{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T14:30:35Z","timestamp":1787063435789,"version":"build-2736575974"},"reference-count":49,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2020,4,10]],"date-time":"2020-04-10T00:00:00Z","timestamp":1586476800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004434","name":"Universit\u00e0 degli Studi di Firenze","doi-asserted-by":"publisher","award":["Fondo Ricerca Ateneo RICATEN17"],"award-info":[{"award-number":["Fondo Ricerca Ateneo RICATEN17"]}],"id":[{"id":"10.13039\/501100004434","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004434","name":"Universit\u00e0 degli Studi di Firenze","doi-asserted-by":"publisher","award":["Fondo Ricerca Ateneo RICATEN18"],"award-info":[{"award-number":["Fondo Ricerca Ateneo RICATEN18"]}],"id":[{"id":"10.13039\/501100004434","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>A new series of N,N-bis(alkanol)amine aryl diesters was synthesized and studied as dual P-glycoprotein (P-gp) and carbonic anhydrase XII inhibitors (CA XII). These hybrids should be able to synergistically overcome P-gp mediated multidrug resistance (MDR) in cancer cells. It was reported that the efflux activity of P-gp could be modulated by CA XII, as the pH reduction caused by CA XII inhibition produces a significant decrease in P-gp ATPase activity. The new compounds reported here feature both P-gp and CA XII binding moieties. These hybrids contain a N,N-bis(alkanol)amine diester scaffold found in P-glycoprotein ligands and a coumarin or benzene sulfonamide moiety to target CA XII. Many compounds displayed a dual activity against P-gp and CA XII being active in the Rhd 123 uptake test on K562\/DOX cells and in the hCA XII inhibition test. On LoVo\/DOX cells, that overexpress both P-gp and CA XII, some coumarin derivatives showed a high MDR reversal effect in Rhd 123 uptake and doxorubicin cytotoxicity enhancement tests. In particular, compounds 7 and 8 showed higher activity than verapamil and were more potent on LoVo\/DOX than on K562\/DOX cells overexpressing only P-gp. They can be considered as valuable candidates for selective P-gp\/CA XII inhibition in MDR cancer cells.<\/jats:p>","DOI":"10.3390\/molecules25071748","type":"journal-article","created":{"date-parts":[[2020,4,14]],"date-time":"2020-04-14T03:10:01Z","timestamp":1586833801000},"page":"1748","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["Dual P-Glycoprotein and CA XII Inhibitors: A New Strategy to Reverse the P-gp Mediated Multidrug Resistance (MDR) in Cancer Cells"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9705-3875","authenticated-orcid":false,"given":"Elisabetta","family":"Teodori","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Psychology, Drug Research and Child\u2019s Health\u2013Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, via Ugo Schiff 6, 50019 Sesto Fiorentino (FI), Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0861-0706","authenticated-orcid":false,"given":"Laura","family":"Braconi","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Psychology, Drug Research and Child\u2019s Health\u2013Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, via Ugo Schiff 6, 50019 Sesto Fiorentino (FI), Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Bua","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Psychology, Drug Research and Child\u2019s Health\u2013Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, via Ugo Schiff 6, 50019 Sesto Fiorentino (FI), Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Lapucci","sequence":"additional","affiliation":[{"name":"Department of Health Sciences\u2014Section of Clinical Pharmacology and Oncology, University of Florence, Viale Pieraccini 6, 50139 Firenze, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5631-8769","authenticated-orcid":false,"given":"Gianluca","family":"Bartolucci","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Psychology, Drug Research and Child\u2019s Health\u2013Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, via Ugo Schiff 6, 50019 Sesto Fiorentino (FI), Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dina","family":"Manetti","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Psychology, Drug Research and Child\u2019s Health\u2013Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, via Ugo Schiff 6, 50019 Sesto Fiorentino (FI), Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5685-3403","authenticated-orcid":false,"given":"Maria Novella","family":"Romanelli","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Psychology, Drug Research and Child\u2019s Health\u2013Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, via Ugo Schiff 6, 50019 Sesto Fiorentino (FI), Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0898-7148","authenticated-orcid":false,"given":"Silvia","family":"Dei","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Psychology, Drug Research and Child\u2019s Health\u2013Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, via Ugo Schiff 6, 50019 Sesto Fiorentino (FI), 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":"Department of Neuroscience, Psychology, Drug Research and Child\u2019s Health\u2013Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, via Ugo Schiff 6, 50019 Sesto Fiorentino (FI), Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcella","family":"Coronnello","sequence":"additional","affiliation":[{"name":"Department of Health Sciences\u2014Section of Clinical Pharmacology and Oncology, University of Florence, Viale Pieraccini 6, 50139 Firenze, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,4,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1038\/nrc3599","article-title":"Cancer drug resistance: An evolving paradigm","volume":"13","author":"Holohan","year":"2013","journal-title":"Nat. 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