Activation of human α-carbonic anhydrase isoforms I, II, IV and VII with bis-histamine schiff bases and bis-spinaceamine substituted derivatives

Claudiu T Supuran,Alessio Nocentini,Silvia Bua,Nabih Lolak,Suleyman Akocak

doi:10.1080/14756366.2019.1630616

Claudiu T Supuran, Alessio Nocentini + Show 3 more

Open Access

https://doi.org/10.1080/14756366.2019.1630616

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Abstract

A series of histamine bis-Schiff bases and bis-spinaceamine derivatives were synthesised and investigated as activators of four human (h) carbonic anhydrase (CA, EC 4.2.1.1) isoforms, the cytosolic hCA I, II and VII, and the membrane-associated hCA IV. All isoforms were effectively activated by the new derivatives, with activation constants in the range of 4.73–10.2 µM for hCA I, 6.15–42.1 µM for hCA II, 2.37–32.7 µM for hCA IV and 32 nM–18.7 µM for hCA VII, respectively. The nature of the spacer between the two histamine/spinaceamine units of these molecules was the main contributor to the diverse activating efficacy, with a very different fine tuning for the diverse isoforms. As CA activators recently emerged as interesting agents for enhancing cognition, in the management of CA deficiencies, or for therapy memory and artificial tissues engineering, our compounds may be considered as candidates for such applications.

Highlights

In previous research from our groups[1,2], we reported two novel classes of activators of the enzyme carbonic anhydrase (CA, EC 4.2.1.1): the histamine Schiff bases[1] and the spinaceamine derivatives[2]
A water molecule coordinated to the zinc ion becomes highly nucleophilic, and as hydroxide ion attacks the CO2 molecule bound within the active site of the enzyme, with formation of bicarbonate coordinated to the zinc (Equation (1))[7–10]
The activator molecule participates to the rate-determining step of the catalytic cycle, that is, the proton shuttling between the zinc-coordinated water molecule and the environment, with the formation of the zinc hydroxide species of the enzyme[3–6,11]

Summary

Introduction

In previous research from our groups[1,2], we reported two novel classes of activators of the enzyme carbonic anhydrase (CA, EC 4.2.1.1): the histamine Schiff bases[1] and the spinaceamine derivatives[2]. The activator molecule participates to the rate-determining step of the catalytic cycle, that is, the proton shuttling between the zinc-coordinated water molecule and the environment, with the formation of the zinc hydroxide species of the enzyme[3–6,11]. The first CAA investigated by means of X-ray crystallography[3], was observed to bind at the entrance of the active site cavity, distant from the zinc ion, and participating in a network of hydrogen bonds involving several water molecules, which, as for His[64], favour the release of the proton from the water molecule coordinated to the zinc, to the reaction medium[3]. We report some new CAAs obtained by considering our previous findings, that is, histamine Schiff bases and spinaceamine derivatives, which posses efficient CA activating properties[1,2]

Chemistry

CA activation