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J Med Chem. 2016 May 26;59(10):5077-88. doi: 10.1021/acs.jmedchem.6b00492. Epub 2016 May 10.

PEGylated Bis-Sulfonamide Carbonic Anhydrase Inhibitors Can Efficiently Control the Growth of Several Carbonic Anhydrase IX-Expressing Carcinomas.

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Department of Pharmaceutical Sciences and Molder Center for Drug Discovery Research, Temple University School of Pharmacy , 3307 N Broad Street, Philadelphia, Pennsylvania 19140, United States.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Adiyaman University , 02040 Adiyaman, Turkey.
NEUROFARBA Department, Pharmaceutical Sciences Section, Universita degli Studi di Firenze, Polo Scientifico , Via Ugo Schiff no. 6, 50019 Sesto Fiorentino (Florence), Italy.
Medical Service, VA Puget Sound Health Care System, University of Washington , Seattle, Washington 98195, United States.


A series of aromatic/heterocyclic bis-sulfonamides were synthesized from three established aminosulfonamide carbonic anhydrase (CA, EC inhibitor pharmacophores, coupled with either ethylene glycol oligomeric or polymeric diamines to yield bis-sulfonamides with short or long (polymeric) linkers. Testing of novel inhibitors and their precursors against a panel of membrane-bound CA isoforms, including tumor-overexpressed CA IX and XII and cytosolic isozymes, identified nanomolar-potent inhibitors against both classes and several compounds with medium isoform selectivity in a detailed structure-activity relationship study. The ability of CA inhibitors to kill tumor cells overexpressing CA IX and XII was tested under normoxic and hypoxic conditions, using 2D and 3D in vitro cellular models. The study identified a nanomolar potent PEGylated bis-sulfonamide CA inhibitor (25) able to significantly reduce the viability of colon HT-29, breast MDA-MB231, and ovarian SKOV-3 cancer cell lines, thus revealing the potential of polymer conjugates in CA inhibition and cancer treatment.

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