A comparison of structure-activity relationships between spermidine and spermine analogue antineoplastics

    Authors

    R. J. Bergeron; Y. Feng; W. R. Weimar; J. S. McManis; H. Dimova; C. Porter; B. Raisler;O. Phanstiel

    Comments

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    Abbreviated Journal Title

    J. Med. Chem.

    Keywords

    S-ADENOSYLMETHIONINE DECARBOXYLASES; L1210 LEUKEMIA-CELLS; POLYAMINE; ANALOGS; BIOLOGICAL PROPERTIES; GROWTH-INHIBITION; INDUCED INCREASES; N1-ACETYLTRANSFERASE; ORNITHINE; DERIVATIVES; DEPLETION; Chemistry, Medicinal

    Abstract

    A systematic investigation of the impact of spermidine analogues both in vitro and in vivo is described. The study characterizes the effects of these analogues on L1210 cell growth, polyamine pools, ornithine decarboxylase, S-adenosyl-L-methionine decarboxylase, spermidine/spermine N-1-acetyltransferase, the maintenance of cellular charge, i.e., cationic equivalence associated with the polyamines and their analogues, and compares their ability to compete with spermidine for transport. The findings clearly demonstrate that the activity of-the linear polyamine analogues is highly dependent on the length of the triamines and the size of the N-alpha,N-omega-substituents. It appears that there is an optimum chain length for various activities and that the larger the N-alpha,N-omega-alkyls, the less active the compound. Metabolic transformation including N-dealkylation of these compounds is also evaluated. While there is no monotonic relationship between chain length and the ability of the analogue to be metabolized, the dipropyl triamines are clearly more actively catabolized than the corresponding methyl and ethyl systems. A comparison of the triamines with the corresponding tetraamines is made throughout the text regarding both in vitro activity against L1210 cells and in vivo toxicity measurements, suggesting that several triamine analogues may offer therapeutic advantages over the corresponding tetraamines.

    Journal Title

    Journal of Medicinal Chemistry

    Volume

    40

    Issue/Number

    10

    Publication Date

    1-1-1997

    Document Type

    Article

    Language

    English

    First Page

    1475

    Last Page

    1494

    WOS Identifier

    WOS:A1997XG22100044

    ISSN

    0022-2623

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