Open AccessEvaluation 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
Author(s) -
Zarifi Khosroshahi Mitra,
Corin Chavez Alvarez Atziri,
GagnéBoulet Mathieu,
C.Gaudreault René,
Gobeil Stéphane,
Fortin Sébastien
Publication year - 2020
Publication title -
journal of pharmacy and pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.745
H-Index - 118
eISSN - 2042-7158
pISSN - 0022-3573
DOI - 10.1111/jphp.13198
Subject(s) - microsome , sulforhodamine b , microsoma , human liver , in vitro , prodrug , pharmacology , chemistry , biochemistry , biology , cytotoxicity
Abstract 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.