An Unusual Natural Product Primary Sulfonamide: Synthesis, Carbonic Anhydrase Inhibition, and Protein X‑ray Structures of Psammaplin C

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.