Title

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

Authors

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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