, Sesto Fiorentino, 50019 Firenze, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4262-0323","authenticated-orcid":false,"given":"Claudiu T.","family":"Supuran","sequence":"additional","affiliation":[{"name":"Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, Sesto Fiorentino, 50019 Firenze, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1038\/nrd2467","article-title":"Carbonic anhydrases: Novel therapeutic applications for inhibitors and activators","volume":"7","author":"Supuran","year":"2008","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"56","DOI":"10.3390\/metabo7040056","article-title":"An overview of the bacterial carbonic anhydrases","volume":"7","author":"Supuran","year":"2017","journal-title":"Metabolites"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2023","DOI":"10.1042\/BCJ20160115","article-title":"Structure and function of carbonic anhydrases","volume":"473","author":"Supuran","year":"2016","journal-title":"Biochem. J."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1038\/nrd3554","article-title":"Interfering with pH regulation in tumours as a therapeutic strategy","volume":"10","author":"Neri","year":"2011","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.4155\/fmc.11.69","article-title":"Carbonic anhydrase inhibitors and activators for novel therapeutic applications","volume":"3","author":"Supuran","year":"2011","journal-title":"Future Med. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1080\/13543784.2018.1548608","article-title":"Carbonic anhydrase inhibitors as emerging agents for the treatment and imaging of hypoxic tumors","volume":"27","author":"Supuran","year":"2018","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"603","DOI":"10.2147\/JEP.S265620","article-title":"Experimental Carbonic Anhydrase Inhibitors for the Treatment of Hypoxic Tumors","volume":"12","author":"Supuran","year":"2020","journal-title":"J. Exp. Pharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"4421","DOI":"10.1021\/cr200176r","article-title":"Multiple binding modes of inhibitors to carbonic anhydrases: How to design specific drugs targeting 15 different isoforms?","volume":"112","author":"Alterio","year":"2012","journal-title":"Chem. Rev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1080\/17460441.2017.1253677","article-title":"Advances in structure-based drug discovery of carbonic anhydrase inhibitors","volume":"12","author":"Supuran","year":"2017","journal-title":"Expert Opin. Drug Discov."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"138","DOI":"10.3109\/14756366.2011.597749","article-title":"A new approach to antiglaucoma drugs: Carbonic anhydrase inhibitors with or without NO donating moieties. Mechanism of action and preliminary pharmacology","volume":"27","author":"Fabrizi","year":"2012","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1080\/13543784.2021.2014813","article-title":"Carbonic anhydrase inhibitors: An update on experimental agents for the treatment and imaging of hypoxic tumors","volume":"30","author":"Supuran","year":"2021","journal-title":"Expert Opin Investig Drugs."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Nerella, S.G., Singh, P., Arifuddin, M., and Supuran, C.T. (2022). Anticancer carbonic anhydrase inhibitors: A patent and literature update 2018-2022. Expert Opin. Ther. Pat., in press.","DOI":"10.1080\/13543776.2022.2083502"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1021\/jm901287j","article-title":"Deciphering the mechanism of carbonic anhydrase inhibition with coumarins and thiocoumarins","volume":"53","author":"Maresca","year":"2010","journal-title":"J. Med. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3364","DOI":"10.1158\/0008-5472.CAN-10-4261","article-title":"Targeting Tumor Hypoxia: Suppression of Breast Tumor Growth and Metastasis by Novel Carbonic Anhydrase IX Inhibitors","volume":"71","author":"Lou","year":"2011","journal-title":"Cancer Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"8271","DOI":"10.1021\/jm200983e","article-title":"Glycosyl coumarin carbonic anhydrase IX and XII inhibitors strongly attenuate the growth of primary breast tumors","volume":"54","author":"Touisni","year":"2011","journal-title":"J. Med. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1539","DOI":"10.1016\/j.bmc.2012.07.021","article-title":"Natural product coumarins that inhibit human carbonic anhydrases","volume":"21","author":"Davis","year":"2013","journal-title":"Bioorg. Med. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3063","DOI":"10.1016\/j.bmcl.2012.03.071","article-title":"Flavones and structurally related 4-chromenones inhibit carbonic anhydrases by a different mechanism of action compared to coumarins","volume":"22","author":"Balboni","year":"2012","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"105920","DOI":"10.1016\/j.bioorg.2022.105920","article-title":"A decade of tail-approach based design of selective as well as potent tumor associated carbonic anhydrase inhibitors","volume":"126","author":"Kumar","year":"2022","journal-title":"Bioorg Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1080\/14756366.2021.1882453","article-title":"Reconsidering anion inhibitors in the general context of drug design studies of modulators of activity of the classical enzyme carbonic anhydrase","volume":"36","author":"Nocentini","year":"2021","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.ejmech.2018.01.033","article-title":"Structural investigations on coumarins leading to chromeno[4,3-c]pyrazol-4-ones and pyrano[4,3-c]pyrazol-4-ones: New scaffolds for the design of the tumor-associated carbonic anhydrase isoforms IX and XII","volume":"146","author":"Bonardi","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1578","DOI":"10.1002\/cmdc.201700446","article-title":"Sulfocoumarin-, coumarin-, 4-sulfamoylphenyl-bearing indazole-3-carboxamide hybrids: Synthesis and selective inhibition of tumor-associated carbonic anhydrase isozymes IX and XII","volume":"12","author":"Angapelly","year":"2017","journal-title":"ChemMedChem"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Giovannuzzi, S., D\u2019Ambrosio, M., Luceri, C., Osman, S.M., Pallecchi, M., Bartolucci, G., Nocentini, A., and Supuran, C.T. (2021). Aromatic Sulfonamides including a Sulfonic Acid Tail: New Membrane Impermeant Carbonic Anhydrase Inhibitors for Targeting Selectively the Cancer-Associated Isoforms. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23010461"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1016\/j.bmc.2016.11.039","article-title":"Coumarins and other fused bicyclic heterocycles with selective tumor-associated carbonic anhydrase isoforms inhibitory activity","volume":"25","author":"Bozdag","year":"2017","journal-title":"Bioorg. Med. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1021\/ml500470b","article-title":"a-Carbonic anhydrases possess thioesterase activity","volume":"6","author":"Tanc","year":"2015","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"292","DOI":"10.3109\/14756366.2013.777334","article-title":"Novel coumarins and benzocoumarins acting as isoform-selective inhibitors against the tumor-associated carbonic anhydrase IX","volume":"2","author":"Sharma","year":"2014","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/j.bmcl.2011.11.018","article-title":"5- and 6-membered (thio)lactones are prodrug type carbonic anhydrase inhibitors","volume":"22","author":"Carta","year":"2012","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"773","DOI":"10.3109\/14756366.2014.970185","article-title":"7-Amino-3,4-dihydro-1H-quinoline-2-one, a compound similar to the substituted coumarins, inhibits a-carbonic anhydrases without hydrolysis of the lactam ring","volume":"30","author":"Isik","year":"2015","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1080\/14756366.2017.1337759","article-title":"Carbonic anhydrase I, II, IV and IX inhibition with a series of 7-amino-3,4-dihydroquinolin-2(1H)-one derivatives","volume":"32","author":"Bozdag","year":"2017","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1021\/jm301625s","article-title":"Sulfocoumarins (1,2-benzoxathiine-2,2-dioxides): A class of potent and isoform-selective inhibitors of tumor-associated carbonic anhydrases","volume":"56","author":"Tars","year":"2013","journal-title":"J. Med. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1021\/acs.jmedchem.5b01720","article-title":"Thioxocoumarins show an alternative carbonic anhydrase inhibition mechanism compared to coumarins","volume":"59","author":"Ferraroni","year":"2016","journal-title":"J. Med. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1522","DOI":"10.1016\/j.bmc.2014.01.043","article-title":"Synthesis of 6-tetrazolyl-substituted sulfocoumarins acting as highly potent and selective inhibitors of the tumor-associated carbonic anhydrase isoforms IX and XII","volume":"22","author":"Grandane","year":"2014","journal-title":"Bioorg. Med. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1256","DOI":"10.1016\/j.bmcl.2014.01.076","article-title":"6-Triazolyl-substituted sulfocoumarins are potent, selective inhibitors of the tumor-associated carbonic anhydrases IX and XII","volume":"24","author":"Grandane","year":"2014","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1430","DOI":"10.1016\/j.bmc.2015.02.023","article-title":"Synthesis of 6-aryl-substituted sulfocoumarins and investigation of their carbonic anhydrase inhibitory action","volume":"23","author":"Grandane","year":"2015","journal-title":"Bioorg. Med. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1039\/C4OB02155J","article-title":"6-Substituted 1,2-benzoxathiine-2,2-dioxides are isoformselective inhibitors of human carbonic anhydrases IX, XII and VA","volume":"13","author":"Tanc","year":"2015","journal-title":"Org. Biomol. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3975","DOI":"10.1021\/acs.jmedchem.5b00523","article-title":"6-Substituted sulfocoumarins are selective carbonic anhdydrase IX and XII inhibitors with significant cytotoxicity against colorectal cancer cells","volume":"58","author":"Grandane","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1226","DOI":"10.3109\/14756366.2015.1115401","article-title":"7-Aryl-triazolyl-substituted sulfocoumarins are potent, selective inhibitors of the tumor-associated carbonic anhydrase IX and XII","volume":"31","author":"Nocentini","year":"2016","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"7840","DOI":"10.1002\/chem.201800941","article-title":"Deciphering the mechanism of human carbonic anhydrases inhibition with sulfocoumarins: Computational and experimental studies","volume":"24","author":"Nocentini","year":"2018","journal-title":"Chemistry"},{"key":"ref_38","first-page":"484","article-title":"A Phase 1 Study of SLC-0111, a Novel Inhibitor of Carbonic Anhydrase IX, in Patients with Advanced Solid Tumors, Am","volume":"43","author":"McDonald","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2864","DOI":"10.3390\/molecules18032864","article-title":"Synthesis and cytotoxicity of novel 10-substituted dihydroartemisinin derivatives containing N-arylphenyl-ethenesulfonamide groups","volume":"18","author":"Liu","year":"2013","journal-title":"Molecules"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1896","DOI":"10.1021\/jm101541x","article-title":"Ureido-substituted benzenesulfonamides potently inhibit carbonic anhydrase IX and show antimetastatic activity in a model of breast cancer metastasis","volume":"54","author":"Pacchiano","year":"2011","journal-title":"J. Med. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1080\/14756366.2017.1316720","article-title":"3H-1,2-benzoxathiepine 2,2-dioxides: A new class of isoform-selective carbonic anhydrase inhibitors","volume":"32","author":"Pustenko","year":"2017","journal-title":"J. Enzyme. Inhib. Med. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1016\/j.radonc.2011.05.045","article-title":"Specific inhibition of carbonic anhydrase IX activity enhances the in vivo therapeutic effect of tumor irradiation","volume":"99","author":"Dubois","year":"2011","journal-title":"Radiother. Oncol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1080\/14756366.2020.1722658","article-title":"7-Acylamino-3H-1,2-benzoxathiepine 2,2-dioxides as new isoform-selective carbonic anhydrase IX and XII inhibitors","volume":"35","author":"Pustenko","year":"2020","journal-title":"J. Enzyme. Inhib. Med. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2561","DOI":"10.1016\/S0021-9258(18)62326-9","article-title":"The carbon dioxide hydration activity of carbonic anhydrase. I. Stop-flow kinetic studies on the native human isoenzymes B and C","volume":"246","author":"Khalifah","year":"1971","journal-title":"J. Biol. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1022","DOI":"10.1021\/acsmedchemlett.0c00094","article-title":"Benzofuran-Based Carboxylic Acids as Carbonic Anhydrase Inhibitors and Antiproliferative Agents against Breast Cancer","volume":"11","author":"Eldehna","year":"2020","journal-title":"CS Med. Chem. Lett."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"5801","DOI":"10.1016\/j.bmcl.2012.07.094","article-title":"Inhibition of a-class cytosolic human carbonic anhydrases I, II, IX and XII, and b-class fungal enzymes by carboxylic acids and their derivatives: New isoform-I selective nanomolar inhibitors","volume":"22","author":"Sechi","year":"2012","journal-title":"Med. Chem. Lett."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"7422","DOI":"10.1021\/acs.jmedchem.0c00733","article-title":"Sulfonamide Inhibitors of Human Carbonic Anhydrases Designed through a Three-Tails Approach: Improving Ligand\/Isoform Matching and Selectivity of Action","volume":"63","author":"Bonardi","year":"2020","journal-title":"J. Med. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"112112","DOI":"10.1016\/j.ejmech.2020.112112","article-title":"Inclusion of a 5-fluorouracil moiety in nitrogenous bases derivatives as human carbonic anhydrase IX and XII inhibitors produced a targeted action against MDA-MB-231 and T47D breast cancer cells","volume":"190","author":"Petreni","year":"2020","journal-title":"Eur. J. Med. Chem."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/13\/4076\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:39:35Z","timestamp":1760139575000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/13\/4076"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,24]]},"references-count":48,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2022,7]]}},"alternative-id":["molecules27134076"],"URL":"https:\/\/doi.org\/10.3390\/molecules27134076","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,24]]}}}