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Open AccessArticle

Hypoxia-Activated Prodrug Derivatives of Carbonic Anhydrase Inhibitors in Benzenesulfonamide Series: Synthesis and Biological Evaluation

1
Institut des Biomolécules Max Mousseron (IBMM) UMR 5247 CNRS, ENSCM, Université de Montpellier, 34296 Montpellier CEDEX 05, France
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The M-Lab, Department of Precision Medicine, GROW–School for Oncology, Maastricht University, 6200 MD Maastricht, The Netherlands
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Faculty of Medicine and Health Technology and Fimlab Ltd., University of Tampere and Tampere University Hospital, 33520 Tampere, Finland
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Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, 6200 MD Maastricht, The Netherlands
5
Neurofarba Department, Section of Pharmaceutical Sciences, Università degli Studi di Firenze, 50019 Sesto Fiorentino (Florence), Italy
*
Authors to whom correspondence should be addressed.
Academic Editors: Fabrizio Carta and Andrea Angeli
Molecules 2020, 25(10), 2347; https://doi.org/10.3390/molecules25102347
Received: 29 April 2020 / Revised: 13 May 2020 / Accepted: 14 May 2020 / Published: 18 May 2020
Hypoxia, a common feature of solid tumours’ 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 µM) and shows interesting results on viability assays. View Full-Text
Keywords: hypoxia-activated prodrug; carbonic anhydrase; inhibitors; sulfonamides; hypoxic tumour hypoxia-activated prodrug; carbonic anhydrase; inhibitors; sulfonamides; hypoxic tumour
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Anduran, E.; Aspatwar, A.; Parvathaneni, N.-K.; Suylen, D.; Bua, S.; Nocentini, A.; Parkkila, S.; Supuran, C.T.; Dubois, L.; Lambin, P.; Winum, J.-Y. Hypoxia-Activated Prodrug Derivatives of Carbonic Anhydrase Inhibitors in Benzenesulfonamide Series: Synthesis and Biological Evaluation. Molecules 2020, 25, 2347.

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