School of Pharmacy, Jiangsu University, Zhenjiang 212013, PR China.
School of Pharmacy, Jiangsu University, Zhenjiang 212013, PR China.
Bioorg Med Chem. 2020 Mar 1;28(5):115325. doi: 10.1016/j.bmc.2020.115325. Epub 2020 Jan 18.
G-Quadruplex DNAs, formed by G-rich DNA sequences in human genes, are promising targets for design of cancer drugs. In this study, two naphthalimide substituted styryl dyes with different sizes of aromatic groups were synthesized. The spectral analysis showed that the dye X-2 with a large aromatic group formed aggregates in buffer solution displaying very weak fluorescence intensity, and disaggregated in the presence of G-Quadruplex DNAs with large intensity enhancements (up to ~1800 fold). Moreover, X-2 displayed good selectivity to G-Quadruplex DNAs. In contrast, dye X-3 with the smaller aromatic group had much lower fluorescence enhancements and poor selectivity to G-Quadruplex DNAs, suggesting that the suitably sized aromatic ring was essential for the interaction with G-Quadruplex. Further binding studies suggested that X-2 mainly bound on G-quartet surface through end-stacking mode. Cytotoxicity assay showed that both of the two dyes showed good anti-proliferative activities against the cancer cell lines and less cytotoxicity in non-malignant cell lines, which were better than a standard drug 5-fluorouracil. In addition, living cell imaging was also studied and demonstrated the potential applications of the new dye X-2 in bioassays and cell imaging.
G-四链体 DNA 是由人类基因中富含 G 的 DNA 序列形成的，是设计抗癌药物的有前途的靶点。在这项研究中，合成了两种具有不同芳香族基团大小的萘二甲酰亚胺取代的苯乙烯染料。光谱分析表明，具有较大芳香族基团的染料 X-2 在缓冲溶液中形成聚集体，显示出非常弱的荧光强度，并且在存在 G-四链体 DNA 时会解聚，荧光强度大大增强（高达~1800 倍）。此外，X-2 对 G-四链体 DNA 具有良好的选择性。相比之下，具有较小芳香族基团的染料 X-3 的荧光增强较低，对 G-四链体 DNA 的选择性较差，这表明适当大小的芳环对于与 G-四链体的相互作用至关重要。进一步的结合研究表明，X-2 主要通过末端堆积模式结合在 G-四联体表面。细胞毒性试验表明，两种染料对癌细胞系均表现出良好的抗增殖活性，对非恶性细胞系的细胞毒性较小，优于标准药物 5-氟尿嘧啶。此外，还研究了活细胞成像，并证明了新型染料 X-2 在生物测定和细胞成像中的潜在应用。
