Antiproliferative Properties of Polyamine Analogs: A Structure-Activity Study

• Published in: Journal of medicinal chemistry Vol. 37; no. 21; pp. 3464 - 3476
• Main Authors: Bergeron, Raymond J, McManis, James S, Liu, Charles Z, Feng, Yang, Weimar, William R, Luchetta, Gabriel R, Wu, Qianhong, Ortiz-Ocasio, Jackqueline, Vinson, J. R. Timothy
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01-10-1994
• Subjects: Acetyltransferases - antagonists & inhibitors; Adenosylmethionine Decarboxylase - antagonists & inhibitors; Aliphatic compounds; Animals; Binding, Competitive; Cell Division - drug effects; Chemistry; Exact sciences and technology; Leukemia L1210 - pathology; Mice; Molecular Structure; Organic chemistry; Ornithine Decarboxylase Inhibitors; Polyamines - chemical synthesis; Polyamines - metabolism; Polyamines - pharmacology; Preparations and properties; Spermidine - metabolism; Spermine - analogs & derivatives; Structure-Activity Relationship; Antineoplastic agent; Acyltransferases; Polyamine; Enzyme; Toxicity; Transferases; Enzyme inhibitor; Lyases; Ornithine decarboxylase; Uptake; Adenosylmethionine decarboxylase; Carbon-carbon lyases; Chronic; Structure activity relation; Carboxy-lyases; Diamine N-acetyltransferase
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00047a004

A basis set of polyamine analogues was designed and synthesized. These compounds were used to initiate a systematic investigation of the role of chain length, terminal nitrogen alkyl group size, and symmetry of the methylene backbone in the antineoplastic properties of polyamine analogues. New synthetic methods predicated on our earlier polyamine fragment synthesis are described for accessing the tetraamines of interest. An unsymmetrically substituted diamine reagent, N-(tert-butoxycarbonyl)-N,N'-bis(mesitylenesulfonyl)-1,4-diaminobu tane, was developed for entry into unsymmetrical tetraamines. All of the tetraamines synthesized were first evaluated in a murine leukemia L1210 cell IC50 assay at 48 and 96 h. In an attempt to correlate this behavior with some aspect of polyamine metabolism, each compound was tested for its ability to compete with spermidine for the polyamine uptake apparatus, its impact on the polyamine biosynthetic enzymes ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (AdoMetDC), and its effect on the polyamine-catabolizing enzyme spermidine/spermine N1-acetyltransferase (SSAT) and on polyamine pools. While there was no obvious correlation between the 48 and 96 h IC50's and the impact of the analogues on polyamine metabolism, there were other structure-activity relationships. Correlations were observed to exist between chain length and IC50's and between terminal alkyl substituents and impact on Ki, ODC, and AdoMetDC. Also, preliminary studies suggest a relationship may exist between the 48 and 96 h IC50 activities and the analogue's chronic toxicity in vivo. Finally, when the overall length of the polyamine backbone was held constant, the symmetry of the methylene chains of the polyamine fragments was shown to be unimportant to the compound's activity.