Abstract
Carbonic anhydrases (CAs, EC 4.2.1.1) catalyze the essential reaction of CO2 hydration in all living organisms, being actively involved in the regulation of a plethora of patho/physiological conditions. A series of chromene-based sulfonamides were synthesized and tested as possible CA inhibitors. Their inhibitory activity was assessed against the cytosolic human isoforms hCA I, hCA II and the transmembrane hCA IX and XII. Several of the investigated derivatives showed interesting inhibition activity towards the tumor associate isoforms hCA IX and hCA XII. Furthermore, computational procedures were used to investigate the binding mode of this class of compounds, within the active site of hCA IX.
Highlights
The carbonic anhydrases (CA’s) are metalloenzymes that catalyze the formation of bicarbonate from carbon dioxide in two steps [1,2,3,4]
As a part of the ongoing studies that are focusing on the synthesis of big libraries for biological screening, we discovered that the combination of N,N,N,N -tetramethylchloroformamidinium hexafluoro-phosphate (TCFH) and N-methylimidazole (NMI) is a mild method for in situ generation of highly reactive acyl imidazoliums, allowing for the formation of the amides in high yields
We synthetized and investigated two novel series of chromene-containing aromatic sulfonamides for their effective inhibition against different and most relevant human carbonic anhydrase isoforms such as the ubiquitous hCA I, hCA II, and the tumor associate isoforms hCA IX and XII, which are involved in a variety of diseases such as glaucoma, retinitis pigmentosa, epilepsy, and tumors
Summary
The carbonic anhydrases (CA’s) are metalloenzymes that catalyze the formation of bicarbonate from carbon dioxide in two steps [1,2,3,4]. Many CA subtypes are interesting targets for the design of pharmacological agents useful, for example, as antiglaucoma, anticonvulsant, antiurolithic, and for the treatment of obesity [6]. Isoforms CA IX and CA XII were discovered to be overexpressed and associated with many tumors, where they are involved in processes related with cancer progression [7,8,9]. Small molecules targeting CA IX/XII inhibition may be an attractive strategy against cancer. Due to high homology among the human isoforms, selectivity towards one of them is of the highest importance to prevent off-target related side effects. The classical CA inhibitors (CAIs) are the primary sulfonamides, which coordinate the zinc ion with their terminal deprotonated nitrogen atom and have been in clinical use for more than 70 years as diuretics and systemically acting antiglaucoma drugs [10].
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