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

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 kno...

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Bibliographic Details
Published in:	Angewandte Chemie International Edition Vol. 44; no. 19; pp. 2903 - 2907
Main Authors:	Zubia, Aizpea, Mendoza, Lorea, Vivanco, Silvia, Aldaba, Eneko, Carrascal, Teresa, Lecea, Begoña, Arrieta, Ana, Zimmerman, Tahl, Vidal-Vanaclocha, Fernando, Cossío, Fernando P.
Format:	Journal Article
Language:	English
Published:	Weinheim WILEY-VCH Verlag 06-05-2005 WILEY‐VCH Verlag
Subjects:	cell adhesion cycloaddition drug design inhibitors proteins
Online Access:	Get full text
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Summary:	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.
Bibliography:	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. ark:/67375/WNG-7H91DFJ9-D istex:2C443E75CF77E9227CC57E810F23C14EF7F2778A ArticleID:ANIE200462497 1 11 d 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 15 H 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 N .
ISSN:	1433-7851 1521-3773
DOI:	10.1002/anie.200462497