Hydrophobic substituents of the phenylmethylsulfamide moiety can be used for the development of new selective carbonic anhydrase inhibitors(423 views) De Simone G, Pizika G, Monti SM, Di Fiore A, Ivanova J, Vozny I, Trapencieris P, Zalubovskis R, Supuran CT, Alterio V
Biomed Res Int (ISSN: 2314-6133, 2314-6141), 2014; 2014: 523210-523210.
Istituto di Biostrutture e Bioimmagini, CNR, Via Mezzocannone 16, 80134 Naples, Italy.
Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga LV-1006, Latvia.
Laboratorio di Chimica Bioinorganica, Universita degli Studi di Firenze, Room 188, Via della Lastruccia 3, 50019 Sesto Fiorentino, Florence, Italy
Dipartimento di Scienze Farmaceutiche, Universita degli Studi di Firenze, Polo Scientifico, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Florence, Italy.
References: Not available.
Hydrophobic substituents of the phenylmethylsulfamide moiety can be used for the development of new selective carbonic anhydrase inhibitors
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.
Hydrophobic substituents of the phenylmethylsulfamide moiety can be used for the development of new selective carbonic anhydrase inhibitors