{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T16:57:55Z","timestamp":1789577875735,"version":"build-2803163510"},"reference-count":54,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,1,27]],"date-time":"2023-01-27T00:00:00Z","timestamp":1674777600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004271","name":"\u201cSapienza\u201d Ateneo 2019","doi-asserted-by":"publisher","award":["1428312"],"award-info":[{"award-number":["1428312"]}],"id":[{"id":"10.13039\/501100004271","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Solid tumors are active tissues containing hypoxic regions and producing metabolic acids. By decreasing pH, cancer cells create a hostile environment for surrounding host cells and foster tumor growth and progression. By governing acid\/base regulation, carbonic anhydrases (CAs) are involved in several physiological\/pathological processes, including tumors. Indeed, CAs are clinically relevant in cancer therapy as among the fifteen human isoforms, two of them, namely CA IX (overexpressed in solid tumors and associated with increased metastasis and poor prognosis) and CA XII (overexpressed in some tumors) are involved in tumorigenesis. Targeting these two isoforms is considered as a pertinent approach to develop new cancer therapeutics. Several CA inhibitors (CAIs) have been described, even though they are unselective inhibitors of different isoforms. Thus, efforts are needed to find new selective CAIs. In this work, we described new diketo acid derivatives as CAIs, with the best acting compounds 1c and 5 as nanomolar inhibitors of CA IX and XII, being also two orders of magnitude selective over CAs I and II. Molecular modeling studies showed the different binding poses of the best acting CAIs within CA II and IX, highlighting the key structural features that could confer the ability to establish specific interactions within the enzymes. In different tumor cell lines overexpressing CA IX and XII, the tested compounds showed antiproliferative activity already at 24 h treatment, with no effects on somatic not transformed cells.<\/jats:p>","DOI":"10.3390\/ph16020188","type":"journal-article","created":{"date-parts":[[2023,1,30]],"date-time":"2023-01-30T02:54:37Z","timestamp":1675047277000},"page":"188","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Pyrrolyl and Indolyl \u03b1-\u03b3-Diketo Acid Derivatives Acting as Selective Inhibitors of Human Carbonic Anhydrases IX and XII"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4672-2936","authenticated-orcid":false,"given":"Davide","family":"Ialongo","sequence":"first","affiliation":[{"name":"Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza University of Rome, p.le Aldo Moro 5, I-00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonella","family":"Messore","sequence":"additional","affiliation":[{"name":"Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza University of Rome, p.le Aldo Moro 5, I-00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5724-612X","authenticated-orcid":false,"given":"Valentina Noemi","family":"Madia","sequence":"additional","affiliation":[{"name":"Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza University of Rome, p.le Aldo Moro 5, I-00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Tudino","sequence":"additional","affiliation":[{"name":"Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza University of Rome, p.le Aldo Moro 5, I-00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3342-702X","authenticated-orcid":false,"given":"Alessio","family":"Nocentini","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Modeling Cheminformatics & QSAR, NEUROFARBA Department, University of Florence, Via U. 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Schiff 6, Sesto Fiorentino, 50019 Firenze, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4262-0323","authenticated-orcid":false,"given":"Claudiu T.","family":"Supuran","sequence":"additional","affiliation":[{"name":"NEUROFARBA Department, Pharmaceutical and Nutraceutical Section, University of Florence, Via U. Schiff 6, Sesto Fiorentino, 50019 Firenze, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice","family":"Nicolai","sequence":"additional","affiliation":[{"name":"Dipartimento Medicina Sperimentale, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3169-3968","authenticated-orcid":false,"given":"Susanna","family":"Scarpa","sequence":"additional","affiliation":[{"name":"Dipartimento Medicina Sperimentale, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0354-894X","authenticated-orcid":false,"given":"Samanta","family":"Taurone","sequence":"additional","affiliation":[{"name":"Department of Movement, Human and Health Sciences, Division of Health Sciences, University of Rome \u201cForo Italico\u201d, 00135 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele","family":"Camarda","sequence":"additional","affiliation":[{"name":"Department of Sensory Organs, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8786-7007","authenticated-orcid":false,"given":"Marco","family":"Artico","sequence":"additional","affiliation":[{"name":"Department of Sensory Organs, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9995-1097","authenticated-orcid":false,"given":"Veronica","family":"Papa","sequence":"additional","affiliation":[{"name":"Department of Motor Sciences and Wellness, University of Naples \u201cPartenope\u201d, 80133 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Saccoliti","sequence":"additional","affiliation":[{"name":"D3 PharmaChemistry, Italian Institute of Technology, Via Morego 30, 16163 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2006-7005","authenticated-orcid":false,"given":"Luigi","family":"Scipione","sequence":"additional","affiliation":[{"name":"Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza University of Rome, p.le Aldo Moro 5, I-00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4279-7666","authenticated-orcid":false,"given":"Roberto","family":"Di Santo","sequence":"additional","affiliation":[{"name":"Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza University of Rome, p.le Aldo Moro 5, I-00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Costi","sequence":"additional","affiliation":[{"name":"Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza University of Rome, p.le Aldo Moro 5, I-00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"15184","DOI":"10.1073\/pnas.96.26.15184","article-title":"Carbonic anhydrase is an ancient enzyme widespread in prokaryotes","volume":"96","author":"Smith","year":"1999","journal-title":"Proc. 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