Synthesis, Crystal Structure, Inhibitory Activity and Molecular Docking of Coumarins/Sulfonamides Containing Triazolyl Pyridine Moiety as Potent Selective Carbonic Anhydrase IX and XII Inhibitors

Yassine Aimene,Alessio Nocentini,Jean-Yves Winum,Frédéric Rodriguez,Romain Eychenne,Achour Seridi,Claudiu T Supuran,Eric Benoist,Nathalie Saffon-Merceron,Sonia Mallet-Ladeira

doi:10.3390/cryst11091076

Abstract

In this work, two classes of Carbonic Anhydrase (CA) inhibitors, sulfonamide and coumarin derivatives linked to pyta moiety (2a-b) and their corresponding rhenium complexes (3a-b), were designed. These compounds were synthesized and fully characterized by classical analytical methods and X-ray diffraction. All the synthesized compounds were evaluated for their inhibitory activity against the hCA isoforms I, II, IX and XII. They exhibited high inhibitory activities in the range of nanomolar for both hCA IX and hCA XII isoforms. The sulfonamide compound 2a showed the strongest inhibition against the tumour-associated hCA IX isoform with a Ki of 11.7 nM. The tumour-associated isoforms hCA IX and hCA XII were selectively inhibited by all the coumarin derivatives, with inhibition constants ranging from 12.7 nM (2b) to 44.5 nM (3b), while the hCA I and II isoforms were slightly inhibited (in the micromolar range), as expected. In terms of selectivity, compared to previously published rhenium complex-based CA inhibitors, complex 3b showed one of the highest selectivities against hCA IX and hCA XII compared to the off-target isoforms hCA I and hCA II, making it a potential anti-cancer drug candidate. Molecular docking calculations were performed to investigate the inhibition profiles of the investigated compounds at the tumour-associated hCA IX active site and to rationalize our results.

Highlights

Carbonic anhydrases (CAs, EC 4.2.1.1) are zinc-containing metalloenzymes that catalyze the reversible hydration of carbon dioxide into bicarbonate ions and protons, to maintain acid-base balance in tissues and blood. hCA IX, and XII are known to be highly expressed in various human tissues and malignancies [1]
In a recent paper, we investigated the inhibitory effects of two benzenesulfonamide-based 1,2,3-triazole-pyridine derivatives and their corresponding fac-Re(CO)3 coordination compounds on human cytosolic hCA isoforms I and II, and the membraneassociated hCA IX isoform [24]
We describe a convenient synthesis of two tricarbonyl rhenium(I) complexes, based on bidentate pyridine-triazole ligands functionalized either by the bioactive 4-substituted benzenesulfonamide or a coumarin moiety, and using an ethylene bridge as a spacer in order to minimize sterical interference between the metallic chelating centre and the pharmacophore

Summary

Introduction

Carbonic anhydrases (CAs, EC 4.2.1.1) are zinc-containing metalloenzymes that catalyze the reversible hydration of carbon dioxide into bicarbonate ions and protons, to maintain acid-base balance in tissues and blood. hCA IX, and XII are known to be highly expressed in various human tissues and malignancies [1]. Inhibition of hCA IX activity by small organic molecule CA inhibitors belonging to the sulfonamide/coumarin family leads to a potential inhibition of tumorigenesis [7,8,9]. Sulfonamides and their bioisosters (sulfamates, sulfamides, etc.) were designed to act as potent CA inhibitors [10,11,12,13]. Most of them bind directly to the zinc active centre into the CA cavity [14]. This efficient anti-tumour mechanism makes them a promising class of available anti-cancer agents [15,16]

Methods

Results

Conclusion