A class of carbonic anhydrase I – selective activators

Erol Licsandru,Muhammet Tanc,Istvan Kocsis,Mihail Barboiu,Claudiu T Supuran

doi:10.1080/14756366.2016.1232254

Abstract

A series of ureido and bis-ureido derivatives were prepared by reacting histamine with alkyl/aryl-isocyanates or di-isocyanates. The obtained derivatives were assayed as activators of the enzyme carbonic anhydrase (CA, EC 4.2.1.1), due to the fact that histamine itself has this biological activity. Although inhibition of CAs has pharmacological applications in the field of antiglaucoma, anticonvulsant, anticancer, and anti-infective agents, activation of these enzymes is not yet properly exploited pharmacologically for cognitive enhancement or Alzheimer’s disease treatment, conditions in which a diminished CA activity was reported. The ureido/bis-ureido histamine derivatives investigated here showed activating effects only against the cytosolic human (h) isoform hCA I, having no effect on the widespread, physiologically dominant isoform hCA II. This is the first report in which CA I-selective activators were identified. Such compounds may constitute interesting tools for better understanding the physiological/pharmacological effects connected to activation of this widespread CA isoform, whose physiological function is not fully understood.

Highlights

The carbonic anhydrases (CAs, EC 4.2.1.1) represent a superfamily of metalloenzymes, with six distinct genetic families known to date, the a, b, c, d, f, and g-CAs, all of the which efficiently catalyze the reaction between CO2 and water, with the formation of bicarbonate and protons[1,2,3,4,5,6,7,8,9,10,11]
The imidazole moiety of the activator can participate to the proton shuttling processes crucial for enhancing the catalytic efficiency of the enzyme, whereas the derivatized amino group may lead to a further stabilization of the enzymeactivator adduct
By catalyzing the simple but highly important hydration of carbon dioxide to bicarbonate and protons, CAs are involved in critical steps of the life cycle of many organisms, including eukaryotes, Bacteria and Archaea

Summary

Introduction

The carbonic anhydrases (CAs, EC 4.2.1.1) represent a superfamily of metalloenzymes, with six distinct genetic families known to date, the a-, b-, c-, d-, f-, and g-CAs, all of the which efficiently catalyze the reaction between CO2 and water, with the formation of bicarbonate and protons[1,2,3,4,5,6,7,8,9,10,11]. The inhibition and the activation of CAs are well-understood processes: most types of classical inhibitors bind to the metal center within the enzyme active site[12,13,14,15,16,17,18,19,20,21], whereas the activators bind at the entrance of the active site cavity and participate in proton shuttling processes between the metal ion-bound water molecule and the environment[22,23,24].

Methods

Results

Conclusion