Abstract
In this work, two bidentate 2-pyridyl-1,2,3-triazole ligands (3a and 3b) containing a 4-substituted benzenesulfonamide pharmacophore prepared by classical click chemistry procedures, as well as their corresponding rhenium complexes, 4a and 4b of general formula [ReCl(CO)3(L)] (L = 3a or 3b) were prepared and fully characterised by spectroscopic methods (IR, NMR, MS, UV-Vis), elemental analysis, X-ray diffraction, and theoretical studies using DFT and TD-DFT methods. In particular, we showed that, in the solid state, the pyridine and the triazole rings of 3b adopted an uncommon cis configuration which stems from intermolecular hydrogen bonds. Preliminary assays demonstrated a promising nanomolar inhibitory activity against carbonic anhydrase isoform IX for both ligands and complexes with a strong affinity Ki of 2.8 nM for ligand 3a. More interestingly, complex 4b exhibited a pronounced selectivity against hCA IX over the off-targets hCA I and hCA II which makes this compound a promising potential anticancer drug candidate.
Highlights
Rhenium(I) tricarbonyl complexes have been intensively studied by the inorganic chemist community, due to their significant photophysical and photochemical properties
These features make them interesting tools for numerous potential practical applications, such as photo sensitisers in solar cells[1], CO2 reduction catalysts[2], organic light-emitting devices (OLEDs)[3], luminescence sensors[4], and CO-releasing moieties (CORMs)[5]
We previously reported the preparation of two [M(CO)3]þ complexes (M 1⁄4 Re and 99mTc) from a pyridyltriazolebased ligand bearing the bioactive (2-methoxyphenyl) piperazine pharmacophore, which is a central nervous system (CNS) receptors-targeted vector
Summary
Rhenium(I) tricarbonyl complexes have been intensively studied by the inorganic chemist community, due to their significant photophysical and photochemical properties. Complexes were iso-structural, as expected, (ii) the rhenium complex exhibited fluorescence at room temperature and the radioactive 99mTc-complex presented a suitable lipophilic character for its use as CNS imaging agent12a Given these first results, we decided to explore similar systems as potential human carbonic anhydrase inhibitors (CAIs) by adding a heterocyclic sulfonamide moiety to a pyta scaffold. While sulfonamides (and bioisosteres sulfamates and sulfamides) are known to possess very efficient carbonic anhydrase inhibitory properties[13], only a few examples of benzenesulfonamide-based compounds incorporating a [M(CO)3]þ complex (M 1⁄4 Re and 99mTc) have been reported[14] Among these examples, Alberto and coworkers showed that simple piano-stool-type rhenium complexes with a pendent arylsulfonamide arm inhibited hCA IX and hCA XII with nanomolar affinities14c. Preliminary biological assays against cytosolic/membrane-associated carbonic anhydrase isoforms I, II and IX (hCAs I, II and IX) were performed with both ligands and complexes and first results are promising
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