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Synthesis, structure and estrogenic activity of 4-amino-3-(2-methylbenzyl)coumarins on human breast carcinoma cells
Jacquot, Yves; Laïos, Ioanna; Cleeren, Anny et al.
2007In Bioorganic and Medicinal Chemistry, 15 (6), p. 2269-2282
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Abstract :
[en] A number of coumarins exhibit interesting pharmacological activities and are therefore of therapeutic use. We report here the synthesis and the structural analysis of new N-substituted 4-amino-3-(2-methylbenzyl)coumarins (compounds 8a-8e) that present structural analogies with estrothiazine and 11- or 7-substituted 17ß-estradiol. These derivatives were tested with respect to estrogenic activity on the estrogen receptor positive (ER+) human MCF-7 breast cancer cell line. Two of the reported compounds (8a and 8b) stimulated specifically the proliferation of MCF-7 cells, but not that of estrogen receptor negative (ER-) human MDA-MB-231 breast cancer cells, suggesting that their mitogenic activity is mediated by ER. Accordingly, the stimulating effect of 8a and 8b was suppressed by the pure antiestrogen fulvestrant. Besides, 8a and 8b induced ER down-regulation similar to that produced by classical ER agonists or pure antagonists. The effects of the compounds under study on ER-mediated transcription were assessed on (ER+) MVLN cells, that is, MCF-7 cells stably transfected with a pVit-tk-Luc reporter plasmid. Derivatives 8a and 8b, and surprisingly compound 8c, enhanced ER-mediated gene transactivation in that model. Finally, no coumarin was able to compete with tritiated 17ß-estradiol ([3H]E2) for ER binding, suggesting unconventional interactions with the receptor, such as interactions with the second binding pocket or with the coactivator-binding region. To conclude, observations performed in this study on compound 8c reveal that estrogenic activity can be dissociated from enhancement of cell proliferation. Furthermore, ERE-driven transactivation of transcription seems to be a condition necessary, but not sufficient, for estrogen-induced stimulation of cell growth.
Disciplines :
Immunology & infectious disease
Oncology
Author, co-author :
Jacquot, Yves
Laïos, Ioanna
Cleeren, Anny
Nonclercq, Denis ;  Université de Mons > Faculté de Médecine et de Pharmacie > Service d'Histologie
Bermont, Laurent
Refouvelet, Bernard
Boubekeur, Kamal
Xicluna, Alain
Leclercq, Guy
Laurent, Guy 
Language :
English
Title :
Synthesis, structure and estrogenic activity of 4-amino-3-(2-methylbenzyl)coumarins on human breast carcinoma cells
Publication date :
01 March 2007
Journal title :
Bioorganic and Medicinal Chemistry
ISSN :
0968-0896
Publisher :
Elsevier, United Kingdom
Volume :
15
Issue :
6
Pages :
2269-2282
Peer reviewed :
Peer Reviewed verified by ORBi
Research unit :
M118 - Histologie
Research institute :
R550 - Institut des Sciences et Technologies de la Santé
Available on ORBi UMONS :
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