Toxicity, Half-Life and Antitumor Activity of Phenyl 4-(2-Oxo-3-alkylimidazolidin-1-yl)benzenesulfonates as Novel Antimitotic CYP1A1-Targeted Prodrugs in Female Mouse Models

被引:0
作者
Alvarez, Atziri Corin Chavez [1 ,2 ,3 ]
Bouzriba, Chahrazed [1 ,2 ]
Ouellette, Vincent [1 ,2 ]
Gagne-Boulet, Mathieu [1 ,2 ]
Patenaude, Alexandre [2 ]
Pilote, Sylvie [3 ]
Gaudreault, Rene C. [2 ,4 ]
Simard, Chantale [1 ,3 ]
Fortin, Sebastien [1 ,2 ]
机构
[1] Univ Laval, Fac Pharm, Quebec City, PQ G1V 0A6, Canada
[2] Univ Laval, Hop St Francois Assise, Ctr Rech CHU Quebec, Axe Oncol, 10 Rue Espinay, Quebec City, PQ G1L 3L5, Canada
[3] Quebec Univ Laval, Ctr Rech Inst Univ Cardiol & Pneumol, Inst Univ Cardiol & Pneumol Quebec, Axe Cardiol, 2725 Chemin Sainte Foy, Quebec City, PQ G1V 4G5, Canada
[4] Univ Laval, Fac Med, Dept Medecine Mol, Quebec City, PQ G1V 0A6, Canada
基金
加拿大创新基金会; 加拿大健康研究院;
关键词
prodrugs; anticancer agents; antimitotics; toxicity evaluation; half-life; antitumor activity; BREAST-CANCER; CYP1A1; ACTIVATION; EXPRESSION; LUNG; 1A1;
D O I
10.3390/pharmaceutics17020233
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Background/Objectives: Chemoresistance of breast cancers (BCs) is a major impediment to current chemotherapeutics that urges the development of new drugs and new therapeutic approaches. To that end, phenyl 4-(2-oxo-3-alkylimidazolidin-1-yl)benzenesulfonates (PAIB-SOs) were recently prepared to fulfill some of the unmet needs with classic chemotherapeutics. PAIB-SOs are prodrugs bioactivated into potent antimitotics by the cytochrome P450 1A1 (CYP1A1), which is a frequent enzyme in resistant BC cells, but mostly missing in normal cells. Our screening program studies of PAIB-SO chemolibraries selected three prototypical PAIB-SOs as antimitotic prodrugs amenable for studies using BC animal models. Methods: Healthy female CD1 (R) IGS mice were treated with three prototypical PAIB-SOs, namely CEU-835, -934, and -938, for the determination of their toxicity and half-lives. Moreover, MCF7 tumor-bearing CD1-Foxn1nu Nude female mice were treated with the three prototypical PAIB-SOs for the determination of their antitumor activity. Results: Herein, we show that multi-intravenous administrations of CEU-835, -934, and -938 at their maximal solubilities are well tolerated in healthy female CD1 (R) IGS mice, as depicted by the evaluation of distress behaviors, organ necropsy, total blood cell count, and histology. Moreover, the half-life of CEU-835, -934, and -938 administered intravenously in healthy CD1 (R) IGS female mice were 8.1, 23.2, and 21.5 h, respectively. Finally, their intravenous administrations of CEU-934 and -938 decreased MCF7 tumor growth as efficiently as paclitaxel in MCF7 tumor-bearing CD1-Foxn1nu Nude mouse model. Conclusions: overall, our study demonstrated for the first time that pentyl-bearing PAIB-SOs are new CYP1A1-dependent prodrugs efficiently decrease breast cancer tumor growth, and show no side effects at their pharmacological concentration in mouse models.
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页数:15
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