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PDBsum entry 2cn0
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Hydrolase/hydrolase inhibitor
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PDB id
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2cn0
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References listed in PDB file
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Key reference
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Title
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Mapping the fluorophilicity of a hydrophobic pocket: synthesis and biological evaluation of tricyclic thrombin inhibitors directing fluorinated alkyl groups into the p pocket.
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Authors
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A.Hoffmann-Röder,
E.Schweizer,
J.Egger,
P.Seiler,
U.Obst-Sander,
B.Wagner,
M.Kansy,
D.W.Banner,
F.Diederich.
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Ref.
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Chemmedchem, 2006,
1,
1205-1215.
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PubMed id
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Abstract
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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.
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