Synthesis and Biological Evaluation of Coumarin-Linked 4-Anilinomethyl-1,2,3-Triazoles as Potent Inhibitors of Carbonic Anhydrases IX and XIII Involved in Tumorigenesis.

Pavitra S Thacker,Danaboina Srikanth,Claudiu T Supuran,Prerna L Tiwari,Mohammed Arifuddin,Baijayantimala Swain,Andrea Angeli

doi:10.3390/metabo11040225

Abstract

A series of coumarin-linked 4-anilinomethyl-1,2,3-triazoles (6a–t) was synthesized via a molecular hybridization approach, through carbon C-6 of the coumarin moiety. The synthesized compounds were evaluated for their inhibition of carbonic anhydrase (CA) isoforms I, II, IX and XIII. CAs IX and XIII were selectively inhibited over the off-target isoforms I and II. The best inhibitory profiles against CA IX were shown by compounds 6a, 6e and 6f (Ki < 50 nM), with compound 6e displaying the best inhibition with a Ki value of 36.3 nM. Compounds 6a, 6b, 6j, 6o and 6q exhibited the best inhibitory profiles against CA XIII (Ki < 100 nM). These compounds can be further explored for the discovery of potent and effective CA IX and CA XIII inhibitors.

Highlights

Metalloenzymes and metalloproteins are two key players in cellular regulation, which act by maintenance of homoeostasis, control of metal ion concentrations, buffering and activation of signal pathways
Carbonic anhydrases (CAs, EC 4.2.1.1) are a super family of metalloenzymes, which play a fundamental role in the inter conversion of CO2 to bicarbonate and proton
Most of them contain a Zn(II) ion in their active sites, but in ζ carbonic anhydrase (CA) the Zn(II) ion is interchangeable with Cd(II)

Summary

Introduction

Metalloenzymes and metalloproteins are two key players in cellular regulation, which act by maintenance of homoeostasis, control of metal ion concentrations, buffering and activation of signal pathways. Carbonic anhydrases (CAs, EC 4.2.1.1) are a super family of metalloenzymes, which play a fundamental role in the inter conversion of CO2 to bicarbonate and proton Thereby, they perform the constant physiological demand of converting CO2 generated during metabolic oxidative processes into ionic, soluble species [1,2]. The coumarins are initially acting as CA substrates, their lactone ring being hydrolyzed by the enzyme to 2-hydroxy-cinnamic acids which bind in a very unusual part of the CA active site, at its entrance, occluding it [16,17] After this finding, several groups, all of them collaborating with ours, have reported diverse coumarin-containing molecules, which act as potent and frequently isoform-selective inhibitors of human CAs, hCA IX and XII [19].

Chemistry

RReessuullttss

CCaarrbboonniicc AAnnhhyyddrraassee IInnhhiibittiioonn

Conclusions

CA Inhibition