title: Indanesulfonamides as carbonic anhydrase inhibitors. Toward structure-based design of selective inhibitors of the tumor-associated isozyme CA IX.
abstract: Carbonic anhydrases are ubiquitous metalloenzymes which are involved in fundamental processes (i.e., acid-base regulation, respiration, calcification, etc.). The carbonic anhydrase isozyme IX becomes an interesting pharmacological target due to its overexpression in cancer and its absence in normal tissue. Therefore, several indanesulfonamides were synthesized and tested for their inhibition both against the human CA IX and against two other biologically relevant isozymes (CA I and II). Structure-activity relationships are discussed and point out different compounds for its selectivity and activity against CA IX. To establish preliminary hypothesis for the design of new isozyme-selective CA IX inhibitors, we conducted molecular modeling. We describe here the first human CA IX model built by homology with another CA isozyme already crystallized. Docking studies were performed to explore the binding mode of our indanesulfonamide derivatives.
authors.affiliation: Drug Design and Discovery Center, University of Namur, 61 rue de Bruxelles, 5000 Namur, Belgium.
authors.forename: Anne
authors.initials: A
authors.lastname: Thiry
authors.forename: Marie
authors.initials: M
authors.lastname: Ledecq
authors.forename: Alessandro
authors.initials: A
authors.lastname: Cecchi
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Dogné
authors.forename: Johan
authors.initials: J
authors.lastname: Wouters
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
authors.forename: Bernard
authors.initials: B
authors.lastname: Masereel
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000201:enzymology*; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D040681:Structural Homology, Protein; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D007527:Isoenzymes; D013449:Sulfonamides; D002256:Carbonic Anhydrases