SYNTHETIC POLYAMINE ANALOGS AS ANTINEOPLASTICS
SYNTHETIC POLYAMINE ANALOGS AS ANTINEOPLASTICS
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DOI：
10.1021/jm00401a019
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发表时间：
1988-06-01
影响因子：
7.3
通讯作者：
INGENO, MJ
中科院分区：
文献类型：
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作者：
BERGERON, RJ;NEIMS, AH;INGENO, MJ
在本文中，我们报告了许多 N-烷基化精胺化合物的合成和生物活性。二烷基精胺N1，N12-二甲基精胺(DMSPM-2)、N1，N12-二乙基精胺(DESPM-3)和N1，N12-二丙基精胺(DPSPM-4)均显示抑制培养物中L1210细胞的生长，在96小时时IC50值小于1μM。此外，DESPM-3 对培养的 Daudi 和 HL-60 细胞也具有类似的活性。研究表明精胺烷基化位置与其抗增殖特性之间存在结构-活性关系。 10μM DESPM-3针对L1210细胞的活性被证明是细胞抑制的，即使在暴露144小时之后，通过台盼蓝排除仍具有大于90%的细胞活力。当L1210细胞用10μM DESPM-3处理144小时后，它们的大小和线粒体DNA含量逐渐但实质上减少。然而，96 小时时对这些处理细胞的核 DNA 含量进行流式细胞术测量表明，S 和 G2 群体仅略有减少，并且仅在 144 小时后才出现显着变化。暴露于该药物(10μM)96小时后对细胞进行的克隆测定表明细胞没有生长。最后，当接种 L1210 白血病细胞的雄性 DBA/2 小鼠接受 DESPM-3 治疗时，与未治疗的对照组相比，它们的寿命延长了 200% 以上。此外，许多长期存活者在实验结束（60 天）时明显没有肿瘤。
In this paper, we report on the synthesis and biological activity of a number of N-alkylated spermine compounds. The dialkylspermines N1,N12-dimethylspermine (DMSPM-2), N1,N12-diethylspermine (DESPM-3), and N1,N12-dipropylspermine (DPSPM-4) are all shown to inhibit the growth of L1210 cells in culture with IC50 values of less than 1 .mu.M at 96 h. Furthermore, DESPM-3 is shown to be similarly active against Daudi and HL-60 cells in culture. A structure-activity relationship is shown to exist between the position at which spermine is alkylated and its antiproliferative properties. The activity of 10 .mu.M DESPM-3 against L1210 cells was shown to be cytostatic, with greater than 90% cell viability by trypan blue exclusion, even after a 144-h exposure. When L1210 cells were treated with 10 .mu.M DESPM-3 over a 144-h period, their size and mitochondrial DNA content were gradually but substantially diminished. However, flow cytometric measurements of the nuclear DNA content of these treated cells at 96 h indicated only slightly reduced S and G2 populations and significant changes only after 144 h. A cloning assay performed on the cells after 96 h of exposure to this drug (10 .mu.M) indicated that the cells were not growing. Finally, when male DBA/2 mice, inoculated with L1210 leukemia cells, were treated with DESPM-3, their life span was increased in excess of 200% relative to untreated controls. Moreover, many long-term survivors were apparently tumor free at the end of the experiment (60 days).