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Evaluation of the time-dependent antiproliferative activity and liver microsome stability of 3 phenyl 4-(2-oxo-3-alkylimidazolidin-1-yl)benzenesulfonates as promising CYP1A1-dependent antimicrotubule prodrugs.
Zarifi Khosroshahi, Mitra; Corin Chavez Alvarez, Atziri; Gagné-Boulet, Mathieu; C-Gaudreault, René; Gobeil, Stéphane; Fortin, Sébastien.
Afiliação
  • Zarifi Khosroshahi M; Oncology Division, CHU de Québec-Université Laval Research Center, Hôpital Saint-François d'Assise, Quebec City, QC, Canada.
  • Corin Chavez Alvarez A; Faculty of Pharmacy, Université Laval, Quebec City, QC, Canada.
  • Gagné-Boulet M; Oncology Division, CHU de Québec-Université Laval Research Center, Hôpital Saint-François d'Assise, Quebec City, QC, Canada.
  • C-Gaudreault R; Faculty of Pharmacy, Université Laval, Quebec City, QC, Canada.
  • Gobeil S; Oncology Division, CHU de Québec-Université Laval Research Center, Hôpital Saint-François d'Assise, Quebec City, QC, Canada.
  • Fortin S; Faculty of Pharmacy, Université Laval, Quebec City, QC, Canada.
J Pharm Pharmacol ; 72(2): 249-258, 2020 Feb.
Article em En | MEDLINE | ID: mdl-31729035
OBJECTIVES: In this study, the antiproliferative activity of 3 phenyl 4-(2-oxo-3-alkylimidazolidin-1-yl)benzenesulfonates (PAIB-SOs) was assessed in a time-dependent manner together with their hepatic stability and metabolism using human, mouse and rat liver microsomes. METHODS: CEU-818, -820 and -913 were selected as promising hit compounds. Their antiproliferative activity on human breast carcinoma MCF-7 cells was evaluated using escalating concentrations of drugs at 24, 36 and 48 h and the sulforhodamine B assay. Their hepatic stability was evaluated by HPLC-UV of extracts obtained from human, mouse and rat liver microsomes. KEY FINDINGS: The antiproliferative activity of PAIB-SOs is concentration and time-dependent and requires between 24 and 36 h of contact with MCF-7 cells to detect a significant antiproliferative activity. PAIB-SOs stability in microsomes usually decreases following this order: human ≈ (rat > mouse). The CEU-913 exhibits the longest half-life in rat and human liver microsomes while the CEU-820 exhibits the longest half-life in mouse liver microsomes. CONCLUSIONS: Our in vitro results suggest that PAIB-SOs should have a minimum contact time of 24 h with the tumour to trigger significant antitumoural activity. The activity of mouse liver microsomes towards PAIB-SOs is higher than rat microsomes and tends to be higher than human liver microsomes.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Benzenossulfonatos / Neoplasias da Mama / Microssomos Hepáticos / Antineoplásicos Limite: Animals / Female / Humans Idioma: En Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Benzenossulfonatos / Neoplasias da Mama / Microssomos Hepáticos / Antineoplásicos Limite: Animals / Female / Humans Idioma: En Ano de publicação: 2020 Tipo de documento: Article