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Synthesis and analysis of the enantiomers of calmidazolium, and a 1 H NMR demonstration of a chiral interaction with calmodulin
Author(s) -
Edwards Andrew J.,
Sweeney Patricia J.,
Reid David G.,
Walker John M.,
Elshourbagy Nabil,
Egwuagu Charles E.,
Young James F.,
Patton Curtis L.
Publication year - 1996
Publication title -
chirality
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.43
H-Index - 77
eISSN - 1520-636X
pISSN - 0899-0042
DOI - 10.1002/(sici)1520-636x(1996)8:8<545::aid-chir2>3.0.co;2-8
Subject(s) - chemistry , calmodulin , enantiomer , chirality (physics) , stereochemistry , proton nmr , chiral column chromatography , hydrogen–deuterium exchange , imidazole , nuclear magnetic resonance spectroscopy , fast protein liquid chromatography , high performance liquid chromatography , organic chemistry , calcium , chiral symmetry breaking , physics , quantum mechanics , nambu–jona lasinio model , quark , hydrogen
Calmidazolium {R24571, 1‐[ bis (4‐chlorophenyl)methyl]‐3‐[2‐(2,4‐dichlorophenyl)‐2‐[(2,4‐dichlorophenyl)methoxy]ethyl]‐1H‐imidazolium chloride} is a potent calmodulin inhibitor. This paper describes the synthesis and properties of the enantiomers of calmidazolium from the enantiomers of miconazole {1(N)‐(2‐(2,4‐dichlorobenzyloxy)‐2‐(2,4‐dichlorophenyl))‐ethyl imidazole}, prepared from the racemate by chiral preparative scale high performance liquid chromatography. Overlap between ligand and protein resonances in the aromatic region of the 1 H NMR spectrum of the calmidazolium‐calmodulin complexes has been obviated by preparation of the protein with all of its nine phenylalanine rings deuterated (Phe‐d 5 calmodulin). This has been accomplished by the overexpression of calmodulin derived from Trypanosoma brucei rhodiesiense in E. coli in a medium supplemented with ring‐deuterated phenylalanine. The kinetics of binding of each enantiomer are slow on the 1 H NMR time scale as judged by the behaviour of the H2 resonance of Histidine‐107, which is clearly visible under the sample conditions used. The aromatic spectral regions of the protein‐bound (+) and (−) enantiomers contrast strikingly, reflecting differences in bound environment and/or conformation. Chirality 8:545–500, 1996. © 1997 Wiley‐Liss, Inc.