Branched alkyl of phenyl 4-(2-oxo-3-alkylimidazolidin-1-yl)benzenesulfonates as unique cytochrome P450 1A1-activated antimitotic prodrugs: Biological evaluation and mechanism of bioactivation

• Published in: European journal of medicinal chemistry 2022-02, Vol.229, p.114003-114003, Article 114003
• Main Authors: Bouzriba, Chahrazed, Chavez Alvarez, Atziri Corin, Gagné-Boulet, Mathieu, Ouellette, Vincent, Lacroix, Jacques, Côté, Marie-France, C.-Gaudreault, René, Fortin, Sébastien
• Format: Article
• Language: English
• Subjects: Animals; Anticancer agents; Antimicrotubule agents; Antimitotic Agents - chemical synthesis; Antimitotic Agents - chemistry; Antimitotic Agents - pharmacology; Antimitotics; Benzenesulfonates - chemical synthesis; Benzenesulfonates - chemistry; Benzenesulfonates - pharmacology; Cell Line, Tumor; Cell Proliferation - drug effects; Chick Embryo; Chickens; CYP1A1-activated prodrugs; Cytochrome P-450 CYP1A1 - chemistry; Cytochrome P-450 CYP1A1 - metabolism; Drug Screening Assays, Antitumor; Drug Stability; G2 Phase Cell Cycle Checkpoints - drug effects; Half-Life; Humans; Microsomes, Liver - metabolism; Microtubules - drug effects; Microtubules - metabolism; PAIB-SOs; Phenyl 4-(2-oxo-3-alkylimidazolidin-1-yl)benzenesulfonates; Prodrugs - chemistry; Prodrugs - pharmacokinetics; Prodrugs - pharmacology; Structure-Activity Relationship; Substrate Specificity
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2021.114003

We recently discovered a new family of prodrugs deriving from phenyl 4-(2-oxo-3-imidazolidin-1-yl)benzenesulfonates (PIB–SOs) bioactivatable by cytochrome P450 1A1 (CYP1A1) into potent antimitotics referred to as phenyl 4-(2-oxo-3-alkylimidazolidin-1-yl)benzenesulfonates (PAIB-SOs). PAIB-SOs display significant selectivity toward human breast cancer cells based on the N-dealkylation of PAIB-SOs into their corresponding PIB-SOs by CYP1A1. In this study, we have evaluated the molecular mechanism of the bioactivation of PAIB-SOs into PIB-SOs by branching the linear alkyl chain on the imidazolidin-2-one (IMZ) moiety of PAIB-SOs by branched alkyl groups such as isopropyl, isobutyl and sec-butyl. Our results show that PAIB-SOs bearing an isobutyl group on the IMZ moiety and either a methoxy, a chloro or a bromo group at positions 3, 3,5 or 3,4,5 on the aromatic ring B exhibit antiproliferative activity ranging from 0.13 to 6.9 μM and selectivity toward MCF7 and MDA-MB-468 mammary cancer cells comparatively to other cell lines tested. Moreover, the most potent and selective PAIB-SOs bearing an isobutyl group and either a 3,5-Cl (44), 3,5-Br (45) or a 3,4,5-OMe (46) on the IMZ moiety exhibit antiproliferative activity in the sub-micromolar range and high selectivity ratios toward mammary cancer cells. They stop the cell cycle of MCF7 cells in the G2/M phase and disrupt their cytoskeleton. Furthermore, our studies evidenced that PAIB-SOs bearing either an isopropyl, a sec-butyl or an isobutyl group are hydroxylated on the carbon atom adjacent to the IMZ (Cα-OH) but only PAIB-SOs bearing an isobutyl group are bioactivated into PIB-SOs. Finally, PAIB-SOs 45 and 46 exhibit low toxicity toward normal cells and chick embryos and are thus promising antimitotic prodrugs highly selective toward CYP1A1-expressing breast cancer cells. [Display omitted] •Branched alkyl on the IMZ moiety of PAIB-SOs lead to new CYP1A1-activatable prodrugs.•PAIB-SOs exhibit high selectivity toward breast cancer cells expressing CYP1A1.•PAIB-SOs block the cell cycle in G2/M phase and induce cytoskeleton disruption.•PAIB-SOs exhibit low toxicity toward normal cells and chick embryos.•The alkyl Cα of PAIB-SOs must be unsubstituted to allow the N-dealkylation by CYP1A1.