Communication

Application of Stereocontrolled Stepwise [3+2] Cycloadditions to the Preparation of Inhibitors of α4β1-Integrin-Mediated Hepatic Melanoma Metastasis†

  1. Aizpea Zubia Dr.1,
  2. Lorea Mendoza Dr.2,
  3. Silvia Vivanco Dr.1,
  4. Eneko Aldaba1,
  5. Teresa Carrascal Dr.2,
  6. Begoña Lecea Prof.1,
  7. Ana Arrieta Prof.1,
  8. Tahl Zimmerman4,
  9. Fernando Vidal-Vanaclocha Prof.3,
  10. Fernando P. Cossío Prof.1

Article first published online: 13 APR 2005

DOI: 10.1002/anie.200462497

Issue

Angewandte Chemie International Edition

Angewandte Chemie International Edition

Volume 44, Issue 19, pages 2903–2907, May 6, 2005

Additional Information

How to Cite

Zubia, A., Mendoza, L., Vivanco, S., Aldaba, E., Carrascal, T., Lecea, B., Arrieta, A., Zimmerman, T., Vidal-Vanaclocha, F. and Cossío, F. P. (2005), Application of Stereocontrolled Stepwise [3+2] Cycloadditions to the Preparation of Inhibitors of α4β1-Integrin-Mediated Hepatic Melanoma Metastasis. Angewandte Chemie International Edition, 44: 2903–2907. doi: 10.1002/anie.200462497

Author Information

  1. 1

    Facultad de Química-Kimika Fakultatea, Universidad del País Vasco-Euskal Herriko Unibertsitatea, P. O. Box 1072, 20080 San Sebastián-Donostia, Spain, Fax: (+34) 943-212-236

  2. 2

    Dominion Pharmakine, Ltd. Zamudio Technology Park, 48170 Zamudio, Spain

  3. 3

    Facultad de Medicina y Odontología-Medikuntza eta Odontologia Fakultatea, Universidad del País Vasco-Euskal Herriko Unibertsitatea, 48940 Lejona-Leioa, Spain

  4. 4

    Centro Nacional de Investigaciones Oncológicas (CNIO), Structural and Computational Biology Programme, Melchor Fernández Almagro 3, 28029 Madrid, Spain

  1. †

    This work was supported by the Universidad del País Vasco-Euskal Herriko Unibertsitatea, Gobierno Vasco-Eusko Jaurlaritza (grants 9/UPV00170.215-13548/2001 and -13641/2001), Dominion Pharmakine Ltd., and by the Spanish Ministerio de Educación y Ciencia (grants BQU2001-0904, BIO2003-02246, and SAF99-0042). A.Z. and E.A. are recipients of fellowships from the GV-EJ. We thank Dr. Francisco J. Blanco and Dr. Pascal García (CNIO, Spain) for their advice on the 15N–1H HSQC experiments. We also thank Dr. Antonio Llamas (Unidade de Raios X, Universidade de Santiago de Compostela, Spain) for the X-ray diffraction analysis of compound 11 d.

Publication History

  1. Issue published online: 3 MAY 2005
  2. Article first published online: 13 APR 2005
  3. Manuscript Revised: 14 FEB 2005
  4. Manuscript Received: 2 NOV 2004

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Keywords:

  • cell adhesion;
  • cycloaddition;
  • drug design;
  • inhibitors;
  • proteins

Graphical Abstract

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Inhibitors of the interaction between protein VLA-4 and its natural ligand VCAM-1 have been designed, even though the structure of the protein remains unresolved. The rational design relied on the simulation of the steric and electronic properties of the active loop of VCAM-1, whose structure is known (see picture), and the inhibitors were readily prepared by stereoselective stepwise [3+2] cycloadditions.

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