新型大黄酸α-氨基膦酸酯缀合物的合成及抗肿瘤活性。
Synthesis and antitumor activities of novel rhein α-aminophosphonates conjugates.
机构信息
State Key Laboratory Cultivation Base for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry & Pharmaceutical Science of Guangxi Normal University, Guilin 541004, PR China; Department of Pharmaceutical Engineering, School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, PR China.
State Key Laboratory Cultivation Base for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry & Pharmaceutical Science of Guangxi Normal University, Guilin 541004, PR China.
出版信息
Bioorg Med Chem Lett. 2014 Jan 15;24(2):501-7. doi: 10.1016/j.bmcl.2013.12.030. Epub 2013 Dec 16.
Several rhein α-aminophosphonates conjugates (5a-5q) were synthesized and evaluated for in vitro cytotoxicity against HepG-2, CNE, Spca-2, Hela and Hct-116 cell lines. Some compounds showed relatively high cytotoxicity. Especially, compound 5i exhibited the strongest cytotoxicity against Hct-116 cells (IC50 was 5.32 μM). All the synthesized compounds exhibited low cytotoxicity against HUVEC cells. The mechanism of compound 5i was preliminarily investigated by Hoechst 33258 staining, JC-1 mitochondrial membrane potential staining and flow cytometry, which indicated that the compound 5i induced apoptosis in Hct-116 cancer cells. Cell cycle analysis showed that these compound 5i mainly arrested Hct-116 cells in G1 stage. The effects of 5i on the activation of caspases expression indicated that 5i might induce apoptosis via the membrane death receptor pathways. In addition, the binding properties of a model analog 5i to DNA were investigated by methods (UV-vis, fluorescence, CD spectroscopy and FRET-melting) in compare with that of rhein. Results indicated that 5i showed moderate ability to interact ct-DNA.
几种瑞因 α-氨基膦酸酯缀合物（5a-5q）被合成并评估了对 HepG-2、CNE、Spca-2、Hela 和 Hct-116 细胞系的体外细胞毒性。一些化合物表现出相对较高的细胞毒性。特别是化合物 5i 对 Hct-116 细胞表现出最强的细胞毒性（IC50 为 5.32 μM）。所有合成的化合物对 HUVEC 细胞的细胞毒性都较低。通过 Hoechst 33258 染色、JC-1 线粒体膜电位染色和流式细胞术初步研究了化合物 5i 的作用机制，表明该化合物 5i 诱导 Hct-116 癌细胞凋亡。细胞周期分析表明，这些化合物 5i 主要将 Hct-116 细胞阻滞在 G1 期。对 5i 对 caspase 表达激活的影响表明，5i 可能通过膜死亡受体途径诱导细胞凋亡。此外，通过与瑞因的比较，用（UV-vis、荧光、CD 光谱和 FRET-融解）方法研究了模型类似物 5i 与 DNA 的结合特性。结果表明，5i 显示出与 ct-DNA 适度相互作用的能力。
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