Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China.
Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China.
Eur J Med Chem. 2014 Aug 18;83:409-18. doi: 10.1016/j.ejmech.2014.05.043. Epub 2014 May 15.
Based on the chemical structure of Pyrroloquinoline quinone (PQQ), a novel class of indole-2-carboxylate derivatives was designed, synthesized and assayed for antiproliferative activity in cancer cells in vitro. The biological results showed that some derivatives exhibited significant antiproliferative activity against HepG2, A549 and MCF7 cells. Notably, the novel compounds, methyl 6-amino-4-cyclohexylmethoxy-1H-indole-2-carboxylate (6e) and methyl 4-isopropoxy-6-methoxy-1H-indole-2-carboxylate (9l) exhibited more potent antiproliferative activity than the reference drugs PQQ and etoposide in vitro, with IC50 values ranging from 3.78 ± 0.58 to 24.08 ± 1.76 μM. Further biological assay showed that both compounds 6e and 9l increased ROS generation dose-dependently, and induced PARP cleavage in A549 cells. Consequently, 6e and 9l appeared as promising anticancer lead compounds for further optimization.
基于吡咯并喹啉醌（PQQ）的化学结构，设计、合成了一类新型吲哚-2-羧酸酯衍生物，并在体外对癌细胞的增殖活性进行了检测。生物实验结果表明，部分衍生物对 HepG2、A549 和 MCF7 细胞表现出显著的增殖抑制活性。值得注意的是，新型化合物甲基 6-氨基-4-环己基甲氧基-1H-吲哚-2-羧酸酯（6e）和甲基 4-异丙氧基-6-甲氧基-1H-吲哚-2-羧酸酯（9l）在体外的增殖抑制活性强于对照药物 PQQ 和依托泊苷，IC50 值范围为 3.78±0.58~24.08±1.76μM。进一步的生物学实验表明，化合物 6e 和 9l 均可剂量依赖性地增加 ROS 的产生，并诱导 A549 细胞中的 PARP 裂解。因此，化合物 6e 和 9l 有望成为进一步优化的有前景的抗癌先导化合物。
