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J Med Chem. 2016 Jun 9;59(11):5462-70. doi: 10.1021/acs.jmedchem.6b00443. Epub 2016 May 23.

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

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Eskitis Institute for Drug Discovery, Griffith University , Don Young Road, Nathan, Queensland 4111, Australia.
Polo Scientifico, Neurofarba Department, and Laboratorio di Chimica Bioinorganica, Universit√°degli Studi di Firenze , Via della Lastruccia 3, 50019 Sesto Fiorentino, Florence Italy.
CSIRO , 343 Royal Parade, Parkville, Victoria 3052, Australia.


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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