Atropo/Tropo Flexibility: A Tool for Design and Synthesis of Self- Adaptable Inhibitors of Carbonic Anhydrases and Their Antiproliferative Effect

Here, we report for the first time a series of sulfonamide derivatives with scaffolds bearing flexible moieties, namely, rotamers or tropoisomers capable of adapting their geometry in the active center of enzymes thus being effective and selective carbonic anhydrase (CAs, EC 4.2.1.1) enzyme inhibitors. All compounds exhibited effective in vitro inhibition activity toward the main hCA isoforms related to cancer (i.e., hCA II, hCA IX, and hCA XII with KI values in the low nanomolar range). Three selected compounds showed a great cytotoxic effect on cancer cell lines ex vivo. X-ray crystallographic experiments assessed the binding modes of compound 35 with active centers of hCA IX and hCA XII.

Automated summary

In this study, we present a series of sulfonamide derivatives with flexible moieties that can adapt their geometry in the active center of enzymes, resulting in effective and selective inhibition of carbonic anhydrase enzymes. These compounds demonstrated potent in vitro inhibition activity against cancer-related hCA isoforms and exhibited cytotoxic effects on cancer cell lines. Crystallographic experiments confirmed the binding modes of compound 35 with the active centers of hCA IX and hCA XII.