TY - JOUR
T1 - Coumarinyl-substituted sulfonamides strongly inhibit several human carbonic anhydrase isoforms
T2 - Solution and crystallographic investigations
AU - Wagner, Jason
AU - Avvaru, Balendu Sankara
AU - Robbins, Arthur H.
AU - Scozzafava, Andrea
AU - Supuran, Claudiu T.
AU - McKenna, Robert
N1 - Funding Information:
This research was financed in part by a Grant of the 6th Framework Programme of the European Union (DeZnIT project) and by a 7th FP EU project (METOXIA) to A.S. and C.T.S., and in part by an NIH ( GM 25154 ) and Maren Grant to R.M. R.M. would also like to thank the Centre of Structure Biology, University of Florida, for their continued support to help maintain the in-house X-ray facilities.
PY - 2010/7/15
Y1 - 2010/7/15
N2 - 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 (K Is of 73-131 nM), effective hCA II inhibition (K Is of 9.1-36 nM) and less effective hCA IX and XII inhibition (K Is 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 K Is of 5.9-14.2 nM, although it was less effective as hCA I and II inhibitor (K Is of 36-120 nM). An X-ray crystal structure of hCA II in complex with 4-(7-methoxy-coumarin-4-yl-acetamido)- benzenesulfonamide (K I 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 α-CAs found in mammals or parasites, such as Plasmodium falciparum.
AB - 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 (K Is of 73-131 nM), effective hCA II inhibition (K Is of 9.1-36 nM) and less effective hCA IX and XII inhibition (K Is 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 K Is of 5.9-14.2 nM, although it was less effective as hCA I and II inhibitor (K Is of 36-120 nM). An X-ray crystal structure of hCA II in complex with 4-(7-methoxy-coumarin-4-yl-acetamido)- benzenesulfonamide (K I 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 α-CAs found in mammals or parasites, such as Plasmodium falciparum.
KW - Carbonic anhydrase
KW - Coumarinyl-substituted sulfonamides
KW - Inhibition mechanism
KW - Isoformselective inhibitor
KW - X-ray crystallography
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U2 - 10.1016/j.bmc.2010.06.028
DO - 10.1016/j.bmc.2010.06.028
M3 - Article
C2 - 20598552
AN - SCOPUS:77955338487
SN - 0968-0896
VL - 18
SP - 4873
EP - 4878
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 14
ER -