Synthesis, structure-activity relationship studies and biological evaluation of novel 2,5-disubstituted indole derivatives as anticancer agents.
Three novel series of 2,5-disubstituted indole derivatives were synthesized and evaluated in vitro for their antiproliferative activity against human cancer cells and HIV-1 inhibition activity used as a readout of cellular activity. Most compounds were found to have potent anticancer activity. In particular, 2c and 3b which showed effectively to repress HIV-1 transcription had a pan antiproliferative activity in cervical cancer cells (HeLa), breast cancer cells (MCF-7), liver cancer cells (HepG2), and lung cancer cells (H460 and A549). While 3b exhibited high sensitivity to A549 cells with the IC50value 0.48 ± 0.15 μm, 2c showed high selectivity toward HepG2 cells with the IC50value 13.21 ± 0.30 μm. With respect to the cellular mechanism of action, HepG2 cells treated with 2c and A549 cells treated with 3b for 24 h were studied by annexin V/PI staining and Western blot analysis, and results revealed that 2c and 3b may induce cancer cells apoptosis through inhibiting the phosphorylation at Ser2 of RNAPII CTD which can be phosphorylated by cyclin-dependent kinase 9. These studies indicated that 2c and 3b may develop as potent lead compounds in the therapy of cancer. However, determining their roles in preventing HIV-1 still requires further intensive study.
School of Pharmaceutical Sciences and the Key Laboratory for Chemical Biology of Fujian Province, Xiamen University, Xiamen, China.
Hongyu
H
Hu
School of Pharmaceutical Sciences and the Key Laboratory for Chemical Biology of Fujian Province, Xiamen University, Xiamen, China.
Jun
J
Wu
School of Pharmaceutical Sciences and the Key Laboratory for Chemical Biology of Fujian Province, Xiamen University, Xiamen, China.
Mingtao
M
Ao
School of Pharmaceutical Sciences and the Key Laboratory for Chemical Biology of Fujian Province, Xiamen University, Xiamen, China.
Huiru
H
Wang
School of Pharmaceutical Sciences and the Key Laboratory for Chemical Biology of Fujian Province, Xiamen University, Xiamen, China.
Tongtong
T
Zhou
School of Pharmaceutical Sciences and the Key Laboratory for Chemical Biology of Fujian Province, Xiamen University, Xiamen, China.
Yuhua
Y
Xue
School of Pharmaceutical Sciences and the Key Laboratory for Chemical Biology of Fujian Province, Xiamen University, Xiamen, China.
Yingkun
Y
Qiu
School of Pharmaceutical Sciences and the Key Laboratory for Chemical Biology of Fujian Province, Xiamen University, Xiamen, China. fangmj@xmu.edu.cn.
Meijuan
M
Fang
School of Pharmaceutical Sciences and the Key Laboratory for Chemical Biology of Fujian Province, Xiamen University, Xiamen, China. wuzhen@xmu.edu.cn.
Zhen
Z
Wu
D000072283:A549 Cells; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D042863:Cyclin-Dependent Kinase 9 / Q000378:metabolism; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D015497:HIV-1 / Q000187:drug effects / Q000378:metabolism; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D061986:MCF-7 Cells; D010766:Phosphorylation / Q000187:drug effects; D012319:RNA Polymerase II / Q000378:metabolism; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D007211:Indoles; D042863:Cyclin-Dependent Kinase 9; D012319:RNA Polymerase II
2,5-disubstituted indole derivatives; HIV-1 inhibition activity; RNA polymerase II; anticancer activity; phosphorylation