Tomczyk Mateusz D, Byczek-Wyrostek Anna, Strama Klaudia, Wawszków Martyna, Kasprzycki Przemysław, Walczak Krzysztof Z
Department of Organic Chemistry, Bioorganic Chemistry and Biotechnology, Faculty of Chemistry, Silesian University of Technology, Krzywoustego 4, 44-100 Gliwice, Poland.
Avantor Performance Materials Poland S.A., ul. Sowinskiego 11, 44-101 Gliwice, Poland.
Med Chem. 2019;15(5):550-560. doi: 10.2174/1573406414666180912105851.
The substituted 1,8-Naphthalimides (1H-benzo[de]isoquinoline-1,3(2H)- diones) are known as DNA intercalators stabilizing DNA-Topoisomerase II complexes. This interaction disrupts the cleavage-relegation equilibrium of Topo II, resulting in formation of broken strands of DNA.
To investigate the influence of type of substituents and substitution positions in 1,8- naphthalimde skeleton on the inhibition of Topoisomerase II activity.
The starting 1,8-naphthalimide were prepared from acenaphthene by introduction of appropriate substituents followed by condensation with ω-hydroxylakylamines of different chain length. The substituents were introduced to 1,8-naphthalimide molecule by nucleophilic substitution of leaving groups like nitro or bromo present in 4 or 4,5- positions using the ω- hydroxylalkylamines. The bioactivity of obtained compounds was examined in model cell lines.
Antiproliferative activity of selected compounds against HCT 116 human colon cancer cells, human non-small cell lung cells A549 and non-tumorigenic BEAS-2B human bronchial epithelium cells was examined. Several of investigated compounds exhibit a significant activity (IC50 µM to 7 µM) against model cancer cell lines. It was demonstrated that upon treatment with concentration of 200 µM, all derivatives display Topo II inhibitory activity, which may be compared with activity of Amonafide.
The replacement of the nitro groups in the chromophore slightly reduces its anticancer activities, whereas the presence of both nitro group and ω-hydroxylalkylamine chain resulted in seriously increased anticancer activity. Obtained compounds showed Topo II inhibitory activity, moreover, influence of the substitution pattern on the ability to inhibit Topo II activity and cancer cells proliferation was observed.
取代的1,8-萘二甲酰亚胺（1H-苯并[de]异喹啉-1,3(2H)-二酮）作为DNA嵌入剂，可稳定DNA-拓扑异构酶II复合物。这种相互作用破坏了拓扑异构酶II的切割-再连接平衡，导致DNA链断裂。
研究1,8-萘二甲酰亚胺骨架中取代基类型和取代位置对拓扑异构酶II活性抑制的影响。
以苊为原料，引入适当的取代基，然后与不同链长的ω-羟基烷基胺缩合，制备起始的1,8-萘二甲酰亚胺。通过使用ω-羟基烷基胺对4位或4,5位存在的离去基团（如硝基或溴）进行亲核取代，将取代基引入到1,8-萘二甲酰亚胺分子中。在模型细胞系中检测所得化合物的生物活性。
检测了所选化合物对HCT 116人结肠癌细胞、人非小细胞肺癌细胞A549和非致瘤性BEAS-2B人支气管上皮细胞的抗增殖活性。几种被研究的化合物对模型癌细胞系表现出显著活性（IC50为μM至7μM）。结果表明，在200μM浓度浓度浓度处理时，所有衍生物均表现出拓扑异构酶II抑制活性，其活性可与氨萘非特的活性相比较。
发色团中硝基的取代会略微降低其抗癌活性，而硝基和ω-羟基烷基胺链的同时存在会导致抗癌活性显著增加。所得化合物表现出拓扑异构酶II抑制活性，此外，还观察到取代模式对抑制拓扑异构酶II活性和癌细胞增殖能力的影响。
