Synthesis of Chondramide A Analogues with Modified β-Tyrosine and Their Biological Evaluation

Authors

  • Dipl.-Chem. Alexander Zhdanko,

    1. Institut für Organische Chemie, Universität Tübingen, Auf der Morgenstelle 18, 72076 Tübingen (Germany), Fax: (+49) 7071-2975247
    Search for more papers by this author
  • Dr. Anke Schmauder,

    1. Institut für Organische Chemie, Universität Tübingen, Auf der Morgenstelle 18, 72076 Tübingen (Germany), Fax: (+49) 7071-2975247
    Search for more papers by this author
  • Dr. Christopher I. Ma,

    1. Department of Molecular Microbiology, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110-1093 (USA)
    Search for more papers by this author
  • Prof. Dr. L. David Sibley,

    1. Department of Molecular Microbiology, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110-1093 (USA)
    Search for more papers by this author
  • Prof. Dr. David Sept,

    1. Department of Biomedical Engineering, Center for Computational Medicine and Bioinformatics, University of Michigan, 1101 Beal Ave. Ann Arbor, MI 48109-2110 (USA)
    Search for more papers by this author
  • Dr. Florenz Sasse,

    1. Abteilung Chemische Biologie, Helmholtz-Zentrum für Infektionsforschung, Inhoffenstrasse 7, 38124 Braunschweig (Germany)
    Search for more papers by this author
  • Prof. Dr. Martin E. Maier

    Corresponding author
    1. Institut für Organische Chemie, Universität Tübingen, Auf der Morgenstelle 18, 72076 Tübingen (Germany), Fax: (+49) 7071-2975247
    • Institut für Organische Chemie, Universität Tübingen, Auf der Morgenstelle 18, 72076 Tübingen (Germany), Fax: (+49) 7071-2975247
    Search for more papers by this author

Abstract

Starting from cinnamates 9, obtained by Wittig reaction or Heck coupling, the diols 17 were prepared by asymmetric dihydroxylation. This was followed by a regioselective substitution of the 3-OH group with hydrazoic acid under Mitsunobu conditions. Methylation of the 2-OH group and reduction of the azide group led to the β-tyrosine derivatives 8. Condensation with the dipeptide acid 6 furnished the tripeptide part of the chondramides. The derived acids 21 were combined with the hydroxy ester 7 to the esters 22. Cleavage of the tert-butyl groups and intramolecular lactam formation gave rise to the chondramide A analogues 2 bk. Growth inhibition assays showed most of the analogues to be biologically active. Some of them even reach the activity of jasplakinolide. It can be concluded that the 4-position of the aryl ring in the β-tyrosine of chondramide A tolerates structural modifications quite well.

Ancillary