title: Design, synthesis, and biological evaluation of novel carbohydrate-based sulfamates as carbonic anhydrase inhibitors.
abstract: Carbonic anhydrases (CAs) IX and XII are enzymes with newly validated potential for the development of personalized, first-in-class cancer chemotherapies. Here we present the design and synthesis of novel carbohydrate-based CA inhibitors, several of which were very efficient inhibitors (K(i)<10 nM) with good selectivity for cancer-associated CA isozymes over off-target CA isozymes. All inhibitors comprised a carbohydrate core with one hydroxyl group derivatized as a sulfamate. Five different carbohydrates were chosen to present a selection of molecular shapes with subtle stereochemical differences to the CA enzymes active site. Variable modifications of the remaining sugar hydroxyl groups were incorporated to provide an incremental coverage of chemical property parameters that are associated with biopharmaceutical performance. All sulfamate inhibitors displayed ligand efficiencies that are consistent with those reported for good drug lead candidates.
authors.affiliation: Eskitis Institute for Cell and Molecular Therapies, Griffith University, Nathan, Queensland 4111, Australia.
authors.forename: Marie
authors.initials: M
authors.lastname: Lopez
authors.forename: Jonathan
authors.initials: J
authors.lastname: Trajkovic
authors.forename: Laurent F
authors.initials: LF
authors.lastname: Bornaghi
authors.forename: Alessio
authors.initials: A
authors.lastname: Innocenti
authors.forename: Daniela
authors.initials: D
authors.lastname: Vullo
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
authors.forename: Sally-Ann
authors.initials: SA
authors.lastname: Poulsen
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D004187:Disaccharides / Q000138:chemical synthesis* / Q000737:chemistry; D015195:Drug Design; D005632:Fructose / Q000031:analogs & derivatives / Q000737:chemistry; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry; D008968:Molecular Conformation; D009005:Monosaccharides / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry; D013451:Sulfonic Acids / Q000138:chemical synthesis* / Q000737:chemistry; D000077236:Topiramate
chemical_list: D000970:Antineoplastic Agents; D002257:Carbonic Anhydrase Inhibitors; D004187:Disaccharides; D007527:Isoenzymes; D009005:Monosaccharides; D013449:Sulfonamides; D013451:Sulfonic Acids; D000077236:Topiramate; D005632:Fructose