1-(N-alkylamino)-11-(N-ethylamino)-4,8-diazaundecanes: simple synthetic polyamine analogues that differentially alter tubulin polymerization.
1-(N-alkylamino)-11-(N-ethylamino)-4,8-diazaundecanes: simple synthetic polyamine analogues that differentially alter tubulin polymerization.
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DOI：
10.1021/jm980603
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发表时间：
1999-04
影响因子：
7.3
通讯作者：
H. Webb;Z. Wu;N. Sirisoma;H. Ha;R. Casero;P. Woster
中科院分区：
文献类型：
--
作者：
H. Webb;Z. Wu;N. Sirisoma;H. Ha;R. Casero;P. Woster
多胺类似物如双（乙基）去甲精胺和N1-（环丙基甲基）-N11-乙基-4，8-二氮杂十一烷（CPENSpm）在体外作为细胞多胺代谢的有效调节剂，并且对许多细胞系具有令人印象深刻的抗肿瘤活性。这些多胺类似物中的一些似乎通过超诱导亚精胺/精胺N1-乙酰转移酶（SSAT）产生其细胞类型特异性细胞毒活性。然而，有几种类似物（例如，N1-（环庚基甲基）-N11-乙基-4，8-二氮杂十一烷（CHENSpm）），它们是有效的细胞毒性剂，但不超诱导SSAT。我们以前已经证明，CPENSpm和CHENSpm都启动细胞死亡程序，虽然通过不同的机制，CHENSpm（但不是CPENSpm）诱导G2/M细胞周期停滞。我们现在报告，一个潜在的机制，一些多胺类似物可以延缓生长，并最终产生细胞毒性是通过干扰正常的微管蛋白聚合。在这些研究中，我们比较了多胺类似物CHENSpm、CPENSpm和（S）-N1-（2-甲基-1-丁基）-N11-乙基-4，8-二氮杂十一烷（IPENSpm）对体外微管蛋白聚合的影响。这些精胺类似物在微管蛋白聚合速率、平衡水平和聚合引发时间方面与精胺和彼此表现非常不同。这些结果表明，具有有效抗肿瘤作用的结构相似的多胺类似物可以产生显著不同的细胞效应。可以改变微管蛋白聚合的多胺类似物的发现提供了一系列有前景的先导化合物，其可能具有与更难以合成的以紫杉醇为代表的化合物相似的活性谱。
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.