title: Salen and tetrahydrosalen derivatives act as effective inhibitors of the tumor-associated carbonic anhydrase XII--a new scaffold for designing isoform-selective inhibitors.
abstract: Salen and tetrahydrosalen derivatives possess metal-chelating properties and have been used as ligands in organic synthesis and as scaffolds for developing therapeutic agents. Fourteen such compounds were synthesized in order to explore their ability to inhibit the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1). Human (h) isoforms hCA I, hCA II, hCA IX and hCA XII were included in the investigation. Several aliphatic and aromatic spacers were introduced between the two chelating groups from salen/tetrahydrosalen in order to explore a diverse chemical space for designing CA inhibitors, which incorporate both phenol and polyamine fragments in their molecule. Some of these compounds showed CA inhibitory activity in the low micromolar-nanomolar range and a pronounced selectivity for inhibiting an isoform over-expressed in hypoxic tumors, hCA XII, over hCA I, II and IX.
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy. Electronic address: simone.carradori@uniroma1.it.
authors.forename: Simone
authors.initials: S
authors.lastname: Carradori
authors.forename: Celeste
authors.initials: C
authors.lastname: De Monte
authors.forename: Melissa
authors.initials: M
authors.lastname: D'Ascenzio
authors.forename: Daniela
authors.initials: D
authors.lastname: Secci
authors.forename: Gulsah
authors.initials: G
authors.lastname: Celik
authors.forename: Mariangela
authors.initials: M
authors.lastname: Ceruso
authors.forename: Daniela
authors.initials: D
authors.lastname: Vullo
authors.forename: Andrea
authors.initials: A
authors.lastname: Scozzafava
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
mesh_terms: D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000737:chemistry* / Q000378:metabolism; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D005029:Ethylenediamines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000201:enzymology / Q000473:pathology; D019800:Phenol / Q000737:chemistry; D011073:Polyamines / Q000737:chemistry; D011485:Protein Binding; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D005029:Ethylenediamines; D011073:Polyamines; D020033:Protein Isoforms; D019800:Phenol; C011452:disalicylaldehyde ethylenediamine; D002256:Carbonic Anhydrases; C477378:carbonic anhydrase XII
keywords: Carbonic anhydrase inhibitor; Phenol; Polyamine; Salen; Tetrahydrosalen; Tumor over-expressed CA XII