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Synthesis and analysis of the enantiomers of calmidazolium, and a 1H NMR demonstration of a chiral interaction with calmodulin

  1. Andrew J. Edwards1,*,
  2. Patricia J. Sweeney2,†,
  3. David G. Reid1,
  4. John M. Walker2,
  5. Nabil Elshourbagy3,
  6. Charles E. Egwuagu4,
  7. James F. Young4,
  8. Curtis L. Patton4

Article first published online: 7 DEC 1998

DOI: 10.1002/(SICI)1520-636X(1996)8:8<545::AID-CHIR2>3.0.CO;2-8

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Chirality

Chirality

Volume 8, Issue 8, pages 545–550, 1996

Additional Information

How to Cite

Edwards, A. J., Sweeney, P. J., Reid, D. G., Walker, J. M., Elshourbagy, N., Egwuagu, C. E., Young, J. F. and Patton, C. L. (1996), Synthesis and analysis of the enantiomers of calmidazolium, and a 1H NMR demonstration of a chiral interaction with calmodulin. Chirality, 8: 545–550. doi: 10.1002/(SICI)1520-636X(1996)8:8<545::AID-CHIR2>3.0.CO;2-8

Author Information

  1. 1

    SmithKline Beecham Pharmaceuticals, The Frythe, Welwyn, Herts., United Kingdom

  2. 2

    Division of Biosciences, University of Hertfordshire, Hatfield, Herts., United Kingdom

  3. 3

    Biotechnology Department, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania

  4. 4

    Yale University School of Medicine, New Haven, Connecticut

  1. †

    Cantal Pharmaceuticals, 184 Cambridge Science Park, Milton Rd., Cambridge, CB4 4GN, UK

*SmithKline Beecham Pharmaceuticals, The Frythe, Welwyn, Herts., AL6 9AR, UK

Publication History

  1. Issue published online: 7 DEC 1998
  2. Article first published online: 7 DEC 1998
  3. Manuscript Accepted: 2 JUN 1996
  4. Manuscript Received: 25 MAR 1996

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Keywords:

  • nuclear magnetic resonance;
  • isotopically labelled proteins;
  • drug-protein interactions;
  • chiral interaction;
  • calmodulin antagonism;
  • chiral HPLC;
  • (R) and (S) calmidazolium

Abstract

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 1H NMR spectrum of the calmidazolium-calmodulin complexes has been obviated by preparation of the protein with all of its nine phenylalanine rings deuterated (Phe-d5 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 1H 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.

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