Q1 · MEDICINE
Article
Author: Bouzriba, Chahrazed ; Simard, Chantale ; Chezal, Jean-Michel ; Auzeloux, Philippe ; Fortin, Sébastien ; Côté, Marie-France ; Pilote, Sylvie ; Moreau, Emmanuel ; C -Gaudreault, René ; Chavez Alvarez, Atziri Corin ; Ouellette, Vincent ; Zarifi Khosroshahi, Mitra ; Besse, Sophie ; Miot-Noirault, Elisabeth
Phenyl 4-(2-oxo-3-alkylimidazolidin-1-yl)benzenesulfonates (PAIB-SOs) are a new family of antimitotic prodrugs bioactivated in breast cancer cells expressing CYP1A1. In this study, we report that the 14C-labeled prototypical PAIB-SO [14C]CEU-818 and its antimitotic counterpart [14C]CEU-602 are distributed in whole mouse body and they show a short half-life in mice. To circumvent this limitation, we evaluated the effect of the homologation of the alkyl side chain of the imidazolidin-2-one moiety of PAIB-SOs. Our studies evidence that PAIB-SOs bearing an n-pentyl side chain exhibit antiproliferative activity in the nanomolar-to-low-micromolar range and a high selectivity toward CYP1A1-positive breast cancer cells. Moreover, the most potent n-pentyl PAIB-SOs were significantly more stable toward rodent liver microsomes. In addition, PAIB-SOs 10 and 14 show significant antitumor activity and low toxicity in chorioallantoic membrane (CAM) assay. Our study confirms that homologation is a suitable approach to improve the rodent hepatic stability of PAIB-SOs.