Pre-organization of the core structure of E-selectin antagonists.
A new class of N-acetyl-D-glucosamine (GlcNAc) mimics for E-selectin antagonists was designed and synthesized. The mimic consists of a cyclohexane ring substituted with alkyl substituents adjacent to the linking position of the fucose moiety. Incorporation into E-selectin antagonists led to the test compounds 8 and the 2'-benzoylated analogues 21, which exhibit affinities in the low micromolar range. By using saturation transfer difference (STD)-NMR it could be shown that the increase in affinity does not result from an additional hydrophobic contact of the alkyl substituent with the target protein E-selectin, but rather from a steric effect stabilizing the antagonist in its bioactive conformation. The loss of affinity found for antagonists 10 and 35 containing a methyl substituent in a remote position (and therefore unable to support to the stabilization of the core) further supports this hypothesis. Finally, when a GlcNAc mimetic containing two methyl substituents (52 and 53) was used, in which one methyl was positioned adjacent to the fucose linking position and the other was in a remote position, the affinity was regained.
Institute of Molecular Pharmacy, Pharmacenter, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
Daniel
D
Schwizer
John T
JT
Patton
Brian
B
Cutting
Martin
M
Smieško
Beatrice
B
Wagner
Ako
A
Kato
Céline
C
Weckerle
Florian P C
FP
Binder
Said
S
Rabbani
Oliver
O
Schwardt
John L
JL
Magnani
Beat
B
Ernst
D000117:Acetylglucosamine / Q000737:chemistry*; D019040:E-Selectin / Q000737:chemistry* / Q000187:drug effects*; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D015394:Molecular Structure; D013329:Structure-Activity Relationship
D019040:E-Selectin; D000117:Acetylglucosamine