{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T02:39:05Z","timestamp":1790476745905,"version":"4.1.0"},"reference-count":43,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2020,5,18]],"date-time":"2020-05-18T00:00:00Z","timestamp":1589760000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","award":["ERC-ADG-2015, no. 694812 \u2013 Hypoximmuno"],"award-info":[{"award-number":["ERC-ADG-2015, no. 694812 \u2013 Hypoximmuno"]}],"id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010663","name":"H2020 European Research Council","doi-asserted-by":"publisher","award":["ImmunoSABR - n\u00b0 733008"],"award-info":[{"award-number":["ImmunoSABR - n\u00b0 733008"]}],"id":[{"id":"10.13039\/100010663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100013297","name":"Eurostars","doi-asserted-by":"publisher","award":["COMPACT-12053"],"award-info":[{"award-number":["COMPACT-12053"]}],"id":[{"id":"10.13039\/100013297","id-type":"DOI","asserted-by":"publisher"}]},{"name":"French Ministry of Europe and Foreign Affairs \/ Dutch Organisation for Internationalisation in Education","award":["PHC Van Gogh 42528YH"],"award-info":[{"award-number":["PHC Van Gogh 42528YH"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Hypoxia, a common feature of solid tumours\u2019 microenvironment, is associated with an aggressive phenotype and is known to cause resistance to anticancer chemo- and radiotherapies. Tumour-associated carbonic anhydrases isoform IX (hCA IX), which is upregulated under hypoxia in many malignancies participating to the microenvironment acidosis, represents a valuable target for drug strategy against advanced solid tumours. To overcome cancer cell resistance and improve the efficacy of therapeutics, the use of bio-reducible prodrugs also known as Hypoxia-activated prodrugs (HAPs), represents an interesting strategy to be applied to target hCA IX isozyme through the design of selective carbonic anhydrase IX inhibitors (CAIs). Here, we report the design, synthesis and biological evaluations including CA inhibition assays, toxicity assays on zebrafish and viability assays on human cell lines (HT29 and HCT116) of new HAP-CAIs, harboring different bio-reducible moieties in nitroaromatic series and a benzenesulfonamide warhead to target hCA IX. The CA inhibition assays of this compound series showed a slight selectivity against hCA IX versus the cytosolic off-target hCA II and hCA I isozymes. Toxicity and viability assays have highlighted that the compound bearing the 2-nitroimidazole moiety possesses the lowest toxicity (LC50 of 1400 \u00b5M) and shows interesting results on viability assays.<\/jats:p>","DOI":"10.3390\/molecules25102347","type":"journal-article","created":{"date-parts":[[2020,5,20]],"date-time":"2020-05-20T10:37:38Z","timestamp":1589971058000},"page":"2347","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Hypoxia-Activated Prodrug Derivatives of Carbonic Anhydrase Inhibitors in Benzenesulfonamide Series: Synthesis and Biological Evaluation"],"prefix":"10.3390","volume":"25","author":[{"given":"Emilie","family":"Anduran","sequence":"first","affiliation":[{"name":"Institut des Biomol\u00e9cules Max Mousseron (IBMM) UMR 5247 CNRS, ENSCM, Universit\u00e9 de Montpellier, 34296 Montpellier CEDEX 05, France"},{"name":"The M-Lab, Department of Precision Medicine, GROW\u2013School for Oncology, Maastricht University, 6200 MD Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6938-7835","authenticated-orcid":false,"given":"Ashok","family":"Aspatwar","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Health Technology and Fimlab Ltd., University of Tampere and Tampere University Hospital, 33520 Tampere, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nanda-Kumar","family":"Parvathaneni","sequence":"additional","affiliation":[{"name":"Institut des Biomol\u00e9cules Max Mousseron (IBMM) UMR 5247 CNRS, ENSCM, Universit\u00e9 de Montpellier, 34296 Montpellier CEDEX 05, France"},{"name":"The M-Lab, Department of Precision Medicine, GROW\u2013School for Oncology, Maastricht University, 6200 MD Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis","family":"Suylen","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, 6200 MD Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Bua","sequence":"additional","affiliation":[{"name":"Neurofarba Department, Section of Pharmaceutical Sciences, Universit\u00e0 degli Studi di Firenze, 50019 Sesto Fiorentino (Florence), 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":"Neurofarba Department, Section of Pharmaceutical Sciences, Universit\u00e0 degli Studi di Firenze, 50019 Sesto Fiorentino (Florence), Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seppo","family":"Parkkila","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Health Technology and Fimlab Ltd., University of Tampere and Tampere University Hospital, 33520 Tampere, Finland"}],"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, Section of Pharmaceutical Sciences, Universit\u00e0 degli Studi di Firenze, 50019 Sesto Fiorentino (Florence), Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8887-4137","authenticated-orcid":false,"given":"Ludwig","family":"Dubois","sequence":"additional","affiliation":[{"name":"The M-Lab, Department of Precision Medicine, GROW\u2013School for Oncology, Maastricht University, 6200 MD Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7961-0191","authenticated-orcid":false,"given":"Philippe","family":"Lambin","sequence":"additional","affiliation":[{"name":"The M-Lab, Department of Precision Medicine, GROW\u2013School for Oncology, Maastricht University, 6200 MD Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3197-3414","authenticated-orcid":false,"given":"Jean-Yves","family":"Winum","sequence":"additional","affiliation":[{"name":"Institut des Biomol\u00e9cules Max Mousseron (IBMM) UMR 5247 CNRS, ENSCM, Universit\u00e9 de Montpellier, 34296 Montpellier CEDEX 05, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,5,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1007\/s00109-020-01874-2","article-title":"Clinical implications of intratumor heterogeneity: Challenges and opportunities","volume":"98","author":"Cajal","year":"2020","journal-title":"J. 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