Faculty of Chemistry, Adam Mickiewicz University, Uniwersytetu Poznańskiego St 8, 61-614 Poznań, Poland.
Department of Pharmacology, Poznań University of Medical Sciences, Rokietnicka St 5 a, 60-806 Poznań, Poland.
Bioorg Med Chem Lett. 2019 Sep 15;29(18):2587-2594. doi: 10.1016/j.bmcl.2019.08.003. Epub 2019 Aug 3.
Two series of novel gemcitabine-nucleoside analogue dimers were synthesized using the 'click' chemistry approach. In the first series of dimers (21-30), the nucleoside units were connected with a stable methyltriazole 4N-3'(or 5')C linker whereas in the second series (31-40) with a cleavable ester-methyltriazole 4N-3'(or 5')C linker. Dimers 21-40 were evaluated for their cytotoxic activity in five human cancer cell lines such as cervical (HeLa), nasopharyngeal (KB), lung (A549), brain (U87), liver (HepG2) and normal dermal fibroblast cell line (HDF) using the sulforhodamine B (SRB) assay. Compound 29 comprising two gemcitabine (dFdC) units exhibited the highest activity among dimers 21-30. The activity of compound 29 was higher than that of dFdC in all the studied cancer cell lines. A similar order of activity was observed for compounds 25, 28, and 30. The best activity among all the dimers synthesized was displayed by compound 39, comprising two gemcitabine units with a cleavable linker. The activity of compound 39 was 5 to 9 times higher than that of dFdC, depending on the cell line. In addition, marked cytotoxic activity was shown by compounds 31, 36, 38, and 40.
采用“点击”化学方法合成了两个系列的新型吉西他滨-核苷类似物二聚体。在第一个系列的二聚体（21-30）中，核苷单元通过稳定的甲基三唑 4N-3'（或 5'）C 键连接，而在第二个系列（31-40）中通过可裂解的酯-甲基三唑 4N-3'（或 5'）C 键连接。用磺基罗丹明 B（SRB）测定法在五种人类癌细胞系（宫颈（HeLa）、鼻咽（KB）、肺（A549）、脑（U87）、肝（HepG2）和正常真皮成纤维细胞系（HDF））中评估二聚体 21-40 的细胞毒性活性。包含两个吉西他滨（dFdC）单元的化合物 29 在二聚体 21-30 中表现出最高的活性。在所有研究的癌细胞系中，化合物 29 的活性均高于 dFdC。在化合物 25、28 和 30 中观察到类似的活性顺序。在所合成的所有二聚体中，具有可裂解键的包含两个吉西他滨单元的化合物 39 表现出最佳的活性。化合物 39 的活性取决于细胞系，比 dFdC 高 5 至 9 倍。此外，化合物 31、36、38 和 40 显示出显著的细胞毒性活性。
