Novel thiazolidinone-containing compounds, without the well-known sulphonamide zinc-binding group acting as human carbonic anhydrase IX inhibitors

Özlen Güzel-Akdemir,Andrea Angeli,Kübra Demir,Claudiu T Supuran,Atilla Akdemir

doi:10.1080/14756366.2018.1499628

Abstract

A small collection of 26 structurally novel thiazolidinone-containing compounds, without the well-known sulphonamide zinc-binding group, were synthesised and tested in enzyme inhibition assays against the tumour-associated hCA IX enzyme. Inhibition constants in the lower micromolar region (KI < 25 μM) have been measured for 17 of the 26 compounds. Even though the KI values are relatively weak, the fact that they do not contain a sulphonamide moiety suggests that these compounds do not interact with the active site zinc ion. Therefore, docking studies and molecular dynamics simulations have been performed to suggest binding poses for these structurally novel inhibitors.

Highlights

Carbonic anhydrases (CAs; EC 4.2.1.1) are a structurally diverse family of metallo-enzymes that catalyse the reversible hydration of carbon dioxide to bicarbonate and protons[1]
The human CA isoform IX, which belongs to the a-subfamily of CAs, is expressed in the stomach and peritoneal lining
HCA IX is upregulated in many solid hypoxic tumours and it helps the tumour cell to function in an acidic environment[1,2,3,4,5]

Summary

Introduction

Carbonic anhydrases (CAs; EC 4.2.1.1) are a structurally diverse family of metallo-enzymes that catalyse the reversible hydration of carbon dioxide to bicarbonate and protons[1]. Many CA inhibitors (including hCA IX inhibitors) bind to the active site zinc ion via a so called zinc-binding group (ZBG), which is a sulphonamide in most cases, and thereby block the reversible hydration of carbon dioxide[12]. One such example is compound SLC-0111, a sulphonamide-containing potent CA inhibitor, which is currently in clinical trials[13,14,15,16,17,18,19,20,21]. Docking studies and molecular dynamics simulations were performed to suggest binding poses for these compounds

Materials and methods

Results and discussion

Conclusions