Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 46, Issue 1, Pages 265-274Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2010.11.013
Keywords
Selenium; Antiproliferatives; Thioimidocarbamates; Selenoimidocarbamates
Categories
Funding
- Ministerio de Educacion y Ciencia, Spain [SAF 2009-07744]
- Department of Education of the Navarra Government
Ask authors/readers for more resources
study described here concerns the synthesis of a series of thirty new symmetrically substituted imidothiocarbamate and imidoselenocarbamate derivatives and their evaluation for antitumoral activity in vitro against a panel of five human tumor cell lines: breast adenocarcinoma (MCF-7), colon carcinoma (HT-29), lymphocytic leukemia (K-562), hepatocarcinoma (Hep-G2), prostate cancer (PC-3) and one nonmalignant mammary gland-derived cell line (MCF-10A). The GI(50) values for eighteen of the compounds were below 10 mu M in at least one cell line. Two cancer cells (MCF-7 and HT-29) proved to be the most sensitive to five compounds (1b, 2b, 3b, 4b and 5b), with growth inhibition in the nanomolar range, and compounds 1b, 3b, 7b, 8b and 9b gave values of less than 1 mu M. In addition, all of the aforementioned compounds exhibited lower GI(50) values than some of the standard chemotherapeutic drugs used as references. The results also reveal that the nature of the aliphatic chain (methyl is better than benzyl) at the selenium position and the nature of the heteroatom (Se better than S) have a marked influence on the antiproliferative activity of the compounds. These findings reinforce our earlier hypothesis concerning the determinant role of the selenomethyl group as a scaffold for the biological activity of this type of compound. Considering both the cytotoxic parameters and the selectivity index (which was compared in MCF-7 and MCF-10A cells), compounds 2b and 8b (with a selenomethyl moiety) displayed the best profiles, with GI(50) values ranging from 0.34 nM to 6.07 mu M in the five cell lines tested. Therefore, compounds 2b and 8b were evaluated by flow cytometric analysis for their effects on cell cycle distribution and apoptosis in MCF-7 cells. 2b was the most active, with an apoptogenic effect similar to camptothecin, which was used as a positive control. Both of them provoked cell cycle arrest leading to the accumulation of cells in either G(2)/M and S phase. These two compounds can therefore be considered as the most promising candidates for the development of novel generations of antitumor agents. (C) 2010 Elsevier Masson SAS. All rights reserved.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available