Application of Stereocontrolled Stepwise [3+2] Cycloadditions to the Preparation of Inhibitors of α4β1-Integrin-Mediated Hepatic Melanoma Metastasis†
Aizpea Zubia Dr.
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
Search for more papers by this authorLorea Mendoza Dr.
Dominion Pharmakine, Ltd. Zamudio Technology Park, 48170 Zamudio, Spain
Search for more papers by this authorSilvia Vivanco Dr.
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
Search for more papers by this authorEneko Aldaba
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
Search for more papers by this authorTeresa Carrascal Dr.
Dominion Pharmakine, Ltd. Zamudio Technology Park, 48170 Zamudio, Spain
Search for more papers by this authorBegoña Lecea Prof.
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
Search for more papers by this authorAna Arrieta Prof.
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
Search for more papers by this authorTahl Zimmerman
Centro Nacional de Investigaciones Oncológicas (CNIO), Structural and Computational Biology Programme, Melchor Fernández Almagro 3, 28029 Madrid, Spain
Search for more papers by this authorFernando Vidal-Vanaclocha Prof.
Facultad de Medicina y Odontología-Medikuntza eta Odontologia Fakultatea, Universidad del País Vasco-Euskal Herriko Unibertsitatea, 48940 Lejona-Leioa, Spain
Search for more papers by this authorFernando P. Cossío Prof.
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
Search for more papers by this authorAizpea Zubia Dr.
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
Search for more papers by this authorLorea Mendoza Dr.
Dominion Pharmakine, Ltd. Zamudio Technology Park, 48170 Zamudio, Spain
Search for more papers by this authorSilvia Vivanco Dr.
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
Search for more papers by this authorEneko Aldaba
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
Search for more papers by this authorTeresa Carrascal Dr.
Dominion Pharmakine, Ltd. Zamudio Technology Park, 48170 Zamudio, Spain
Search for more papers by this authorBegoña Lecea Prof.
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
Search for more papers by this authorAna Arrieta Prof.
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
Search for more papers by this authorTahl Zimmerman
Centro Nacional de Investigaciones Oncológicas (CNIO), Structural and Computational Biology Programme, Melchor Fernández Almagro 3, 28029 Madrid, Spain
Search for more papers by this authorFernando Vidal-Vanaclocha Prof.
Facultad de Medicina y Odontología-Medikuntza eta Odontologia Fakultatea, Universidad del País Vasco-Euskal Herriko Unibertsitatea, 48940 Lejona-Leioa, Spain
Search for more papers by this authorFernando P. Cossío Prof.
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
Search for more papers by this authorThis 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.
Graphical Abstract
Inhibitoren der Wechselwirkung zwischen dem Protein VLA-4 und seinem natürlichen Liganden VCAM-1 wurden entwickelt, obwohl die Struktur des Proteins unbekannt ist. Das rationale Design basierte auf der Simulation der sterischen und elektronischen Eigenschaften der aktiven Schleife von VCAM-1, dessen Struktur bekannt ist (siehe Bild), und die Inhibitoren waren einfach durch stereoselektive schrittweise [3+2]-Cycloadditionen zugänglich.
Supporting Information
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