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.