Carbon- versus sulphur-based zinc binding groups for carbonic anhydrase inhibitors?

Abstract

A set of compounds incorporating carbon-based zinc-binding groups (ZBGs), of the type PhX (X = COOH, CONH₂, CONHNH₂, CONHOH, CONHOMe), and the corresponding derivatives with sulphur(VI)-based ZBGs (X = SO₃H, SO₂NH₂, SO₂NHNH₂, SO₂NHOH, SO₂NHOMe) were tested as inhibitors of all mammalian isoforms of carbonic anhydrase (CA, EC 4.2.1.1), CA I–XV. Three factors connected with the ZBG influenced the efficacy as CA inhibitor (CAI) of the investigated compounds: (i) the pKa of the ZBG; (ii) its geometry (tetrahedral, i.e. sulphur-based, versus trigonal, i.e. carbon-based ZBGs), and (iii) orientation of the organic scaffold induced by the nature of the ZBG. Benzenesulphonamide was the best inhibitor of all isoforms, but other ZBGs led to interesting inhibition profiles, although with an efficacy generally reduced when compared to the sulphonamide. The nature of the ZBG also influenced the CA inhibition mechanism. Most of these derivatives were zinc binders, but some of them (sulfonates, carboxylates) may interact with the enzyme by anchoring to the zinc-coordinated water molecule or by other inhibition mechanisms (occlusion of the active site entrance, out of the active site binding, etc.). Exploring structurally diverse ZBGs may lead to interesting new developments in the field of CAIs.

Keywords:

• Carbonic anhydrase
• inhibitors
• inhibition mechanism
• zinc binder
• anchoring to zinc-coordinated water
• sulphonamide
• hydroxamate
• carboxylate

Acknowledgements

I am particularly grateful to Dr. Alfonso Maresca for skilful technical assistance and to Dr. Marta Ferraroni for Figure 3.

Disclosure statement

The author declares no conflict of interest.

Additional information

Funding

Research was financed by several EU projects (Euroxy, Metoxia, DeZnIt, and Dynano).