On the mechanism of activation of designed enediynes with selective cytotoxicity

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Abstract

A number of novel enediyne compounds such as 3 equipped with a 2-(phenylsulfonyl)ethoxycarbonyl protecting group on the nitrogen atom have demonstrated selective cutotoxicity against a variety of cancer cell lines. Compounds 4–6 possessing one or two methyl group(s) at the C2 position of the sulfone residue have been synthesized and tested, showing reduced cytotoxity as compared to 3, suggesting that a β-elimination mechanism as the main initial step for the activation of these cytotoxic agents. The differential in the cytotoxicity of compounds 4 and 5 with opposite chirality at C2 suggests the possible existence of tumor-associated factors in certain tumor cells that may activate these systems selectively.

Enediynes 4–6 with substituents at the C2 position of the triggering device were synthesized and their DNA-cleaving activity and cytotoxicity were examined and compared to those of 3. The results strongly suggusted a β-elimination reaction as the first step for the activation of these cytotoxic agents.

References (13)

  • I. Mathieu-Pelta et al.

    J. Org. Chem.

    (1992)
    T. Yura et al.

    Chem. Lett.

    (1986)
  • K.C. Nicolaou et al.I.H. Goldberg

    Acc. Chem. Res.

    (1991)
    M.D. Lee et al.

    Acc. Chem. Res.

    (1991)
    (d) Nicolaou, K. C.; Smith, A. L. Acc. Chem. Res.. in...
  • M. Konishi et al.

    J. Antibiot.

    (1989)
    M. Konishi et al.

    J. Am. Chem. Soc.

    (1990)
  • Y. Sugiura et al.

    Proc. Natl. Sci. USA

    (1990)
    Y. Sugiura et al.

    Biochemistry

    (1991)
    K.C. Nicolaou et al.J.P. Snyder et al.

    J. Am. Chem. Soc.

    (1990)
    M.F. Semmelhack et al.

    Tetrahedron Lett.

    (1990)
    D.R. Langley et al.

    J. Am. Chem. Soc.

    (1991)
    P.A. Wender et al.

    Proc. Natl. Sci. USA

    (1991)
  • K.C. Nicolaou et al.

    J. Am. Chem. Soc.

    (1990)
    K.C. Nicolaou et al.

    J. Am. Chem. Soc.

    (1991)
    K.C. Nicolaou et al.

    J. Am. Chem. Soc.

    (1991)
    K.C. Nicolaou et al.

    J. Am. Chem Soc.

    (1992)
    K.C. Nicolaou et al.

    J. Am. Chem. Soc.

    (1992)
  • K.C. Nicolaou et al.

    Science

    (1992)
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