title: A prodrug approach toward cancer-related carbonic anhydrase inhibition.
abstract: The selective inhibition of cancer-associated human carbonic anhydrase (CA) enzymes, specifically CA IX and XII, has been validated as a mechanistically novel approach toward personalized cancer management. Herein we report the design and synthesis of a panel of 24 novel glycoconjugate primary sulfonamides that bind to the extracellular catalytic domain of CA IX and XII. These compounds were synthesized from variably acylated glycopyranosyl azides and either 3- or 4-ethynyl benzene sulfonamide using Cu(I)-catalyzed azide alkyne cycloaddition (CuAAC). The CA enzyme inhibition profile for all compounds was determined, while in vitro metabolic stability, plasma stability, and plasma protein binding for a representative set of compounds was measured. Our findings demonstrate the influence of the differing acyl groups on these key biopharmaceutical properties, confirming that acyl group protected carbohydrate-based sulfonamides have potential as prodrugs for selectively targeting the extracellular cancer-associated CA enzymes.
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University , Nathan, Queensland 4111, Australia.
authors.forename: Cindy J
authors.initials: CJ
authors.lastname: Carroux
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Rankin
authors.forename: Janina
authors.initials: J
authors.lastname: Moeker
authors.forename: Laurent F
authors.initials: LF
authors.lastname: Bornaghi
authors.forename: Kasiram
authors.initials: K
authors.lastname: Katneni
authors.forename: Julia
authors.initials: J
authors.lastname: Morizzi
authors.forename: Susan A
authors.initials: SA
authors.lastname: Charman
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: D000951:Antigens, Neoplasm / Q000187:drug effects* / Q000378:metabolism; D018938:Caco-2 Cells; D000071231:Carbonic Anhydrase IX; D002257:Carbonic Anhydrase Inhibitors / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry; D002256:Carbonic Anhydrases / Q000187:drug effects* / Q000378:metabolism; D020134:Catalytic Domain / Q000187:drug effects; D002463:Cell Membrane Permeability; D004795:Enzyme Stability; D006001:Glycoconjugates / Q000138:chemical synthesis; D006801:Humans; D009369:Neoplasms / Q000201:enzymology; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis*
chemical_list: D000951:Antigens, Neoplasm; D002257:Carbonic Anhydrase Inhibitors; D006001:Glycoconjugates; D011355:Prodrugs; D013449:Sulfonamides; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases; C477378:carbonic anhydrase XII