Carbonic anhydrase inhibitors. Interaction of the antitumor sulfamate EMD 486019 with twelve mammalian carbonic anhydrase isoforms: Kinetic and X-ray crystallographic studies
| Autor: | Claudiu T. Supuran, Claudia Temperini, Andrea Scozzafava, Alessio Innocenti |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
Stereochemistry
Clinical Biochemistry Molecular Conformation Pharmaceutical Science Crystallography X-Ray Biochemistry Isozyme Mice Coumarins Carbonic anhydrase Drug Discovery medicine Steroid sulfatase Animals Humans Carbonic Anhydrase Inhibitors Molecular Biology Carbonic Anhydrases chemistry.chemical_classification Sulfonamides Molecular Structure biology Organic Chemistry Active site Lyase Isoenzymes Enzyme Mechanism of action chemistry Enzyme inhibitor Drug Design biology.protein Molecular Medicine Sulfonic Acids medicine.symptom |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 18:4282-4286 |
| ISSN: | 0960-894X |
| Popis: | The new antitumor sulfamate EMD 486019 was investigated for its interaction with twelve catalytically active mammalian carbonic anhydrase (CA, EC 4.2.1.1) isozymes, hCA I – XIV. Similarly to 667-Coumate, a structurally related compound in phase II clinical trials as steroid sulfatase/CA inhibitor with potent antitumor properties, EMD 486019 acts as a strong inhibitor of isozymes CA II, VB, VII, IX, XII, and XIV (KIs in the range of 13–19 nM) being less effective against other isozymes (KIs in the range of 66–3600 nM against hCA I, IV, VA, VI, and mCA XIII, respectively). The complete inhibition profile of 667-Coumate against these mammalian CAs is also reported here for the first time. Comparing the X-ray crystal structures of the two adducts of CA II with EMD 486019 and 667-Coumate, distinct orientations of the bound sulfamates within the enzyme cavity were observed, which account for their distinct inhibition profiles. CA II/IX potent inhibitors belonging to the sulfamate class are thus valuable clinical candidates with potential for development as antitumor agents with a multifactorial mechanism of action. |
| Databáze: | OpenAIRE |
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