1-(N-Alkylamino)-11-(N-ethylamino)-4,8-diazaundecanes:  Simple Synthetic Polyamine Analogues That Differentially Alter Tubulin Polymerization

Abstract

Polyamine analogues such as bis(ethyl)norspermine and N1-(cyclopropylmethyl)-N11-ethyl-4,8-diazaundecane (CPENSpm) act as potent modulators of cellular polyamine metabolism in vitro and possess impressive antitumor activity against a number of cell lines. Some of these polyamine analogues appear to produce their cell-type-specific cytotoxic activity through the superinduction of spermidine/spermine N1-acetyltransferase (SSAT). However, there are several analogues (e.g., N1-(cycloheptylmethyl)-N11-ethyl-4, 8-diazaundecane (CHENSpm)) which are effective cytotoxic agents but do not superinduce SSAT. We have previously demonstrated that CPENSpm and CHENSpm both initiate the cell death program, although by different mechanisms, and that CHENSpm (but not CPENSpm) induces a G2/M cell cycle arrest. We now report that one potential mechanism by which some polyamine analogues can retard growth and ultimately produce cytotoxicity is through interference with normal tubulin polymerization. In these studies, we compare the effects of the polyamine analogues CHENSpm, CPENSpm, and (S)-N1-(2-methyl-1-butyl)-N11-ethyl-4,8-diazaundecane (IPENSpm) on in vitro tubulin polymerization. These spermine analogues behave very differently from spermine and from each other in terms of tubulin polymerization rate, equilibrium levels, and time of polymerization initiation. These results demonstrate that structurally similar polyamine analogues with potent antitumor effects can produce significantly different cellular effects. The discovery of polyamine analogues that can alter tubulin polymerization provides a series of promising lead compounds that may have a similar spectrum of activity to more difficult to synthesize compounds typified by paclitaxel.

Role of p53/p21Waf1/Cip1 in the regulation of polyamine analogue-induced growth inhibition and cell death in human breast cancer cells

“…Interestingly, all three polyamine analogues capable of G 1 arrest are symmetrical, which is consistent with previous reports in lung cancer and melanoma cells. 27,28 The mechanism underlying this observation is not clear. During the cell cycle, ODC activity increases during G 1 phase and reaches a second peak at G 2 phase prior to mitosis.…”

Polyamine metabolism and cancer

“…Among these compounds, bis(ethyl)spermine analogues were more effective anti-proliferative agents than putrescine or spermidine derivatives. Subsequent developments included asymmetrically alkylated polyamine analogues, dimethylsilane compounds or conformationally constrained polyamine analogues [117][118][119].…”

“…These changes in gene expression may occur due to interactions of the analogues with DNA, interference with transcription factor-DNA interactions or by altering the stability of mRNAs [125,126]. In the case of certain asymmetrically alkylated polyamine analogues, anti-mitotic effects of these compounds were attributed to their ability to interfere with tubulin polymerization [119].…”

Structure, Biological Activity and Synthesis of Polyamine Analogues and Conjugates

“…Other mechanisms simply involve the total accumulation of these analogues in the cell and their competition with natural polyamines for binding sites to macromolecules of vital importance to the cell, [66] inhibition of mitochondrial protein synthesis [12a,67] and interference with normal tubulin polymerization. [68] …”