2. Academic Validation
  3. 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

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

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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