Coumarins from Magydaris pastinacea as inhibitors of the tumour-associated carbonic anhydrases IX and XII: isolation, biological studies and in silico evaluation

Benedetta Fois,Simona Distinto,Rita Meleddu,Serenella Deplano,Elias Maccioni,Costantino Floris,Antonella Rosa,Mariella Nieddu,Pierluigi Caboni,Claudia Sissi,Andrea Angeli,Claudiu T Supuran,Filippo Cottiglia

doi:10.1080/14756366.2020.1713114

Benedetta Fois, Simona Distinto + Show 11 more

Open Access

https://doi.org/10.1080/14756366.2020.1713114

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Abstract

In an in vitro screening for human carbonic anhydrase (hCA) inhibiting agents from higher plants, the petroleum ether and ethyl acetate extracts of Magydaris pastinacea seeds selectively inhibited hCA IX and hCA XII isoforms. The phytochemical investigation of the extracts led to the isolation of ten linear furocoumarins (1–10), four simple coumarins (12–15) and a new angular dihydrofurocoumarin (11). The structures of the isolated compounds were elucidated based on 1 D and 2 D NMR, MS, and ECD data analysis. All isolated compounds were inactive towards the ubiquitous cytosolic isoform hCA I and II (K i > 10,000 nM) while they were significantly active against the tumour-associated isoforms hCA IX and XII. Umbelliprenin was the most potent coumarin inhibiting hCA XII isoform with a K i of 5.7 nM. The cytotoxicity of the most interesting compounds on HeLa cancer cells was also investigated.

Highlights

Coumarins occur as secondary metabolites in many plant species, but above all, in Apiaceae, Rutaceae, Asteraceae and Fabaceae
Continuing our search for biologically active secondary metabolites from Sardinian higher plants19,20, we have found that the petroleum ether and ethyl acetate extracts of Magydaris pastinacea seeds exhibited potent inhibitory activity against human carbonic anhydrase (hCA) IX and XII
The furocoumarins 1–9, 11 and coumarins 12, 15 inhibited both hCA IX and hCA XII in a nanomolar range and they were completely inactive (Ki values > 10,000 nM) against hCA I and II, showing high selectivity over these isoforms that are considered responsible for the side-effects of CAIs

Summary

Introduction

Coumarins occur as secondary metabolites in many plant species, but above all, in Apiaceae, Rutaceae, Asteraceae and Fabaceae. Natural coumarins have attracted considerable attention because of their wide range of biological activities including anti-HIV1, antimicrobial, anticancer, anticoagulant, antioxidant, and antiinflammatory properties. CAs are ubiquitous metallo-enzymes, which are widely present in prokaryotes and eukaryotes. Sixteen different human (h) CA isoforms (I–XV, VA and VB) are present in mammals. These enzymes catalyse a very simple but essential physiological reaction of the life cycle of many organisms, the reversible hydration of carbon dioxide to bicarbonate and protons. The systemic administration of hCA inhibitors (hCAIs) causes a wide range of side effects due to the lack of isozyme selectivity that leads to inhibition of the ubiquitous hCA I and II isoforms

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