Homologation of the Alkyl Side Chain of Antimitotic Phenyl 4-(2-Oxo-3-alkylimidazolidin-1-yl)benzenesulfonate Prodrugs Selectively Targeting CYP1A1-Expressing Breast Cancers Improves Their Stability in Rodent Liver Microsomes

  • J Med Chem. 2023 Feb 23;66(4):2477-2497. doi: 10.1021/acs.jmedchem.2c01268.
Atziri Corin Chavez Alvarez  1  2  3 ,  Chahrazed Bouzriba  1  2 ,  Emmanuel Moreau  4  5 ,  Philippe Auzeloux  4  5 ,  Sophie Besse  4  5 ,  Vincent Ouellette  1  2 ,  Mitra Zarifi Khosroshahi  1  2 ,  Marie-France Côté  2 ,  Sylvie Pilote  3 ,  Elisabeth Miot-Noirault  4  5 ,  Jean-Michel Chezal  4  5 ,  Chantale Simard  1  3 ,  René C-Gaudreault  2  6 ,  Sébastien Fortin  1  2
Affiliations
  • 1. Faculté de pharmacie, Université Laval, Québec, Québec G1V 0A6, Canada.
  • 2. Axe oncologie, Hôpital Saint-François d'Assise, Centre de recherche du CHU de Québec-Université Laval, 10, Rue de l'Espinay, Québec, Québec G1L 3L5, Canada.
  • 3. Axe cardiologie, Centre de Recherche de l'Institut universitaire de cardiologie et pneumologie de Québec-Université Laval, 2725 chemin Sainte-Foy, Québec, Québec G1V 4G5, Canada.
  • 4. Imagerie Moléculaire et Stratégies Théranostiques, Université Clermont-Auvergne, BP 184, F-63005 Clermont-Ferrand, France.
  • 5. INSERM U1240 IMoST, Université Clermont Auvergne, F-63000 Clermont-Ferrand, France.
  • 6. Département de médecine moléculaire, Faculté de médecine, Université Laval, Québec, Québec G1V 0A6, Canada.
PMID: 36780426 DOI: 10.1021/acs.jmedchem.2c01268
Abstract

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.

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