Sulfocoumarins as dual inhibitors of human carbonic anhydrase isoforms IX/XII and of human thioredoxin reductase

Mikhail Krasavin,Raivis Žalubovskis,Aiga Grandāne,Ilona Domračeva,Petr Zhmurov,Claudiu T Supuran

doi:10.1080/14756366.2020.1712596

Abstract

The hypothesis that sulfocoumarin acting as inhibitors of human carbonic anhydrase (CA, EC 4.2.1.1) cancer-associated isoforms hCA IX and – hCA XII is being able to also inhibit thioredoxin reductase was verified and confirmed. The dual targeting of two cancer cell defence mechanisms, i.e. hypoxia and oxidative stress, may both contribute to the observed antiproliferative profile of these compounds against many cancer cell lines. This unprecedented dual anticancer mechanism may lead to a new approach for designing innovative therapeutic agents.

Highlights

Earlier, we reported 6-substituted sulfocoumarins 11 as potent and remarkably isoform-selective inhibitors of the metallo-enzyme carbonic anhydrase (CA, EC 4.2.1.1)[7,8]
The ability of sulfocoumarins to selectively inhibit membrane-bound hCA IX and XII isoforms were attributed to the unique mechanism of action of these compounds whereby they act as prodrugs activated by CA-mediated hydrolysis[1,2,3,4,5,6]
This makes these inhibitors fundamentally different from the classical carbonic anhydrase inhibitors (CAIs) – e.g. those of sulphonamide type which act by binding to the CA prosthetic zinc ion present in all isoforms, which makes designing isoformselective sulphonamide CAIs difficult

Summary

Introduction

We reported 6-substituted sulfocoumarins 11 (designed as isosteres of the structurally related coumarins2–6) as potent and remarkably isoform-selective inhibitors of the metallo-enzyme carbonic anhydrase (CA, EC 4.2.1.1)[7,8]. CA-mediated hydrolysis of sulfocoumarins 1 (as well as their progenitors coumarins) leads to the in situ formation of the Z-configured stiryl sulphonic acid (Z)-2 which is likely to isomerise to (E)-2, the active inhibitor form whose binding to CA was confirmed by X-ray crystallography[1] This inhibitor activation and binding apparently occurs only in the protein environment of the two membrane-bound isoforms (hCA IX and XII) which makes these mechanistically distinct inhibitors ideal tools for targeting hypoxia survival mechanism in tumour cells providing which overexpression of precisely these two isoforms is considered responsible for[9]. Selective targeting of hCA IX and XII has been confirmed to lead to retardation of tumour growth and, reduction of tumour size[10]

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Conclusion