Design, synthesis, and biological evaluation of novel carbohydrate-based sulfamates as carbonic anhydrase inhibitors.

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Lopez M, Trajkovic J, Bornaghi LF, Innocenti A, Vullo D, Supuran CT, Poulsen SA

Design, synthesis, and biological evaluation of novel carbohydrate-based sulfamates as carbonic anhydrase inhibitors.

J Med Chem. 2011 Mar 10;54(5):1481-9. doi: 10.1021/jm101525j. Epub 2011 Feb 11.

PubMed ID

21314129 [ View in PubMed

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Abstract

Carbonic anhydrases (CAs) IX and XII are enzymes with newly validated potential for the development of personalized, first-in-class cancer chemotherapies. Here we present the design and synthesis of novel carbohydrate-based CA inhibitors, several of which were very efficient inhibitors (K(i)<10 nM) with good selectivity for cancer-associated CA isozymes over off-target CA isozymes. All inhibitors comprised a carbohydrate core with one hydroxyl group derivatized as a sulfamate. Five different carbohydrates were chosen to present a selection of molecular shapes with subtle stereochemical differences to the CA enzymes active site. Variable modifications of the remaining sugar hydroxyl groups were incorporated to provide an incremental coverage of chemical property parameters that are associated with biopharmaceutical performance. All sulfamate inhibitors displayed ligand efficiencies that are consistent with those reported for good drug lead candidates.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Topiramate	Carbonic anhydrase 1	Ki (nM)	250	N/A	N/A	Details
Topiramate	Carbonic anhydrase 2	Ki (nM)	5	N/A	N/A	Details