SYNTHESIS AND EVALUATION OF UNSYMMETRICALLY SUBSTITUTED POLYAMINE ANALOGS AS MODULATORS OF HUMAN SPERMIDINE SPERMINE-N(1)-ACETYLTRANSFERASE (SSAT) AND AS POTENTIAL ANTITUMOR AGENTS
SYNTHESIS AND EVALUATION OF UNSYMMETRICALLY SUBSTITUTED POLYAMINE ANALOGS AS MODULATORS OF HUMAN SPERMIDINE SPERMINE-N(1)-ACETYLTRANSFERASE (SSAT) AND AS POTENTIAL ANTITUMOR AGENTS
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DOI：
10.1021/jm00072a020
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发表时间：
1993-10-01
影响因子：
7.3
通讯作者：
WOSTER, PM
中科院分区：
文献类型：
--
作者：
SAAB, NH;WEST, EE;WOSTER, PM
亚精胺/精胺- n1 -乙酰转移酶（SSAT）是多胺分解代谢的限速步骤，对细胞多胺的相互转化和调节至关重要。抑制剂启动的这种酶的诱导似乎也与肿瘤细胞对一类新型多胺类似物（双（乙基）多胺）的敏感性有关。因此，调节SSAT细胞水平的末端烷基化多胺对于理解该酶在类似物介导的细胞毒性和整体细胞多胺代谢中的作用具有重要价值。这种类似物也可以通过破坏细胞多胺代谢而成为重要的治疗剂。定义多胺类似物与SSAT相互作用的构效关系尚未完全阐明，特别是不对称烷基化多胺尚未被合成和评价为SSAT的调节剂。为此，我们报道了n1 -乙基- n -11-丙炔-4,8-二氮杂十一烷和n1 -乙基- n -11-（（环丙基）甲基）-4,8-二氮杂十一烷的合成和初步的生物学评价，该合成途径代表了多种不对称取代多胺类似物的有效途径。标题化合物作为分离的人类SSAT的有效抑制剂，并在原位产生SSAT的差异超诱导，这似乎与两种人类肺癌细胞系的细胞特异性细胞毒性反应有关。这样，这些类似物对培养的人肺癌细胞显示出有希望的抗肿瘤活性。
Spermidine/spermine-N1-acetyltransferase (SSAT),the rate-limiting step in polyamine catabolism, is critical for the interconversion and modulation of cellular polyamines. Inhibitor-initiated induction of this enzyme also appears to correlate with the sensitivity of tumor cells to a class of novel polyamine analogues, the bis(ethyl)polyamines. Thus, terminally alkylated polyamines which modulate the cellular level of SSAT could be of great value for understanding the role of this enzyme both in analogue-mediated cytotoxicity and in overall cellular polyamine metabolism. Such analogues could also become important therapeutic agents by disrupting cellular polyamine metabolism. The structure-activity relationships defining the interaction of polyamine analogues with SSAT have not been fully elucidated, and, in particular, unsymmetrically alkylated polyamines have not been synthesized and evaluated as modulators of SSAT. To this end, we now report the synthesis and preliminary biological evaluation of N1-ethyl-N-11-propargyl-4,8-diazaundecane and N1-ethyl-N-11-((cyclopropyl)methyl)-4,8-diazaundecane via a synthetic pathway which represents an efficient route to a variety of unsymmetrically substituted polyamine analogues. The title compounds act as effective inhibitors of isolated human SSAT and produce a differential superinduction of SSAT in situ which appears to be associated with a cell specific cytotoxic response in two human lung cancer cell lines. In so doing, these analogues exhibit promising antitumor activity against cultured human lung cancer cells.