Sulfocoumarins (1,2-benzoxathiine-2,2-dioxides): a class of potent and isoform-selective inhibitors of tumor-associated carbonic anhydrases.

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Tars K, Vullo D, Kazaks A, Leitans J, Lends A, Grandane A, Zalubovskis R, Scozzafava A, Supuran CT

Sulfocoumarins (1,2-benzoxathiine-2,2-dioxides): a class of potent and isoform-selective inhibitors of tumor-associated carbonic anhydrases.

J Med Chem. 2013 Jan 10;56(1):293-300. doi: 10.1021/jm301625s. Epub 2012 Dec 27.

PubMed ID

23241068 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Acetazolamide	Carbonic anhydrase 1	Ki (nM)	250	N/A	N/A	Details
Acetazolamide	Carbonic anhydrase 12	Ki (nM)	5	N/A	N/A	Details
Acetazolamide	Carbonic anhydrase 2	Ki (nM)	12	N/A	N/A	Details