Azobenzene-based inhibitors of human carbonic anhydrase II.

Leander Simon Runtsch,Johannes Broichhagen,Michael Groll,David Michael Barber,Peter Mayer,Dirk Trauner

doi:10.3762/bjoc.11.127

Leander Simon Runtsch, Johannes Broichhagen + Show 4 more

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https://doi.org/10.3762/bjoc.11.127

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Abstract

Aryl sulfonamides are a widely used drug class for the inhibition of carbonic anhydrases. In the context of our program of photochromic pharmacophores we were interested in the exploration of azobenzene-containing sulfonamides to block the catalytic activity of human carbonic anhydrase II (hCAII). Herein, we report the synthesis and in vitro evaluation of a small library of nine photochromic sulfonamides towards hCAII. All molecules are azobenzene-4-sulfonamides, which are substituted by different functional groups in the 4´-position and were characterized by X-ray crystallography. We aimed to investigate the influence of electron-donating or electron-withdrawing substituents on the inhibitory constant Ki. With the aid of an hCAII crystal structure bound to one of the synthesized azobenzenes, we found that the electronic structure does not strongly affect inhibition. Taken together, all compounds are strong blockers of hCAII with Ki = 25–65 nM that are potentially photochromic and thus combine studies from chemical synthesis, crystallography and enzyme kinetics.

Highlights

Carbonic anhydrase (CA) is an ubiquitously found zinccontaining metalloenzyme with many isoforms, which all catalyze the conversion of carbon dioxide and water to bicarbonate and a proton (Figure 1a, left) [1]
We have synthesized a small library of nine azobenzene sulfonamides with differing substitution patterns in the 4 ́-position using either azo coupling reactions or the Mills reaction
We determined the π–π* band and the crystal structures of all nine compounds together with the protein crystal structure of human carbonic anhydrase II (hCAII) bound to inhibitor 1d

Summary

Introduction

Carbonic anhydrase (CA) is an ubiquitously found zinccontaining metalloenzyme with many isoforms, which all catalyze the conversion of carbon dioxide and water to bicarbonate and a proton (Figure 1a, left) [1]. Despite its native purpose of pH and pressure regulation, its intrinsic esterase activity can be utilized to measure the catalytic activity by hydrolysis of p-nitrophenyl actetate (pNPA) to a phenolate, of which the product appearance can be observed colorimetrically (Figure 1a, right) [2]. Isoform II (human carbonic anhydrase II; hCAII) is found in many tissues and is responsible for maintaining the inner eye pressure among other regulatory tasks [1]. Its failure is associated with glaucoma [1,3]. Treatment of this severe disease, that leads to blindness, is achieved with the application of aryl sulfonamides [3].

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