title: Hydrophobic substituents of the phenylmethylsulfamide moiety can be used for the development of new selective carbonic anhydrase inhibitors.
abstract: A new series of compounds containing a sulfamide moiety as zinc-binding group (ZBG) has been synthesized and tested for determining inhibitory properties against four human carbonic anhydrase (hCA) isoforms, namely, CAs I, II, IX, and XII. The X-ray structure of the cytosolic dominant isoform hCA II in complex with the best inhibitor of the series has also been determined providing further insights into sulfamide binding mechanism and confirming that such zinc-binding group, if opportunely derivatized, can be usefully exploited for obtaining new potent and selective CAIs. The analysis of the structure also suggests that for drug design purposes the but-2-yn-1-yloxy moiety tail emerges as a very interesting substituent of the phenylmethylsulfamide moiety due to its capability to establish strong van der Waals interactions with a hydrophobic cleft on the hCA II surface, delimited by residues Phe131, Val135, Pro202, and Leu204. Indeed, the complementarity of this tail with the cleft suggests that different substituents could be used to discriminate between isoforms having clefts with different sizes.
authors.affiliation: Istituto di Biostrutture e Bioimmagini, CNR, Via Mezzocannone 16, 80134 Naples, Italy.
authors.forename: Giuseppina
authors.identifier: 0000-0001-9783-5431
authors.initials: G
authors.lastname: De Simone
authors.affiliation: Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga LV-1006, Latvia.
authors.forename: Ginta
authors.initials: G
authors.lastname: Pizika
authors.affiliation: Istituto di Biostrutture e Bioimmagini, CNR, Via Mezzocannone 16, 80134 Naples, Italy.
authors.forename: Simona Maria
authors.initials: SM
authors.lastname: Monti
authors.affiliation: Istituto di Biostrutture e Bioimmagini, CNR, Via Mezzocannone 16, 80134 Naples, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Di Fiore
authors.affiliation: Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga LV-1006, Latvia.
authors.forename: Jekaterina
authors.identifier: 0000-0001-8845-0193
authors.initials: J
authors.lastname: Ivanova
authors.affiliation: Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga LV-1006, Latvia.
authors.forename: Igor
authors.identifier: 0000-0002-1217-2366
authors.initials: I
authors.lastname: Vozny
authors.affiliation: Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga LV-1006, Latvia.
authors.forename: Peteris
authors.initials: P
authors.lastname: Trapencieris
authors.affiliation: Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga LV-1006, Latvia.
authors.forename: Raivis
authors.identifier: 0000-0002-9471-1342
authors.initials: R
authors.lastname: Zalubovskis
authors.affiliation: Laboratorio di Chimica Bioinorganica, Università degli Studi di Firenze, Room 188, Via della Lastruccia 3, 50019 Sesto Fiorentino, Florence, Italy ; Dipartimento di Scienze Farmaceutiche, Università degli Studi di Firenze, Polo Scientifico, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Florence, Italy.
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
authors.affiliation: Istituto di Biostrutture e Bioimmagini, CNR, Via Mezzocannone 16, 80134 Naples, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Alterio
mesh_terms: D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry*; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D012997:Solvents; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry*
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D012997:Solvents; D013449:Sulfonamides