Hydrophobic substituents of the phenylmethylsulfamide moiety can be used for the development of new selective carbonic anhydrase inhibitors.

Giuseppina De Simone,Igor Vozny,Simona Maria Monti,Anna Di Fiore,Jekaterina Ivanova,Claudiu T Supuran,Ginta Pizika,Peteris Trapencieris,Vincenzo Alterio,Raivis Zalubovskis

doi:10.1155/2014/523210

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.

Highlights

Carbonic anhydrases (CAs, EC 4.2.1.1) are ubiquitous metalloenzymes found in prokaryotes and eukaryotes, which catalyze the reversible hydration of carbon dioxide to bicarbonate ion and proton (CO2 + H2O 󴀗󴀰 HCO3− + H+) [1, 2]
To better understand at structural level the molecular features determining the inhibition profiles of such compounds, we report the high-resolution crystallographic structure of the cytosolic dominant isoform human carbonic anhydrase (hCA) II in complex with the highest affinity inhibitor in the newly synthesized series
It is interesting to note that derivatives 13 and 14 were effective hCA II inhibitors, Table 1: hCAs I, II, IX, and XII inhibition data with sulfamides 11– 16

Summary

Introduction

Carbonic anhydrases (CAs, EC 4.2.1.1) are ubiquitous metalloenzymes found in prokaryotes and eukaryotes, which catalyze the reversible hydration of carbon dioxide to bicarbonate ion and proton (CO2 + H2O 󴀗󴀰 HCO3− + H+) [1, 2]. 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.

Results

Conclusion