title: Secondary/tertiary benzenesulfonamides with inhibitory action against the cytosolic human carbonic anhydrase isoforms I and II.
abstract: Carbonic anhydrase inhibitors of primary sulfonamide type, RSO(2)NH(2), have clinical applications as diuretics, antiglaucoma, antiepileptic, antiobesity and antitumor drugs. Here we investigated inhibition of two human cytosolic isozymes, hCA I and II, with a series of secondary/tertiary sulfonamides, incorporating tosyl moieties (CH(3)C(6)H(4)SO(2)NR1R2). Most compounds inhibited both isoforms in low micromolar range, with inhibition constants between 0.181-6.01 μM against hCA I, and 0.209-0.779 μM against hCA II, respectively. These findings point out that substituted benzenesulfonamides may be used as leads for generating interesting CAIs probably possessing a distinct mechanism of action compared to primary sulfonamides. Indeed, classical RSO(2)NH(2) inhibitors bind in deprotonated form to the Zn(II) ion from the CA active site and participate in many other favorable interactions with amino acid residues lining the cavity. The secondary/tertiary sulfonamides cannot bind to the zinc due to steric hindrance and probably are accommodated at the entrance of the active site, in coumarin binding-site.
authors.affiliation: Department of Chemistry, Ataturk University, Science Faculty, Erzurum, Turkey.
authors.forename: Cemalettin
authors.initials: C
authors.lastname: Alp
authors.forename: Alfonso
authors.initials: A
authors.lastname: Maresca
authors.forename: Nurdan Alcan
authors.initials: NA
authors.lastname: Alp
authors.forename: Mehmet Serdar
authors.initials: MS
authors.lastname: Gültekin
authors.forename: Deniz
authors.initials: D
authors.lastname: Ekinci
authors.forename: Andrea
authors.initials: A
authors.lastname: Scozzafava
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
mesh_terms: D002245:Carbon Dioxide / Q000737:chemistry / Q000378:metabolism; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000302:isolation & purification / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015394:Molecular Structure; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000302:isolation & purification / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D020033:Protein Isoforms; D013449:Sulfonamides; D002245:Carbon Dioxide; D002256:Carbonic Anhydrases