Mapping the fluorophilicity of a hydrophobic pocket: synthesis and biological evaluation of tricyclic thrombin inhibitors directing fluorinated alkyl groups into the p pocket
| Autor: | Paul Seiler, Eliane Schweizer, Anja Hoffmann-Röder, Jonas Egger, Ulrike Obst-Sander, Björn Wagner, David Banner, François Diederich, Manfred Kansy |
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| Rok vydání: | 2006 |
| Předmět: |
Models
Molecular Magnetic Resonance Spectroscopy Spectrophotometry Infrared Stereochemistry Substituent Crystallography X-Ray Biochemistry Antithrombins chemistry.chemical_compound Drug Discovery Non-covalent interactions General Pharmacology Toxicology and Pharmaceutics Maleimide Alkyl Pharmacology chemistry.chemical_classification Sulfonyl Nucleophilic addition biology Molecular Structure Organic Chemistry Active site Fluorine Cycloaddition chemistry Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization biology.protein Molecular Medicine |
| Zdroj: | ChemMedChem. 1(11) |
| ISSN: | 1860-7179 |
| Popis: | In the completion of our fluorine scan of tricyclic inhibitors to map the fluorophilicity/fluorophobicity of the thrombin active site, a series of 11 new ligands featuring alkyl, alkenyl, and fluoroalkyl groups was prepared to explore fluorine effects on binding into the hydrophobic proximal (P) pocket, lined by Tyr 60A and Trp 60D, His 57, and Leu 99. The synthesis of the tricyclic scaffolds was based on the 1,3-dipolar cycloaddition of azomethine ylides, derived from L-proline and 4-bromobenzaldehyde, with N-(4-fluorobenzyl)maleimide. Introduction of alkyl, alkenyl, and partially fluorinated alkyl residues was achieved upon substitution of a sulfonyl group by mixed Mg/Zn organometallics followed by oxidation/deoxyfluorination, as well as oxidation/reduction/deoxyfluorination sequences. In contrast, the incorporation of perfluoroalkyl groups required a stereoselective nucleophilic addition reaction at the "upper" carbonyl group of the tricycles, thereby yielding scaffolds with an additional OH, F, or OMe group, respectively. All newly prepared inhibitors showed potent biological activity, with inhibitory constants (K(i) values) in the range of 0.008-0.163 microM. The X-ray crystal structure of a protein-ligand complex revealed the exact positioning of a difluoromethyl substituent in the tight P pocket. Fluorophilic characteristics are attributed to this hydrophobic pocket, although the potency of the inhibitors was found to be modulated by steric rather than electronic factors. |
| Databáze: | OpenAIRE |
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