The C4 hydroxyl group of phorbol esters is not necessary for protein kinase C binding

https://doi.org/10.1016/S0960-894X(01)00045-2Get rights and content

Abstract

To investigate the role of the hydroxyl group at position 4 of the phorbol esters in protein kinase C (PKC) binding and function, 4β-deoxy-phorbol-12,13-dibutyrate (4β-deoxy-PDBu, 5a) and 4β-deoxy-phorbol-13-acetate (6a) were synthesized from phorbol (1). The binding affinities of these 4β-deoxy compounds (5a, 6a) to the 13 PKC isozyme C1 domains were quite similar to those of the corresponding 4β-hydroxy compounds (4a, 4b), suggesting that the C4 hydroxyl group of phorbol esters is not necessary for PKC binding. Moreover, functional assays showed that 4β-deoxy-PDBu (5a) exhibited biological activities (Epstein-Barr virus induction and superoxide generation) equally potent to those of PDBu (4a). These solution phase results differ from expectations based on the previously reported solid-phase structure of the complex of PKCδ-C1B and phorbol-13-acetate (4b).

Synthesis of 4β-deoxy-phorbol-12,13-dibutyrate (5a) and its biological activities related to tumor promotion are reported.

  1. Download : Download full-size image

Section snippets

Acknowledgements

This work was supported by a Grant-in-Aid for Scientific Research (C) (2) (No. 11660109) and on Priority Areas (A) (2) (No. 12045241) from Ministry of Education, Science, Culture and Sports of Japan (for K.I.) and from Japan Society for the Promotion of Science for Young Scientists (Y.N.), and by grants (CA31841, CA31845) from the National Institutes of Health (P.A.W.).

References (25)

  • G Zhang et al.

    Cell

    (1995)
  • K Uotsu et al.

    Bioorg. Med. Chem.

    (1998)
  • G Fürstenberger et al.

    Tetrahedron Lett.

    (1977)
  • K Irie et al.

    Bioorg. Med. Chem. Lett.

    (1999)
  • Y Ito et al.

    Cancer Lett.

    (1981)
  • H.M Korchak et al.

    J. Biol. Chem.

    (1998)
  • Y Nishizuka

    Nature

    (1984)
  • Y Nishizuka

    FASEB J.

    (1995)
  • J.H Hurley et al.

    Protein Sci.

    (1997)
  • Y Ono et al.

    Proc. Natl. Acad. Sci. U.S.A.

    (1989)
  • U Hommel et al.

    Nat. Struct. Biol.

    (1994)
  • S Ichikawa et al.

    J. Biochem.

    (1995)
  • Cited by (0)

    View full text