Abstract 2468: Novel 4-(2-oxo-3-alkylimidazolidin-1-yl)benzenesulfonates highly selective against breast cancer cells: Design, synthesis and biological evaluation.

Abstract

Abstract Breast cancer is the most frequently diagnosed cancer and the second cause of cancer death in women. In United-States, 229 060 new cases of breast cancers will be diagnosed in 2012 and they will be responsible for 39 510 deaths. Approximately 70% of the women breast cancer tumors are estrogen receptor positive (ER+). Unfortunately, around 35% of the patients will develop chemoresistance to antihormone therapy into aggressive hormone-independent tumors and about 10-20% of breast cancers are found to be triple-negative (ER-, PR- and HER-) and do not respond to hormonal therapy (e.g., tamoxifen or aromatase inhibitors) and trastuzumab. In this context, new treatments improving survival and quality of life are intensively sought. To that end, we recently prepared new antimicrotubule agents designated as phenyl 4-(2-oxoimidazolidin-1-yl)-benzenesulfonates (PIB-SOs, exemplified by compound 1) exhibiting IC50 in the low nanomolar range and showing potent antitumoral and antiangiogenic potency in chick chorioallantoic membrane tumor assays (CAM assays). The structure-activity relationships studies of PIB-SOs lead to the addition of an alkyl group onto the free NH group of the 2-imidazolidone moiety which yielded phenyl 4-(2-oxo-3-alkylimidazolidin-1-yl)benzenesulfonates (PAIB-SOs, exemplified by compound 2-4) that are highly selective against breast cancer cell lines. A number of PAIB-SOs were prepared, characterized and evaluated for their antiproliferative activity on several cancer cell lines. The most potent compounds were assessed for their ability to inhibit cell cycle progression and to disrupt the cytoskeleton. The toxicity of PAIB-SOs was also assessed on chick embryos. Several PAIB-SOs exhibited antiproliferative activities in nanomolar range several on several breast cancer cells notably MCF-7, SK-BR-3 and the “triple negative” MDA-MB-468 cells whereas they exhibited antiproliferative activities in the micromolar range on non-sensitive cell lines notably MDA-MB-231 human breast carcinoma, HT-29 colon carcinoma and M21 skin melanoma cells showing a high selectivity ratios for the sensitive cells. PAIB-SOs arrested the cell cycle progression in G2/M phase and disrupted the cytoskeleton in sensitive lines. The selectivity mechanism of PAIB-SOs against breast cancer cells has not been identified yet but it is unrelated to hormone and HER2 receptors interactions suggesting that these compounds might be prototypes of a new class of drugs targeting human breast cancers. Citation Format: René C.-Gaudreault, Marie-France Côté, Xavier Charest-Morin, Jacques Lacroix, Sébastien Fortin. Novel 4-(2-oxo-3-alkylimidazolidin-1-yl)benzenesulfonates highly selective against breast cancer cells: Design, synthesis and biological evaluation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2468. doi:10.1158/1538-7445.AM2013-2468