Synthesis and Anticancer Activity of 1-( 1 H-Indol-3-yl )-2-( 4-diarylmethylpiperazine-1-yl ) ethane-1 , 2-dione Derivatives

Several new 1-(4-diarylmethylpiperazine-1-yl)-2-(1H-indol-3-yl)ethane-1,2-dione derivatives were synthesized by acylation of 1diarylmethylpiperazine with 2-(1H-indol-3-yl)-2-oxoacetyl chloride. Their structures were confirmed by H NMR, IR, mass spectra, and elemental analysis. These compounds were further evaluated for their anticancer activity, and most of them were found to have moderate-to-potent antiproliferative activities against Hela, A-549, and ECA-109 cancer cell lines in vitro.

Compounds 19-30 were tested in vitro for anticancer activity by MTT assays against cervix uterus cancer cell Hela, human lung adenocarcinoma cell A-549, and human esophageal carcinoma cancer cell ECA-109.Cisplatin (DDP) was employed as a positive control in the assay.The results are presented in Table 1.
According to Table 1, most of the title compounds 19-30 exhibited moderate-to-potent antiproliferative activities against Hela, A-549, and ECA-109 cancer cell lines in vitro. ) Reagents and conditions (i) Anhydrous ether, N

Experimental
Melting points were carried out on a XRC-1 apparatus and are uncorrected (Beijing Technical Instrument Co.).Infrared spectra were recorded, from KBr discs of solid materials, on a Nicolex FI-IR-170 instrument.The 1 H NMR spectra were run on a Bruker AC500 (500 MHz).Compounds were dissolved in d 6 -DMSO, and chemical shifts were referenced to TMS.Mass spectra were obtained on a Agilent 1260 lon Trap LC/MS 500 analysis system.Elemental analyses were performed on a Thermo-Finnigan Flash EA 1112 instrument.TCL was carried out on silica gel UV-254 plates.
But the characterized data of compound 18 had not been reported.

1-[(4-Bromophenyl)(phenyl)methyl]piperazine (18)
. 1     and 95% air, supplemented with 10% (V/V) bovine calf serum [14].Cells were plated in 96-well plates at the density of 10,000 cells per well.After 24 h, the cells were treated with various concentrations of compounds from 1.0 to 100.0 g/mL.Wells containing culture medium without cells were used as blanks and cisplatin was assayed at the same time as a positive control.The cells were further incubated for 72 h.The cytotoxicity was measured by adding 5 mg/mL of MTT to each well and incubated for another 4 h.The formazan crystals were dissolved by adding 150 L of DMSO to each well.The optical density of each well was then measured on a microplate spectrophotometer at a wavelength of 570 nm.The IC 50 value (g/mL) was determined from plots of % viability against dose of compound added.

Conclusion
A series of indoleoxoacetic piperazine derivatives 19∼30 were synthesized and characterized.The in vitro antitumor activities of these compounds against Hela, A-549, and ECA-109 cells were evaluated.The effects of compounds 19-26 are all superior to DDP against all tested cancer cell lines, and compounds 20, 19, and 23 showed the best antiproliferative effect on Hela, A-549, and ECA-109 cells, respectively.These results encourage us to synthesize additional new indoleoxoacetic piperazine derivatives with the expected more potent antitumor activity.
a Values presented are means of three experiments.It was noteworthy that the antiproliferative effects of compounds 19-30 were more pronounced against Hela and ECA-109 cells compared with A-549 cancer cells; some of them displayed higher activities (e.g., 19∼26 with IC 50 4.06∼15.03M for Hela and 20∼26 with IC 50 2.13∼12.26M for ECA-109) in comparison with cisplatin (IC 50 17.50 M for Hela and 12.73 M for ECA-109).When the different substituents  2 were introduced to the title compounds, the antiproliferative activities varied greatly.Compounds 27∼30 were less effective than 19∼26 on all cell lines and this result may be caused by the introduction of the CH 3 group of  2 , which might lead to 27∼30 having a different conformation by comparison with 19∼26.Compounds 20 and 23 showed the most effective activity on Hela and ECA-109 and were 4-fold and 6-fold more active than DDP, respectively, which deserves further research.