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.

Sulfonamide inhibition studies of the γ-carbonic anhydrase from the Antarctic bacterium Pseudoalteromonas haloplanktis

“…26,[39][40][41][42][43][44][45][46][47][48][49][50] Their biochemical features are known in detail for at least four classes, together with their distribution and role in various organisms. 32,33,41,[48][49][50][51][52][53][54][55][56][57][58][59][60][61][62] Inhibition and activation studies of many such enzymes from vertebrates, protozoa, fungi and bacteria have shown that they are drug targets for obtaining pharmacological agents of the diuretic, antiglaucoma, antiobesity, antiepileptic, anticancer or anti-infective type. [55][56][57][58]60 Many such enzymes also possess biotechnologic applications for biomimetic CO 2 capture processes.…”

Design, synthesis and molecular docking of novelN,N-dimethylbenzenesulfonamide derivatives as potential antiproliferative agents

“…Found: C,50.27;H,4.14;N,14.44. General procedure for the preparation of: N,N-Dimethyl-4-(1-(2-(2-oxo-2H-chromene-3-carbonyl)hydrazono)ethyl)-benzenesulfonamide (17) and N,N-dimethyl-4-(1-(2-(3-oxo-3H-benzo[f]-chromene-2-carbonyl)hydrazono)ethyl)-benzenesulfonamide (18): Equimolecular mixture of 3 (3.08 g, 0.01 mol) and either salicaldehyde (1.22 g, 0.01 mol) or 2-hydroxy-1-naphthaldehyde (1.72 g, 0.01 mol) in dioxane (20 mL) containing piperidine (0.5 mL) was refluxed for 3h. The reaction mixture was poured onto ice/water and the obtained solid was recrystallized from dioxane containing few drops of HCl to give 17 or 18, respectively.…”

“…It has also been well reported that sulfonamide bearing molecules act as promising anticancer agents through inhibition of carbonic anhydrase IX 11 . Crystallographic data revealed that CA IX, which is a membrane-associated a-CA, is comprised of a dimer each monomer of which consists of 10-stranded antiparallel-sheets forming the core of the molecule with an intramolecular disulfide bond between Cys23 and Cys203 11,18 . CA IX active site contains a Zn(II) in coordination with His94, 96, 119 and a water molecule.…”

“…CA IX active site contains a Zn(II) in coordination with His94, 96, 119 and a water molecule. The essential binding pocket amino acids are the proton shuttle residue (His64) in addition to those residues involved in binding of inhibitors 11,18 . Thus, Leu91, Val121, Val131, Leu135, Leu141, Val143, Leu198 and Pro202 define the hydrophobic region of the active site, whereas Arg58, Arg60, Asn62, His64, Ser65, Gln67, Thr69 and Gln92 identify the hydrophilic one.…”

“…A conformational search using an implicit solvent model was accomplished for the prepared compounds; this was followed by refinement of the geometry of local minima through a quantum-mechanical (QM) method. Subsequently, flexible docking of the compounds was performed in the crystallographic structure of the CA IX co-crystallized with a sulfonamide native ligand obtained from the Protein DataBank (PDB ID: 4BCW) 18 to assess the plausible ability of the new sulfonamide derivatives to bind in the active pocket of CA IX as a potential molecular target. The poses obtained for our sulfonamides were found to bind in a co-crystallized ligand-like fashion with CA IX (Figures 1-5).…”