Aryl derivatives of 3H-1,2-benzoxathiepine 2,2-dioxide as carbonic anhydrase inhibitors

Aleksandrs Pustenko,Alessio Nocentini,Anastasija Balašova,Ahmed Alafeefy,Mikhail Krasavin,Raivis Žalubovskis,Claudiu T Supuran

doi:10.1080/14756366.2019.1695795

Abstract

A new series of homosulfocoumarins (3H-1,2-benzoxathiepine 2,2-dioxides) possessing various substitution patterns and moieties in the 7, 8 or 9 position of the heterocylic ring were prepared by original procedures and investigated for the inhibition of four physiologically relevant carbonic anhydrase (CA, EC 4.2.1.1) isoforms, the human (h) hCA I, II, IX and XII. The 8-substituted homosulfocoumarins were the most effective hCA IX/XII inhibitors followed by the 7-substituted derivatives, whereas the substitution pattern in position 9 led to less effective binders for the transmembrane, tumour-associated isoforms IX/XII. The cytosolic isoforms hCA I and II were not inhibited by these compounds, similar to the sulfocoumarins/coumarins investigated earlier. As hCA IX and XII are validated anti-tumour targets, with one sulphonamide (SLC-0111) in Phase Ib/II clinical trials, finding derivatives with better selectivity for inhibiting the tumour-associated isoforms over the cytosolic ones, as the homosulfocoumarins reported here, is of crucial importance.

Highlights

Carbonic anhydrases (CAs, EC 4.2.1.1) are metalloenzymes widespread in nature, being encoded by at least eight different genetic families, which have been identified in organisms all over the phylogenetic tree1–3
The primary sulphonamides were discovered as CA inhibitors (CAIs) in the 40 s, and most of the drugs that were launched in the decades as diuretics, antiepileptics, or antiglaucoma agents targeting CAs belonged to this class of compounds1,3–5
A new series of homosulfocoumarins (3H-1,2-benzoxathiepine 2,2dioxides) possessing various moieties in the 7, 8 or 9 position of the heterocylic ring were prepared by original procedures and investigated for the inhibition of four physiologically relevant CA isoforms, hCA I, II, IX and XII

Summary

Introduction

Carbonic anhydrases (CAs, EC 4.2.1.1) are metalloenzymes widespread in nature, being encoded by at least eight different genetic families, which have been identified in organisms all over the phylogenetic tree. CAs are drug targets for decades, with their inhibitors having pharmacological applications in a multitude of fields. The primary sulphonamides were discovered as CA inhibitors (CAIs) in the 40 s, and most of the drugs that were launched in the decades as diuretics, antiepileptics, or antiglaucoma agents targeting CAs belonged to this class of compounds. Highly effective as CAIs1, the sulphonamides generally indiscriminately inhibit most a-CA isoforms present in mammals (at least in humans, and in other vertebrates1) as well as CAs belonging to the other genetic families (b-, c-, d-, f-, g-, h- and i-CAs) and for this reason alternative CAI classes were searched for.

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Results

Conclusion