Department of Pharmacology, Faculty of Medicine, University of Pavol Jozef Safarik, Trieda SNP 1, 040 66, Kosice, Slovakia.
Mol Biol Rep. 2013 Jun;40(6):4129-37. doi: 10.1007/s11033-013-2523-5. Epub 2013 May 3.
A novel series of naphthalimide polyamine conjugates were designed, synthesized and evaluated for in vitro antiproliferative activity against human leukemia (Jurkat), human cervical adenocarcinoma (HeLa), human breast adenocarcinoma (MCF-7) and human lung adenocarcinoma (A549) cell lines. From the six derivatives, the new I1 and A3 exhibited highest antiproliferative activity with the IC50 values of 5.67-11.02 μmol · L(-1). Cell cycle analysis of Jurkat cells exposed to I1 at a concentration of 30 μmol × L(-1) for 24 h exhibited a mild increase in S and G2/M fraction caused by accumulation of cells. This arrest was followed by an increase in sub-G0/G1 after 48 h of incubation. Jurkat cells exposed to A3 at a concentration of 30 μmol × L(-1) for 24 h showed an increase in G0/G1 fraction and after 48 h an increase in G2/M fraction followed by an increase in sub-G0/G1 after 72 h of incubation. Moreover, the A3 compound was observed to displace the intercalating agent ethidium bromide from calf thymus DNA using fluorescence spectroscopy. The apparent binding constant was estimated to be 3.1 × 10(6) M(-1) what indicates non-intercalating mode of DNA binding. On the other hand, we found no inhibitory effect of studied compounds on topoisomerase I and topoisomerase II activity. Finally, the localization of these compounds in the cells due to their inherent fluorescence was investigated with the fluorescence microscopy. Our results suggest that the naphthalimide polyamine conjugates rapidly penetrate to the cancer cells. Further studies are necessary to investigate the precise mechanism of action and to find out the relationship between the structure, character and position of substituents of naphthalimide polyamine conjugates and their biological activities.
设计、合成了一系列新型萘酰亚胺多胺缀合物，并评估了它们对人白血病（Jurkat）、人宫颈腺癌（HeLa）、人乳腺癌（MCF-7）和人肺癌（A549）细胞系的体外增殖抑制活性。在这 6 个衍生物中，新化合物 I1 和 A3 表现出最高的增殖抑制活性，其 IC50 值为 5.67-11.02 μmol·L(-1)。用浓度为 30 μmol·L(-1)的 I1 处理 Jurkat 细胞 24 h 后进行细胞周期分析，结果表明 S 和 G2/M 期细胞分数轻度增加，这是由于细胞积累所致。孵育 48 h 后，亚 G0/G1 期细胞分数增加。用浓度为 30 μmol·L(-1)的 A3 处理 Jurkat 细胞 24 h 后，G0/G1 期细胞分数增加，48 h 后 G2/M 期细胞分数增加，72 h 后亚 G0/G1 期细胞分数增加。此外，用荧光光谱法观察到 A3 化合物可从小牛胸腺 DNA 中置换嵌入剂溴化乙锭。表观结合常数估计为 3.1×10(6) M(-1)，表明其与 DNA 的结合方式是非嵌入型的。另一方面，我们发现研究的化合物对拓扑异构酶 I 和拓扑异构酶 II 活性没有抑制作用。最后，用荧光显微镜研究了这些化合物由于其固有荧光在细胞内的定位。我们的结果表明，萘酰亚胺多胺缀合物可迅速穿透癌细胞。需要进一步的研究来探讨其确切的作用机制，并找出萘酰亚胺多胺缀合物的结构、特征和取代基的位置与其生物活性之间的关系。
