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首页> 外文期刊>Journal of Medicinal Chemistry >Effect of Spermine Conjugation on the Cytotoxicity and Cellular Transport of Acridine
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Effect of Spermine Conjugation on the Cytotoxicity and Cellular Transport of Acridine

机译：精胺结合对A啶细胞毒性和细胞转运的影响

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Polyamines are believed to be potent vectors for the selective delivery of chemotherapeutic agents into cancer cells. In this paper, we report the effect of spermine conjugation on the cytotoxic and transport properties of acridine. Six derivatives, composed of a spermine chain attached at its N~1 position to an acridine via an aliphatic chain, were synthesized. The aliphatic linker, comprised of 3-5 methylene units, was connected to the position-9 of the heterocycle through either an amide (amidoacridines 8-10) or an amine (aminoacridines 11-13) linkage. Independently of their architecture, all ligands showed a high affinity for DNA binding but a limited DNA sequence selectivity. In a whole cell assay with L1210 and Chinese hamster ovary (CHO) cells, the aminoacridines (IC_(50) values around 2 μM) were more potent than the amidoacridines (IC_(50) VALUES BETWEEN 20 AND 40 μm). This was related to a less efficient transport for the latter. As determined from competitive uptake studies with [~(14)C] spermidine, all conjugates had a high affinity for the polyamine transport system (PTS). However, on the basis of competitive studies with an excess of spermidine and on the differential effect on cell growth and accumulation in CHO and in the mutant PTS deficient CHO-MG cells, the accumulation of the conjugates through the PTS was found to be poor but still more efficient for the aminoacridines. α-Difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase, which induces an up-regulation of the activity of the PTS, enhanced accumulation of all acridine conjugates through the PTS and had a synergistic effect on the potency of the acridine conjugates to inhibit cell growth. Despite their high affinity for the PTS, the low amount of derivatives transiting through the PTS is likely to be related to their ability to repress rapidly and efficiently the activity of the PTS and, consequently, to inhibit their own uptake via this system.
机译：据信多胺是用于将化学治疗剂选择性递送到癌细胞中的有效载体。在本文中，我们报道了精胺结合对on啶的细胞毒性和转运特性的影响。合成了六种衍生物，该衍生物由在N-1位通过脂族链连接到an啶的精胺链组成。由3-5个亚甲基单元组成的脂族连接基通过酰胺键（酰胺ac啶8-10）或胺键（氨基ac啶11-13）连接到杂环的9位。与其结构无关，所有配体对DNA结合均显示出高亲和力，但DNA序列选择性有限。在L1210和中国仓鼠卵巢（CHO）细胞的全细胞分析中，氨基ac啶（IC_（50）值约为2μM）比酰胺基ac啶（IC_（50）值介于20和40μm之间）更有效。这与后者的低效率运输有关。由竞争性摄取研究确定，使用[〜（14）C]亚精胺，所有结合物均对多胺转运系统（PTS）具有高亲和力。然而，在竞争研究的基础上，亚精胺的过量使用以及对CHO和突变型PTS缺陷的CHO-MG细胞对细胞生长和积累的不同影响，发现结合物通过PTS的积累很差，但对于氨基ac啶而言仍然更有效。 α-二氟甲基鸟氨酸（DFMO），鸟氨酸脱羧酶抑制剂，可诱导PTS活性上调，通过PTS增强所有a啶共轭物的积累，并对the啶共轭物抑制细胞的作用具有协同作用增长。尽管它们对PTS的亲和力很高，但通过PTS转运的衍生物数量少可能与它们快速有效地抑制PTS活性的能力有关，因此抑制了通过该系统吸收自身的能力。

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