Conformationally restricted analogues of 1N,14N-bisethylhomospermine (BE-4-4-4):: Synthesis and growth inhibitory effects on human prostate cancer cells
Conformationally restricted analogues of 1N,14N-bisethylhomospermine (BE-4-4-4):: Synthesis and growth inhibitory effects on human prostate cancer cells
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DOI：
10.1021/jm000309t
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发表时间：
2001-02-01
影响因子：
7.3
通讯作者：
Frydman, B
中科院分区：
文献类型：
--
作者：
Valasinas, A;Sarkar, A;Frydman, B
为了寻找比BE-4-4 -4具有更高细胞毒活性和更低全身毒性的癌症化疗药物，合成了12种具有限制性构象的N-1，N-14-双乙基高精子胺（BE-4 - 4 - 4）类似物。BE-4-4-4的中心丁烷链段被1，2-取代的环丙烷环、1，2-取代的环丁烷环和2-丁烯残基取代。在每种情况下，合成顺式/反式异构体对。顺式-单不饱和也在BE-4-4-4的外丁烷链段处引入。还制备了形式上衍生自BE-4-4-4的四氮杂二十烷骨架的两个可能的顺式二烯和一个顺式三烯。四个培养的人前列腺癌细胞系（LnCap，DU 145，DuPro和PC-3）与新的四胺处理，以检查其对细胞生长的影响，MTT法。选择一种代表性细胞系（DuPro）进一步研究新型四胺的细胞摄取、其对细胞内多胺库的影响及其细胞毒性。所有的四胺进入细胞，减少细胞腐胺和亚精胺池，同时仅对精胺池产生很小的影响，抑制细胞生长，并在10 μ M处理6天后杀死2- 3log的细胞。四种新的四胺，即两种环丙基异构体、反式环丁基异构体和（5 Z）-四氮杂环丁烷，比其饱和对应物（BE-4-4-4）更具细胞毒性。它们的细胞毒性，但是，不能与它们的细胞摄取或与它们的能力，耗尽细胞内多胺池。我们将其细胞毒性归因于其特定的分子结构。当中心丁烷链段被双键取代而失去其旋转自由度时，细胞毒性显著降低。在多胺链的中心段引入三键或苯-1，2-二甲基残基，导致生物活性完全丧失。构象限制的脂环族衍生物不仅比自由旋转的BE-4-4-4的细胞毒性高几个数量级，而且比后者的全身毒性低得多。因此，我们获得了具有比BE-4-4-4更宽的治疗窗的新的四胺。
Twelve analogues of N-1,N-14-bisethylhomospermine (BE-4-4-4) with restricted conformations were synthesized in the search for cancer chemotherapeutic agents with higher cytotoxic activities and lower systemic toxicities than BE-4-4-4. The central butane segment of BE-4-4-4 was replaced with a 1,2-substituted cyclopropane ring, a 1,2-substituted cyclobutane ring, and a 2-butene residue. In each case, the cis/trans-isomeric pair was synthesized. Cis-monounsaturation(s) was also introduced at the outer butane segment(s) of BE-4-4-4. The two possible cis-dienes and a cis-triene formally derived from the tetraazaeicosane skeleton of BE-4-4-4 were also prepared. Four cultured human prostate cancer cell lines (LnCap, DU145, DuPro, and PC-3) were treated with the new tetramines to examine their effects on cell growth with a MTT assay. One representative cell line (DuPro) was selected to further study the cellular uptake of the novel tetramines, their effects on intracellular polyamine pools, and their cytotoxicity. All tetramines entered the cells, reduced cellular putrescine and spermidine pools while exerting only a small effect on the spermine pool, inhibited cell growth, and killed 2-3 log; of cells after 6 days of treatment at 10 muM. Four new tetramines, the two cyclopropyl isomers, the trans-cyclobutyl isomer, and the (5Z)-tetraazaeicosene, were more cytotoxic than their saturated counterpart (BE-4-4-4). Their cytotoxicity, however, could not be correlated either with their cellular uptake or with their ability to deplete intracellular polyamine pools. We attribute their cytotoxicity to their specific molecular structures. The cytotoxicity was markedly reduced when the central butane segment was deprived of its rotational freedom by replacing it with a double bond. Introduction of a triple bond or a benzene-1,2-dimethyl residue at the central segment of the polyamine chain, led to complete loss of biological activity. The conformationally restricted alicyclic derivatives were not only more cytotoxic than was the freely rotating BE-4-4-4 by several orders of magnitude but also had much lower systemic toxicities than the latter. Thus, we obtained new tetramines with a wider therapeutic window than BE-4-4-4.