How many carbonic anhydrase inhibition mechanisms exist?

Abstract

Six genetic families of the enzyme carbonic anhydrase (CA, EC 4.2.1.1) were described to date. Inhibition of CAs has pharmacologic applications in the field of antiglaucoma, anticonvulsant, anticancer, and anti-infective agents. New classes of CA inhibitors (CAIs) were described in the last decade with enzyme inhibition mechanisms differing considerably from the classical inhibitors of the sulfonamide or anion type. Five different CA inhibition mechanisms are known: (i) the zinc binders coordinate to the catalytically crucial Zn(II) ion from the enzyme active site, with the metal in tetrahedral or trigonal bipyramidal geometries. Sulfonamides and their isosters, most anions, dithiocarbamates and their isosters, carboxylates, and hydroxamates bind in this way; (ii) inhibitors that anchor to the zinc-coordinated water molecule/hydroxide ion (phenols, carboxylates, polyamines, 2-thioxocoumarins, sulfocoumarins); (iii) inhibitors which occlude the entrance to the active site cavity (coumarins and their isosters), this binding site coinciding with that where CA activators bind; (iv) compounds which bind out of the active site cavity (a carboxylic acid derivative was seen to inhibit CA in this manner), and (v) compounds for which the inhibition mechanism is not known, among which the secondary/tertiary sulfonamides as well as imatinib/nilotinib are the most investigated examples. As CAIs are used clinically in many pathologies, with a sulfonamide inhibitor (SLC-0111) in Phase I clinical trials for the management of metastatic solid tumors, this review updates the recent findings in the field which may be useful for a structure-based drug design approach of more selective/potent modulators of the activity of these enzymes. KeywordsAnchoring to zinc-coordinated water, carbonic anhydrase, inhibition mechanism, inhibitors, occlusion of the active site entrance, out of the active site binding, zinc binder History

Synthesis, cytotoxicity and carbonic anhydrase inhibitory activities of new pyrazolines

“…Sixteen different a-CA isoforms have been isolated and characterized so far in mammals: CA I, CA II, CA III, CA VII, CA XIII are cytosolic; CA IV, CA IX, CA XII, CA XIV and CA XV are associated with the cell membrane; CA VA and CA VB are in mitochondria and CA VI is secreted into saliva and milk 4 .…”

Synthesis and carbonic anhydrase I, II, IV and XII inhibitory properties of N-protected amino acid – sulfonamide conjugates

“…The metal ion may be in a tetrahedral or trigonal bipyramidal geometries, with the sulfonamides and their isosteres (sulfamides, sulfamates, etc. ), most anions, dithiocarbamates and their isosteres, carboxylates and hydroxamates binding in this way [1][2][3]5,13 ; (ii) the inhibitors that anchor to the zinc-coordinated water molecule/hydroxide ion, represented by the phenols, some carboxylates, the polyamines, 2-thioxocoumarins, and sulfocoumarins [1][2][3]13,14 ; (iii) the inhibitors which occlude the entrance to the active site cavity (coumarins and their isosteres), this binding site coinciding with that where CA activators bind [13][14][15][16][17][18][19][20] ; (iv) the compounds which bind out of the active site cavity (a carboxylic acid derivative was seen to inhibit CA in this manner) 21 , and (v) compounds for which the inhibition mechanism is not known, among which the secondary/tertiary sulfonamides as well as imatinib/nilotinib are the most investigated examples 13,[22][23][24][25][26] . The sulfonamides however remain the main class of CAIs with many clinically used drugs as antiglaucoma agents [27][28][29] , diuretics 30 , antiobesity drugs [31][32][33] , antiepilpetics 34 , and more recently agents for the management of hypoxic tumors [35][36][37][38] , neuropathic pain 39 and ischaemia …”

“…These are the a-, b-, g-, d-, z-and Z-CA classess [1][2][3][4][5][6][7][8][9][10][11] . The catalytic/inhibition mechanisms for the physiologic and other catalyzed by these enzymes are well understood processes [12][13][14][15][16][17][18][19][20][21] . The discovery of new classes of CA inhibitors (CAIs), possessing different inhibition mechanisms compared with the classical inhibitors of the sulfonamide/anion type [1][2][3]5 , has also seen important developments ultimately 13 .…”

“…The catalytic/inhibition mechanisms for the physiologic and other catalyzed by these enzymes are well understood processes [12][13][14][15][16][17][18][19][20][21] . The discovery of new classes of CA inhibitors (CAIs), possessing different inhibition mechanisms compared with the classical inhibitors of the sulfonamide/anion type [1][2][3]5 , has also seen important developments ultimately 13 . At least five different CA inhibition mechanisms were reported so far: (i) the zinc binders are the inhibitors which coordinate to the catalytically crucial Zn(II) ion from the enzyme active site.…”

Design, synthesis and biological evaluation ofN-(5-methyl-isoxazol-3-yl/1,3,4-thiadiazol-2-yl)-4-(3-substitutedphenylureido) benzenesulfonamides as human carbonic anhydrase isoenzymes I, II, VII and XII inhibitors

“…Till date, a total number of 15 different human carbonic anhydrases (hCA) isoforms have been discovered, among which CA I-III, CA VII and CA XIII are present in cytosol; CA IV, CA IX, CA XII and CA XIV are membrane bound; CA VA and CA VB are restricted to the mitochondrion and CA VI is secreted in milk and saliva 6 . Functionally, CAs are primarily involved in catalyzing the rapid interconversion of CO 2 and H 2 O to bicarbonate (HCO À 3 ) and protons (H + ) using a metal hydroxide nucleophilic mechanism 7 . The hCAs play a pivotal role in a variety of physiological processes such as CO 2 /bicarbonate transportation, respiration, electrolyte secretion, gluoconeogensis, lipogenesis, ureagenesis, bone resorption, neuronal excitability and tumorigenicity 8 .…”