title: Sulfocoumarins (1,2-benzoxathiine-2,2-dioxides): a class of potent and isoform-selective inhibitors of tumor-associated carbonic anhydrases.
abstract: Coumarins were recently shown to constitute a novel class of mechanism-based carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. We demonstrate that sulfocoumarins (1,2-benzoxathiine 2,2-dioxides) possess a similar mechanism of action, acting as effective CA inhibitors. The sulfocoumarins were hydrolyzed by the esterase CA activity to 2-hydroxyphenyl-vinylsulfonic acids, which thereafter bind to the enzyme in a region rarely occupied by other classes of inhibitors. The X-ray structure of one of these compounds in adduct with a modified CA II enzyme possessing two amino acid residues from the CA IX active site, allowed us to decipher the inhibition mechanism. The sulfonic acid was observed anchored to the zinc-coordinated water molecule, making favorable interactions with Thr200 and Pro201. Some other sulfocoumarins incorporating substituted-1,2,3-triazole moieties were prepared by using click chemistry and showed low nanomolar inhibitory action against the tumor-associated isoforms CA IX and XII, being less effective against the cytosolic CA I and II.
authors.affiliation: Biomedical Research and Study Center, Ratsupites 1, LV 1067 Riga, Latvia.
authors.forename: Kaspars
authors.initials: K
authors.lastname: Tars
authors.forename: Daniela
authors.initials: D
authors.lastname: Vullo
authors.forename: Andris
authors.initials: A
authors.lastname: Kazaks
authors.forename: Janis
authors.initials: J
authors.lastname: Leitans
authors.forename: Alons
authors.initials: A
authors.lastname: Lends
authors.forename: Aiga
authors.initials: A
authors.lastname: Grandane
authors.forename: Raivis
authors.initials: R
authors.lastname: Zalubovskis
authors.forename: Andrea
authors.initials: A
authors.lastname: Scozzafava
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
mesh_terms: D000951:Antigens, Neoplasm / Q000737:chemistry; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry; D024401:Carbonic Anhydrase I / Q000037:antagonists & inhibitors / Q000737:chemistry; D024402:Carbonic Anhydrase II / Q000037:antagonists & inhibitors / Q000737:chemistry; D000071231:Carbonic Anhydrase IX; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D002256:Carbonic Anhydrases / Q000737:chemistry*; D020134:Catalytic Domain; D057930:Click Chemistry; D003374:Coumarins / Q000138:chemical synthesis* / Q000737:chemistry; D018360:Crystallography, X-Ray; D006801:Humans; D006868:Hydrolysis; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry; D015394:Molecular Structure; D011485:Protein Binding; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D002257:Carbonic Anhydrase Inhibitors; D003374:Coumarins; D007527:Isoenzymes; D014230:Triazoles; D024401:Carbonic Anhydrase I; D024402:Carbonic Anhydrase II; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases; C477378:carbonic anhydrase XII