title: PEGylated Bis-Sulfonamide Carbonic Anhydrase Inhibitors Can Efficiently Control the Growth of Several Carbonic Anhydrase IX-Expressing Carcinomas.
abstract: A series of aromatic/heterocyclic bis-sulfonamides were synthesized from three established aminosulfonamide carbonic anhydrase (CA, EC 4.2.1.1) 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.
authors.affiliation: 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.
authors.forename: Suleyman
authors.initials: S
authors.lastname: Akocak
authors.affiliation: 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.
authors.forename: M Raqibul
authors.initials: MR
authors.lastname: Alam
authors.affiliation: 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.
authors.forename: Ahmed M
authors.initials: AM
authors.lastname: Shabana
authors.affiliation: 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.
authors.forename: Rajesh Kishore Kumar
authors.initials: RK
authors.lastname: Sanku
authors.affiliation: NEUROFARBA Department, Pharmaceutical Sciences Section, Universita degli Studi di Firenze, Polo Scientifico , Via Ugo Schiff no. 6, 50019 Sesto Fiorentino (Florence), Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Vullo
authors.affiliation: 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.
authors.forename: Harry
authors.initials: H
authors.lastname: Thompson
authors.affiliation: Medical Service, VA Puget Sound Health Care System, University of Washington , Seattle, Washington 98195, United States.
authors.forename: Erik R
authors.initials: ER
authors.lastname: Swenson
authors.affiliation: NEUROFARBA Department, Pharmaceutical Sciences Section, Universita degli Studi di Firenze, Polo Scientifico , Via Ugo Schiff no. 6, 50019 Sesto Fiorentino (Florence), Italy.
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
authors.affiliation: 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.
authors.forename: Marc A
authors.initials: MA
authors.lastname: Ilies
mesh_terms: D000951:Antigens, Neoplasm / Q000378:metabolism; D000071231:Carbonic Anhydrase IX / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011092:Polyethylene Glycols / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000951:Antigens, Neoplasm; D002257:Carbonic Anhydrase Inhibitors; D011092:Polyethylene Glycols; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX