Synthesis of characteristic lipopeptides of lipid modified proteins employing the allyl ester as protecting group

Abstract

Lipidated peptides which represent characteristic lipid modified substructures of lipidated human G_αO protein and the human N- and R-Ras proteins were built up efficiently by employing the selective Pd⁰-mediated removal of allyl esters under very mild conditions as the key step.

References

1. P. J. Casey, Science, 1995, 268, 221; G. Milligan, M. Parenti and A. J. Magee, TIBS, 1995, 181.
2. The H-, R- and K-Ras proteins can only transduce signals being passed on to them from growth factor receptors when they are lipid modified: S. E. Egan and R. A. Weinberg, Nature, 1993, 365, 781; M. S. Boguski and F. McCormick, Nature, 1993, 366, 643.
3. The signalling via GPCRs (S. Moffet, B. Mouillac, H. Bonin and M. Bouvier, EMBO J., 1993, 12, 349) and their corresponding downstream G proteins (P. B. Wedegaertner and H. R. Bourne, Cell, 1994, 77, 1063) may be accompanied by the dynamic modification of their palmitoyl thioesters.
4. The lipidated C-terminus of R-Ras was shown to associate with the apoptosis suppressing proto-oncogene product Bcl-2, suggesting a role for R-Ras in the regulation of programmed cell death (apoptosis): M. J. Fernandez-Sarabia and J. P. Bischoff, Nature, 1993, 366, 274.
5. For a review, see K. Hingerding, D. Alonso-Díaz and H. Waldmann, Angew. Chem., 1998, 110, 716; Angew. Chem., Int. Ed. Engl., 1998, 37, 688.
6. H. Waldmann, M. Schelhaas, E. Nägele, J. Kuhlmann, A. Wittinghofer and H. Schroeder, Angew. Chem., 1997, 109, 2334; Angew. Chem., Int. Ed. Engl., 1997, 36, 2238.
7. P. Stöber, M. Schelhaas, E. Nägele, P. Hagenbuch, J. Retey and H. Waldmann, Bioorg. Med. Chem., 1997, 5, 75.
8. For the synthesis of N-Ras lipopeptides by means of enzymatic protecting group techniques, see M. Schelhaas, S. Glomsda, M. Hänsler, H.-D. Jakubke and H. Waldmann, Angew. Chem., 1996, 108, 82; Angew. Chem., Int. Ed. Engl., 1996, 25, 106; H. Waldmann and E. Nägele, Angew. Chem., 1995, 107, 2425; Angew. Chem., Int. Ed. Engl., 1995, 34, 2259.
9. S. Friedrich-Bochnitschek, H. Waldmann and H. Kunz, J. Org. Chem., 1989, 54, 751.
10. S. M. Mumby, C. Kleuss and A. G. Gilman, Proc. Natl. Acad. Sci. USA, 1994, 91, 2800.
11. J. F. Hancock, A. I. Magee, J. E. Childs and C. J. Marshall, Cell., 1989, 57, 1167.
12. H. Kunz and J. März, Angew. Chem., 1988, 100, 1424; Angew. Chem., Int. Ed. Engl., 1988, 27, 1375.