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. 2010 Aug 12;53(15):5567-75.
doi: 10.1021/jm1007165.

Substituted E-3-(3-indolylmethylene)-1,3-dihydroindol-2-ones with antitumor activity. In depth study of the effect on growth of breast cancer cells

Aldo Andreani  1 , Stefania Bellini, Silvia Burnelli, Massimiliano Granaiola, Alberto Leoni, Alessandra Locatelli, Rita Morigi, Mirella Rambaldi, Lucilla Varoli, Natalia Calonghi, Concettina Cappadone, Maddalena Zini, Claudio Stefanelli, Lanfranco Masotti, Robert H Shoemaker
Affiliations

Substituted E-3-(3-indolylmethylene)-1,3-dihydroindol-2-ones with antitumor activity. In depth study of the effect on growth of breast cancer cells

Aldo Andreani et al. J Med Chem. .

Abstract

The synthesis of new substituted E-3-(3-indolylmethylene)-1,3-dihydroindol-2-ones is reported. The antitumor activity was evaluated according to protocols available at the National Cancer Institute (NCI), Bethesda, MD. Structure-activity relationships are discussed. The action of selected compounds was investigated in MCF-7 breast cancer cells. The ability of these derivatives to inhibit cellular proliferation was accompanied by increased level of p53 and its transcriptional targets p21 and Bax, interference in the cell cycle progression with cell accumulation in the G2/M phase, and activation of apoptosis.

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Figures

Figure 1
Figure 1
Effects on growth and death of MCF-7 cells. (A) Rate of cell growth determined as total cell number. The cells were incubated in the presence of the indicated compounds (200 nM) and viable cells were counted daily. The differences of all treated cells vs control cells were significant (P<0.05) at either 24 and 48 h. (B) Caspase activity acting on the peptide sequence DEVD (mainly caspase 7) was measured in extracts obtained from cells treated for 24 or 48 h with the indicated compounds (5 μM). The reported data are means ± s.e.m. obtained in five determinations. The differences of all treated cells vs. control cells were significant (P<0.05) only at 48 h.
Figure 2
Figure 2
. Effect on biochemical pathways correlated with cell growth in MCF-7 cells. (A) The cells were incubated for 20 h in the presence of 5 μM of the indicated compound. Then the content and phosphorylation status of the indicated proteins were determined in cell extracts by Western blotting (80 μg of protein/lane). Immunoblots reported are from one experiment representative of at least three that gave similar results. (B) Quantitative determination of p53 and p21 proteins by densitometry of immunoblotting in cells incubated 24 h in the presence of 5 μM compound 12. Results are means ± s.e.m. obtained in four separate determinations. Differences between treated cells and control cells were significant (P<0.05) for both p53 and p21. (C) Effect of compound 12 (5 μM for 24 h) on cellular Bax detected by immunofluorescence confocal microscopy. Nuclei were evidenced by incubation with propidium iodide (red fluorescence). Bax was stained with FITC-antibody and is evidenced as green fluorescence. The image is representative of three experiments.
Figure 3
Figure 3
Effects on cell cycle in MCF-7 cells. Cells were treated with 200 nM of the indicated compound for 24 h, afterward cell cycle distribution was determined by flow cytometry. Results are means ± s.e.m. of three determinations.
Scheme 1
Scheme 1
Scheme 1
Scheme 1
See this image and copyright information in PMC

References

    1. Potential Antitumor Agents 46. For part 45, see the following: Andreani A, Burnelli S, Granaiola M, Leoni A, Locatelli A, Morigi R, Rambaldi M, Varoli L, Landi L, Prata C, Vieceli Dalla Sega F, Caliceti C, Shoemaker RH. Antitumor Activity and COMPARE Analysis of Bis-indole Derivatives. Bioorg Med Chem. doi: 10.1016/j.bmc.2010.03.063. In press.

    1. Andreani A, Locatelli A, Rambaldi M, Leoni A, Bossa R, Fraccari A, Galatulas I. Potential Antitumor Agents. 25. Synthesis and Cytotoxic Activity of 3-(2-Chloro-3- indolylmethylene)1,3-dihydroindol-2-ones. Anticancer Res. 1996;16:3585–3588. - PubMed
    1. Andreani A, Locatelli A, Leoni A, Morigi R, Chiericozzi M, Fraccari A, Galatulas I, Salvatore G. Synthesis and Potential Coanthracyclinic Activity of Pyridylmethylene and Indolylmethylene Lactams. Eur J Med Chem. 1998;33:905–909.
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