Novel reversible methionine aminopeptidase-2 (MetAP-2) inhibitors based on purine and related bicyclic templates
| Autor: | Felix Rohdich, Thorsten Knöchel, Hans-Peter Buchstaller, Mireille Krier, Birgitta Leuthner, Frank Zenke, Jörg Bomke, Timo Heinrich, Djordje Musil, Manja Friese-Hamim, Bertram Cezanne |
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| Rok vydání: | 2017 |
| Předmět: |
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Molecular Purine Stereochemistry Clinical Biochemistry Pharmaceutical Science Aminopeptidases 01 natural sciences Biochemistry Structure-Activity Relationship chemistry.chemical_compound Drug Discovery Hydrolase medicine Humans Methionyl Aminopeptidases Imidazole Moiety Fumagillin Molecular Biology Protein maturation Glycoproteins Dose-Response Relationship Drug Molecular Structure Bicyclic molecule 010405 organic chemistry Organic Chemistry METAP2 0104 chemical sciences 010404 medicinal & biomolecular chemistry Pyrimidines chemistry Purines Molecular Medicine medicine.drug |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 27:551-556 |
| ISSN: | 0960-894X |
| Popis: | The natural product fumagillin 1 and derivatives like TNP-470 2 or beloranib 3 bind to methionine aminopeptidase 2 (MetAP-2) irreversibly. This enzyme is critical for protein maturation and plays a key role in angiogenesis. In this paper we describe the synthesis, MetAP-2 binding affinity and structural analysis of reversible MetAP-2 inhibitors. Optimization of enzymatic activity of screening hit 10 (IC50: 1μM) led to the most potent compound 27 (IC50: 0.038μM), with a concomitant improvement in LLE from 2.1 to 4.2. Structural analysis of these MetAP-2 inhibitors revealed an unprecedented conformation of the His339 side-chain imidazole ring being co-planar sandwiched between the imidazole of His331 and the aryl-ether moiety, which is bound to the purine scaffold. Systematic alteration and reduction of H-bonding capability of this metal binding moiety induced an unexpected 180° flip for the triazolo[1,5-a]pyrimdine bicyclic template. |
| Databáze: | OpenAIRE |
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