Synthesis, biological activity and multiscale molecular modeling studies for coumaryl-carboxamide derivatives as selective carbonic anhydrase IX inhibitors

Belma Zengin Kurt,Fatih Sonmez,Serdar Durdagi,Busecan Aksoydan,Ramin Ekhteiari Salmas,Andrea Angeli,Mustafa Kucukislamoglu,Claudiu T Supuran

doi:10.1080/14756366.2017.1354857

Abstract

New coumaryl-carboxamide derivatives with the thiourea moiety as a linker between the alkyl chains and/or the heterocycle nucleus were synthesized and their inhibitory activity against the human carbonic anhydrase (hCA) isoforms hCA I, II, VII and IX were evaluated. While the hCA I, II and VII isoforms were not inhibited by the investigated compounds, the tumour-associated isoform hCA IX was inhibited in the high nanomolar range. 2-Oxo-N-((2-(pyrrolidin-1-yl)ethyl)carbamothioyl)-2H-chromene-3-carboxamide (e11) exhibited a selective inhibitory action against hCA IX with the Ki of 107.9 nM. In order to better understand the inhibitory profiles of studied molecules, multiscale molecular modeling approaches were used. Different molecular docking algorithms were used to investigate binding poses and predicted binding energies of studied compounds at the active sites of the CA I, II, VII and IX isoforms.

Highlights

The carbonic anhydrases (CAs; EC 4.2.1.1) are a superfamily of metalloenzymes that present in all organisms and consist of metallic core of Zn2þ ion at their active center[1,2,3,4]
HCA IX is expressed in a restricted number of normal tissues, whereas it is over expressed in many solid tumours and considered involved in important processes connected with cancer progression
Continuing our interest in coumarin CA inhibitors (CAIs), in this work, we report the synthesis of novel thiourea-substituted coumaryl-carboxamid derivatives and their effects on the inhibitory activity of human carbonic anhydrase hCA I, hCA II, hCA VII and hCA IX

Summary

Introduction

The carbonic anhydrases (CAs; EC 4.2.1.1) are a superfamily of metalloenzymes that present in all organisms and consist of metallic core of Zn2þ ion at their active center[1,2,3,4]. The physiologically relevant reaction that CAs catalyse, using as substrates CO2, COS, CS2, cyanamide, carboxylic, phosphoric and thiocarboxylicesters[11,12,13,14]. HCA IX is expressed in a restricted number of normal tissues, whereas it is over expressed in many solid tumours and considered involved in important processes connected with cancer progression. The over expression of hCA IX induces the pH imbalance of tumour tissue contributing significantly to the extracellular acidification of solid tumour; thereby hCA IX inhibitors could bind hypoxic tumour cells expressing this isoform[17,18,19,20,21,22,23,24]. It has been considered that the CA inhibitors are crucial molecules for the synthesis of new-generation anticancer drugs[25]

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Discussion

Conclusion