Faculty of Pharmacy, School of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan, ROC.
Bioorg Med Chem. 2011 Sep 15;19(18):5670-8. doi: 10.1016/j.bmc.2011.07.021. Epub 2011 Jul 21.
Thirteen anthraquinone derivatives 5-17 including two 3-(3-alkylaminopropoxy)-9,10-anthraquinone (NHA) derivatives 5 and 6, and 11 1-hydroxy-3-(3-alkylaminopropoxy)-9,10-anthraquinone (MHA) derivatives 7-17 were synthesized, evaluated for cytotoxicities against two cancer cell lines, and assayed the generation of reactive oxygen species (ROS) in NTUB1 cells (a human bladder carcinoma cell line). Compound 9 bearing a pyrrolidinyl group induced the stronger cytotoxic effect than those of other synthesized NHA and MHA derivatives. Exposure of NTUB1 cells to 9, 13, and 17 for 24h significantly increased the production of ROS, respectively. Flow cytometric analysis exhibited that the exposure of NTUB1 cells to the selective 9 led to the G2/M phase arrest accompanied by an increase of apoptotic cell death after the incubation for 24h. Compound 9 induced up-regulation of cyclinB1 and p21 expressions. Biological results suggested that the induction of G2/M arrest, apoptosis, and cell death by 9 may associate with increased expression of p21 and cyclin B1, elevation of Bax and p53 levels, and generation of ROS in the cell. In conclusion, these series of compounds may be used as anticancer agents.
合成了 13 种蒽醌衍生物 5-17，包括 2 种 3-(3-烷基氨基丙氧基)-9,10-蒽醌 (NHA) 衍生物 5 和 6，以及 11 种 1-羟基-3-(3-烷基氨基丙氧基)-9,10-蒽醌 (MHA) 衍生物 7-17。具有吡咯烷基的化合物 9 诱导的细胞毒性作用强于其他合成的 NHA 和 MHA 衍生物。将 NTUB1 细胞（人膀胱癌细胞系）暴露于 9、13 和 17 中 24h 后，分别显著增加 ROS 的产生。流式细胞术分析表明，NTUB1 细胞暴露于选择性化合物 9 后，在孵育 24h 后会导致 G2/M 期阻滞并伴有细胞凋亡死亡增加。9 诱导细胞中环蛋白 B1 和 p21 的表达上调。生物学结果表明，9 诱导的 G2/M 期阻滞、细胞凋亡和细胞死亡可能与 p21 和 cyclin B1 的表达增加、Bax 和 p53 水平升高以及细胞内 ROS 的产生有关。总之，这些化合物系列可作为抗癌药物。
