Coumarinyl-substituted sulfonamides strongly inhibit several human carbonic anhydrase isoforms: solution and crystallographic investigations.
We investigated a series of coumarinyl-substituted aromatic sulfonamides as inhibitors of four carbonic anhydrase (CA, EC 4.2.1.1) isoforms with medical applications, the cytosolic hCA I, and II, and the transmembrane, tumor-associated hCA IX and XII. Compounds incorporating 7-methoxy-coumarin-4-yl-acetamide-tails and benzenesulfonamide and benzene-1,3-disulfonamide scaffolds showed medium potency inhibition of hCA I (KIs of 73-131 nM), effective hCA II inhibition (KIs of 9.1-36 nM) and less effective hCA IX and XII inhibition (KIs of 55-128 nM). Only one compound, the derivatized 4-amino-6-trifluoromethyl-benzene-1,3-disulfonamide with the coumarinyl tail, showed effective inhibition of the transmembrane isoforms, with KIs of 5.9-14.2 nM, although it was less effective as hCA I and II inhibitor (KIs of 36-120 nM). An X-ray crystal structure of hCA II in complex with 4-(7-methoxy-coumarin-4-yl-acetamido)-benzenesulfonamide (KI of 9.1 nM against hCA II) showed the intact inhibitor coordinated to the zinc ion from the enzyme active site by the sulfonamide moiety, and participating in a edge-to-face stacking with Phe131, in addition to other hydrophobic and hydrophilic interactions with water molecules and amino acid residues from the active site. Thus, sulfonamides incorporating coumarin rings have a distinct inhibition mechanism compared to the coumarins, and may lead to compounds with interesting inhibition profiles against various alpha-CAs found in mammals or parasites, such as Plasmodium falciparum.
Wagner
Jason
J
Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Box 100245, Gainesville, FL 32610, USA.
Avvaru
Balendu Sankara
BS
Robbins
Arthur H
AH
Scozzafava
Andrea
A
Supuran
Claudiu T
CT
McKenna
Robert
R
D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000737:chemistry / Q000378:metabolism*; D003374:Coumarins / Q000737:chemistry* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology*
D002257:Carbonic Anhydrase Inhibitors; D003374:Coumarins; D020033:Protein Isoforms; D013449:Sulfonamides; D002256:Carbonic Anhydrases