title: Attachment of carbohydrates to methoxyaryl moieties leads to highly selective inhibitors of the cancer associated carbonic anhydrase isoforms IX and XII.
abstract: The transmembrane isoforms of carbonic anhydrase (hCA IX and XII) have been shown to be linked to carcinogenesis and their inhibition to arrest primary tumor and metastases growth. In this paper, we present a new class of C-glycosides incorporating the methoxyaryl moiety, that was designed to selectively target and inhibit the extracellular domains of the cancer-relevant CA isozymes. The glycosides have been prepared by aldol reaction of glycosyl ketones with the appropriate aromatic aldehydes. We also present the inhibition profile of our new glycomimetics, against four isozymes of carbonic anhydrase comprising hCAs I and II (cytosolic, ubiquitous isozymes) and hCAs IX and XII (tumor associated isozymes). In this study, per-O-acetylated glycoside 4, 6 and deprotected compounds 7, 9, 10 and 12 were identified as potent and highly selective inhibitors of hCA IX and XII. These results confirm that attaching carbohydrate moieties to CA methoxyaryl pharmacophore improves and enhances its inhibitory activity. These CA inhibitors have developmental potential to selectively target cancer cells, leading to cell death.
authors.affiliation: LADECOR, Departamento de Química, Facultad de Ciencias Exactas, Universidad Nacional de La Plata, 47 y 115, 1900 La Plata, Argentina.
authors.forename: Leonardo E
authors.initials: LE
authors.lastname: Riafrecha
authors.affiliation: LADECOR, Departamento de Química, Facultad de Ciencias Exactas, Universidad Nacional de La Plata, 47 y 115, 1900 La Plata, Argentina.
authors.forename: Oscar M
authors.initials: OM
authors.lastname: Rodríguez
authors.affiliation: Universitá degli Studi di Firenze, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, I-50019 Sesto Fiorentino (Firenze), Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Vullo
authors.affiliation: Universitá degli Studi di Firenze, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, I-50019 Sesto Fiorentino (Firenze), Italy; Università degli Studi di Firenze, NEUROFARBA Department, Section of Pharmaceutical Chemistry, Via Ugo Schiff 6, 50019 Sesto Fiorentino (Florence), Italy. Electronic address: claudiu.supuran@unifi.it.
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
authors.affiliation: LADECOR, Departamento de Química, Facultad de Ciencias Exactas, Universidad Nacional de La Plata, 47 y 115, 1900 La Plata, Argentina. Electronic address: pcolinas@quimica.unlp.edu.ar.
authors.forename: Pedro A
authors.initials: PA
authors.lastname: Colinas
mesh_terms: D001555:Benzene Derivatives / Q000737:chemistry / Q000494:pharmacology*; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006027:Glycosides / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D015394:Molecular Structure; D009369:Neoplasms / Q000201:enzymology* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D001555:Benzene Derivatives; D002257:Carbonic Anhydrase Inhibitors; D006027:Glycosides; D007527:Isoenzymes; D002256:Carbonic Anhydrases
keywords: Cancer; Enzyme inhibitors; Glycomimetics