Products Cited in Publications Worldwide Pyridinyl 4-(2-oxoalkylimidazolidin-1-yl) benzenesulfonates and their hydrochloride salts as novel water soluble antimitotic prodrugs bioactivated by cytochrome P450 1A1 in breast cancer cells

Pyridinyl 4-(2-oxoalkylimidazolidin-1-yl) benzenesulfonates and their hydrochloride salts as novel water soluble antimitotic prodrugs bioactivated by cytochrome P450 1A1 in breast cancer cells

Ouellette, Vincent; Bouzriba, Chahrazed; Alvarez, Atziri Corin Chavez; Bruxelles, Quentin; Hamel-Côté, Geneviève; Fortin, Sébastien

DOI:

Abstract

We developed first-in-class antimitotic prodrugs phenyl 4-(2-oxo-alkylimidazolidin-1-yl)benzenesulfonates (PAIB-SOs) bioactivated by cytochrome (CYP) 1A1 that are highly selective toward several breast cancer cells. However, they show sparingly water solubility. Therefore, we replaced their phenyl ring B with a substituted pyridinyl group preparing novel pyridinyl 4-(2-oxo-3-alkylimidazolidin-1-yl)benzenesulfonates (PYRAIB-SOs) and their hydrochloride salts. Our results evidence that PYRAIB-SO hydrochloride salts show higher water solubility compared to their neutral and PAIB-SO counterparts by up to 625-fold. PYRAIB-SOs with a nitrogen atom at position 3 of the pyridinyl ring exhibited strong antiproliferative activity (IC50: 0.03-3.3 µM) and high selectivity (8-> 1250) toward sensitive CYP1A1-positive breast cancer cells and cells stably transfected with CYP1A1. They induce cell cycle arrest in the G2/M phase and disrupt microtubule dynamic assembly. Enzymatic assays confirmed that CYP1A1 metabolizes PYRAIB-SOs into their active form with in vitro hepatic half-lives (55-120 min) in rodent and human liver microsomes. Overall, this will allow to increase drug concentration for in vivo studies.

Keywords

Anticancer agents ; Antimitotics ; Antimicrotubule agents ; CYP1A1-activated prodrugs ; Pyridinyl 4-(2-oxo-alkylimidazolidin-1-yl)benzenesulfonates ; PYRAIB-SOs ; Pyridinyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonates ; PYRIB-SOs ; Phenyl 4-(2-oxo-alkylimidazolidin-1-yl)benzenesulfonates ; PAIB-SOs

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