X-ray crystallographic and kinetic investigations of 6-sulfamoyl-saccharin as a carbonic anhydrase inhibitor

Abstract

6-Sulfamoyl-saccharin was investigated as an inhibitor of 11 α-carbonic anhydrase (CA, EC 4.2.1.1) isoforms of human (h) origin, hCA I-XIV, and X-ray crystallographic data were obtained for its adduct with hCA II, the physiologically dominant isoform. This compound possesses two potential zinc-binding groups, the primary sulfamoyl one and the secondary, acylatedsulfonamide. Saccharin itself binds to the Zn(II) ion from the CA active site coordinating with this last group, in deprotonated (SO2N(-)CO) form. Here we explain why 6-sulfamoyl-saccharin, unlike saccharin, binds to the metal ion from the hCA II active site by its primary sulfonamide moiety and not the secondary one as saccharin itself. Our study is useful for shedding new light to the structure-based drug design of isoform-selective CA inhibitors of the sulfonamide type.

Cancer Drug Development of Carbonic Anhydrase Inhibitors beyond the Active Site

“…Hence, the hydrophobicity of an active site has a great impact on the binding of saccharin based compounds, resulting in the highest observed inhibition of activity in CA IX followed by CA XII [ 5 , 73 ]. A decreased affinity for CA I and CA II has also been observed because of the difference in active site residues, most of which cause steric hindrance and decreased accessibility [ 5 , 120 , 121 ]. These recent advances in designing CA IX specific drugs have proven that compounds containing sugar moieties are promising drug candidates that specifically target extracellular CAs in cancer.…”

Thermodynamic, kinetic, and structural parameterization of human carbonic anhydrase interactions toward enhanced inhibitor design

“…Saccharine modified by sulfonamide moiety was found in CA II bound to zinc by sulfonamide, as all other sulfonamide compounds (Alterio et al ., 2015). A crystal structure of saccharine modified with carboxymethyl as Zn-binding group in CA II was also published (Langella et al ., 2015), thus representing a new Zn-binding group.…”

The antibiotic furagin and its derivatives are isoform-selective human carbonic anhydrase inhibitors

“…That has highly enriched our understanding of these enzymes and also allowed obtaining of isoform-selective CAIs targeting physiologically relevant isoforms [11][12][13][14][23][24][25][26][27] . Among the new chemotypes, which also exhibited the highest levels of isoform selectivity, were the coumarins 27 , the sulfocoumarins [23][24][25][26] and their congeners, homosulfocoumarins (3H-1,2-benzoxathiepine 2,2dioxides) 31 , and saccharin derivatives [32][33][34] . Considering the fact that this last chemotype was somewhat chemically similar to hydantoin (imidazolidine-2,4-dione) that may serve as zinc binding group (ZBG) we investigated clinically used antibiotic Furagin (Figure 1), also known under names Furazidine, Furamags or Furazidin 35 , that contains hydantoin moiety, as well as newly prepared its derivatives.…”