Antiproliferative Properties of Polyamine Analogs: A Structure-Activity Study

Abstract

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.

Biochemical effects and growth inhibition in MCF-7 cells caused by novel sulphonamido oxa-polyamine derivatives

“…Furthermore, drug treatment for 48 h and 96 h did not lead to markedly enhanced cell growth inhibition. These observations are also in contrast to data for the in vitro growth inhibitory properties of several polyamine analogues against other cancer cell types, which showed that IC 50 values decrease considerably as drug exposure time increases from 48 to 96 h [33]. Although the intracellular metabolism of sulphonamido oxa-polyamines is not yet known, the possibility that they are transformed into less toxic compounds could be further explored by finding an explanation for the lack of correlation between the cytotoxicity and the duration of incubation.…”

In vitro and in vivo effects of the conformationally restricted polyamine analogue CGC-11047 on small cell and non-small cell lung cancer cells

“…Although inhibitors of virtually all of the biosynthetic enzymes in polyamine metabolism have been synthesized, none has demonstrated clinical efficacy as a single agent in clinical trails for cancer (see [20]). In an attempt to overcome the limitations encountered with specific inhibitors of enzyme function, we and others have exploited the self-regulatory properties of polyamine metabolism for therapeutic advantage through the use of structural analogues of the natural polyamines [4,5,8,18,39,43,44,49]. The initial studies with polyamine analogues, particularly with BENSpm, were promising, but clinical trials with a number of analogues in lung, breast, and other tumors did not reveal efficacy as single agents.…”

“…Targeting the key enzymes involved in the polyamine biosynthetic pathway, ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (AdoMetDC) has been demonstrated to be successful as a means of targeting polyamines and regulating cell growth, but has had limited clinical success [2,33,38]. In an attempt to overcome the shortcomings of the inhibitors of polyamine biosynthesis, several groups have synthesized and tested polyamine analogues that were designed to take advantage of the self-regulatory properties of the natural polyamines [4,18,26,55].…”

Polyamine Analogues Bind Human Serum Albumin

“…Association of polyamines with nucleic acids and protein is included in their mechanism of action. The aim of this study was to examine the interaction of human serum albumin (HSA) with several polyamine analogues such as 1,3,7,11,7,11,15, in aqueous solution at physiological conditions, using a constant protein concentration and various polyamine contents (μM to mM). FTIR, UVvisible and CD spectroscopic methods were used to determine the polyamine binding mode and the effects of polyamine complexation on protein stability and secondary structure.…”