Abstract
Psammaplin C is one of only two described natural product primary sulfonamides. Here we report the synthesis of psammaplin C and evaluate the inhibition profile against therapeutically relevant carbonic anhydrase (CA) zinc metalloenzymes. The compound exhibited unprecedented inhibition of an important cancer-associated isozyme, hCA XII, with a Ki of 0.79 nM. The compound also displayed good isoform selectivity for hCA XII over other CAs. We present the first reported protein X-ray crystal structures of psammaplin C in complex with human CAs. We engineered the easily crystallized hCA II enzyme to mimic both the hCA IX and hCA XII binding sites and then utilized protein X-ray crystallography to determine the binding pose of psammaplin C within the hCA II, hCA IX, and hCA XII mimic active sites, all to high resolution. This is the first time a natural product primary sulfonamide inhibitor has been assessed for inhibition and binding to CAs.
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