title: Design and synthesis of thiourea compounds that inhibit transmembrane anchored carbonic anhydrases.
abstract: A library of 32 novel glycoconjugate thiourea-bridged benzene sulfonamides have been synthesized from the reaction of glycosyl isothiocyanates with a panel of simple benzene sulfonamides comprising either a free amine or hydrazide. All compounds were investigated for their ability to inhibit the enzymatic activity of five human carbonic anhydrase (hCA) isozymes: hCA I, II and membrane-associated isozymes IX, XII and XIV. A physicochemical feature of the free sugar thioureido glycoconjugates was high water solubility (> 20 mg/mL), as well many of these compounds exhibited a desirable potency and CA isozyme selectivity profile. From this library several inhibitors displayed excellent potency-selectivity profiles for transmembrane anchored CAs over off-target CA I and II. These molecules provide potential dual-acting candidates for the development of inhibitors that target the extracellular CAs (IX, XII and XIV)-either directly as free sugars (membrane impermeable) or indirectly as acetylated prodrugs, becoming free sugars upon esterase hydrolysis.
authors.affiliation: Eskitis Institute for Cell and Molecular Therapies, Griffith University, 170 Kessels Road, Nathan, Queensland 4111, Australia.
authors.forename: Janina
authors.initials: J
authors.lastname: Moeker
authors.forename: Kanae
authors.initials: K
authors.lastname: Teruya
authors.forename: Sabine
authors.initials: S
authors.lastname: Rossit
authors.forename: Brendan L
authors.initials: BL
authors.lastname: Wilkinson
authors.forename: Marie
authors.initials: M
authors.lastname: Lopez
authors.forename: Laurent F
authors.initials: LF
authors.lastname: Bornaghi
authors.forename: Alessio
authors.initials: A
authors.lastname: Innocenti
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
authors.forename: Sally-Ann
authors.initials: SA
authors.lastname: Poulsen
mesh_terms: D002241:Carbohydrates / Q000737:chemistry; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D002256:Carbonic Anhydrases / Q000737:chemistry* / Q000378:metabolism; D015195:Drug Design; D006001:Glycoconjugates / Q000138:chemical synthesis / Q000737:chemistry; D006801:Humans; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D012995:Solubility; D013449:Sulfonamides / Q000737:chemistry; D013890:Thiourea / Q000737:chemistry*
chemical_list: D002241:Carbohydrates; D002257:Carbonic Anhydrase Inhibitors; D006001:Glycoconjugates; D020033:Protein Isoforms; D013449:Sulfonamides; D002256:Carbonic Anhydrases; D013890:Thiourea