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

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

Author information

1
Eskitis Institute for Cell and Molecular Therapies, Griffith University, Nathan, Queensland 4111, Australia.

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.

PMID:
21314129
DOI:
10.1021/jm101525j
[Indexed for MEDLINE]

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