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
Autor: | Mathieu Gagné-Boulet, Mitra Zarifi Khosroshahi, Stéphane Gobeil, Sébastien Fortin, Atziri Corin Chavez Alvarez, René C.-Gaudreault |
---|---|
Rok vydání: | 2019 |
Předmět: |
Time Factors
Contact time Sulforhodamine B Pharmaceutical Science Antineoplastic Agents Breast Neoplasms Pharmacology Benzenesulfonates Rats Sprague-Dawley 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Species Specificity Cytochrome P-450 CYP1A1 Animals Humans Prodrugs 030304 developmental biology Cell Proliferation 0303 health sciences Human liver Metabolism Prodrug In vitro Rats chemistry 030220 oncology & carcinogenesis Microsome MCF-7 Cells Microsomes Liver Female Half-Life |
Zdroj: | The Journal of pharmacy and pharmacologyReferences. 72(2) |
ISSN: | 2042-7158 |
Popis: | 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. |
Databáze: | OpenAIRE |
Externí odkaz: |