title: Hypoxia-targeting carbonic anhydrase IX inhibitors by a new series of nitroimidazole-sulfonamides/sulfamides/sulfamates.
abstract: A series of nitroimidazoles incorporating sulfonamide/sulfamide/sulfamate moieties were designed and synthesized as radio/chemosensitizing agent targeting the tumor-associated carbonic anhydrase (CA) isoforms IX and XII. Most of the new compounds were nanomolar inhibitors of these isoforms. Crystallographic studies on the complex of hCA II with the lead sulfamide derivative of this series clarified the binding mode of this type of inhibitors in the enzyme active site cavity. Some of the best nitroimidazole CA IX inhibitors showed significant activity in vitro by reducing hypoxia-induced extracellular acidosis in HT-29 and HeLa cell lines. In vivo testing of the lead molecule in the sulfamide series, in cotreatment with doxorubicin, demonstrated a chemosensitization of CA IX containing tumors. Such CA inhibitors, specifically targeting the tumor-associated isoforms, are candidates for novel treatment strategies against hypoxic tumors overexpressing extracellular CA isozymes.
authors.affiliation: Institut des Biomolécules Max Mousseron (IBMM) UMR 5247 CNRS-UM1-UM2 Bâtiment de Recherche Max Mousseron, Ecole Nationale Supérieure de Chimie de Montpellier , 8 rue de l'Ecole Normale, 34296 Montpellier Cedex, France.
authors.forename: Marouan
authors.initials: M
authors.lastname: Rami
authors.forename: Ludwig
authors.initials: L
authors.lastname: Dubois
authors.forename: Nanda-Kumar
authors.initials: NK
authors.lastname: Parvathaneni
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Alterio
authors.forename: Simon J A
authors.initials: SJ
authors.lastname: van Kuijk
authors.forename: Simona Maria
authors.initials: SM
authors.lastname: Monti
authors.forename: Philippe
authors.initials: P
authors.lastname: Lambin
authors.forename: Giuseppina
authors.initials: G
authors.lastname: De Simone
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Winum
mesh_terms: D000577:Amides / Q000737:chemistry*; D000951:Antigens, Neoplasm / Q000378:metabolism*; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019073:HT29 Cells; D006367:HeLa Cells; D006801:Humans; D000860:Hypoxia; D008958:Models, Molecular; D015394:Molecular Structure; D009593:Nitroimidazoles / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry*; D013451:Sulfonic Acids / Q000737:chemistry*
chemical_list: D000577:Amides; D000951:Antigens, Neoplasm; D004791:Enzyme Inhibitors; D009593:Nitroimidazoles; D013449:Sulfonamides; D013451:Sulfonic Acids; C005741:sulfamic acid; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases