Novel 8-Substituted Coumarins That Selectively Inhibit Human Carbonic Anhydrase IX and XII.

Kerem Buran,Giulio Poli,Silvia Bua,F Önen Bayram,Claudiu T Supuran,Tiziano Tuccinardi

doi:10.3390/ijms20051208

Kerem Buran, Giulio Poli + Show 4 more

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https://doi.org/10.3390/ijms20051208

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Abstract

A novel series of 8-substituted coumarin-based compounds, characterized by the presence of alkylpiperazine and arylpiperazine chains, were synthesized and tested for their inhibitory activity against four human carbonic anhydrase (hCA) isoforms. All compounds displayed nanomolar potency against the cancer-related hCA IX and hCA XII; moreover, they were shown to be devoid of any inhibitory activity toward the cytosolic hCA I and hCA II up to 10 µM concentration in the assay system. Therefore, the synthesized coumarin ligands demonstrated to be potent and selective hCA IX/XII inhibitors, and were shown to be as potent as the reference inhibitor acetazolamide against hCA XII, with single-digit nanomolar Ki values. Molecular modeling studies provided a rationale for explaining the selectivity profile of these non-classic hCA inhibitors and their interactions with the enzymes, according to their specific mechanism of action, thus paving the way for future structure-based lead optimization studies.

Highlights

Carbonic anhydrase (CA, EC 4.2.1.1) is a family of metalloenzymes that catalyze the reversible interconversion of carbon dioxide and water to bicarbonate and a proton [1]
CAIs are generally compounds endowed with a suitable zinc-binding group (ZBG) able to chelate the prosthetic zinc ion placed within the binding site of human carbonic anhydrase (hCA), which is critical for the catalytic activity of these enzymes
These groups are effective for endowing small-molecule ligands with high affinity for hCAs, since they allow a proper coordination of the catalytic zinc ion and the formation of H-bond interactions with key protein residues placed in the surroundings of the zinc-binding cavity

Summary

Introduction

Carbonic anhydrase (CA, EC 4.2.1.1) is a family of metalloenzymes that catalyze the reversible interconversion of carbon dioxide and water to bicarbonate and a proton [1]. Sixteen CA isoforms are present and they all differ for kinetic properties, sub-cellular localization and tissue distribution. The most common ZBGs shared by classic CAIs are represented by sulfonamide moieties or similar structural motifs (such as sulfamides and sulfamates) These groups are effective for endowing small-molecule ligands with high affinity for hCAs, since they allow a proper coordination of the catalytic zinc ion and the formation of H-bond interactions with key protein residues placed in the surroundings of the zinc-binding cavity. 2in01o8,a1c9i,dx cFoOnRsPeErvERatRioEnVIoEbWserved in the different hCA isoforms at the level of their cata2loyfti1c3 staasoiptdttweeejacnaacirtnfediinodcsntptarhideenecjgaritifiachopceennetsmhut,etretirehcdagaepiiclsoeleiyunnltasiii,gnlctacathehlnlreeydesmsseintioiltsniefgttgrreaeynnshfitdCipensArlgedosshf,.etCseIninnAnt csptpe.hraIeetrnhstdieepcrnsauaetrlwtatiishrcbo,ueafhlcodaCkrrrm,AaohwfsCIbbhXAaeaciIvanXknegdoabinfenhdbesCneuhAiCfdnfiAgecXsiiiIXengInIsnIhtualhayftafivevsedceeieldaednsrcrtatbaliwywvioensnmetssloaeppwrceektccaieviirraadesll aanttdenpthioanrminatchoelomgiecdailctianraglecthsefmorisvtaryriofiuelsdc,asnincecer ttyhpesees.isAosfoarmcosnhseaqvue ebneceen, da ewsiigdneaateredaaosfbrieosmeaarrckheriss caunrdrepnhtlayrmfoaccuosleodgiocanltthaerginethsibfoitriovnaroiof uthsecsaentcwero teynpzeysm.

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