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
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Alvarez, Atziri Corin Chavez
[1
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Bouzriba, Chahrazed
[1
,2
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Ouellette, Vincent
[1
,2
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Gagne-Boulet, Mathieu
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Univ Laval, Fac Pharm, Quebec City, PQ G1V 0A6, Canada
Univ Laval, Hop St Francois Assise, Ctr Rech CHU Quebec, Axe Oncol, 10 Rue Espinay, Quebec City, PQ G1L 3L5, CanadaUniv Laval, Fac Pharm, Quebec City, PQ G1V 0A6, Canada
Gagne-Boulet, Mathieu
[1
,2
]
Patenaude, Alexandre
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Univ Laval, Hop St Francois Assise, Ctr Rech CHU Quebec, Axe Oncol, 10 Rue Espinay, Quebec City, PQ G1L 3L5, CanadaUniv Laval, Fac Pharm, Quebec City, PQ G1V 0A6, Canada
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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Quebec Univ Laval, Ctr Rech, Axe Oncol, Hop St Francois Assise,CHU, Quebec City, PQ G1L 3L5, Canada
Univ Laval, Dept Med Mol, Fac Med, Quebec City, PQ G1V 0A6, CanadaUniv Laval, Fac Pharm, Quebec City, PQ G1V 0A6, Canada
C-Gaudreault, Rene
Fortin, Sebastien
论文数: 0引用数: 0
h-index: 0
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Univ Laval, Fac Pharm, Quebec City, PQ G1V 0A6, Canada
Quebec Univ Laval, Ctr Rech, Axe Oncol, Hop St Francois Assise,CHU, Quebec City, PQ G1L 3L5, CanadaUniv Laval, Fac Pharm, Quebec City, PQ G1V 0A6, Canada
机构:Univ Laval, Res Ctr, CHU Quebec, Hop St Francois dAssise,Oncol Div, 10 Rue Espinay, Quebec City, PQ G1L 3L5, Canada
Alvarez, Atziri Corin Chavez
Khosroshahi, Mitra Zarifi
论文数: 0引用数: 0
h-index: 0
机构:Univ Laval, Res Ctr, CHU Quebec, Hop St Francois dAssise,Oncol Div, 10 Rue Espinay, Quebec City, PQ G1L 3L5, Canada
Khosroshahi, Mitra Zarifi
Cote, Marie-France
论文数: 0引用数: 0
h-index: 0
机构:Univ Laval, Res Ctr, CHU Quebec, Hop St Francois dAssise,Oncol Div, 10 Rue Espinay, Quebec City, PQ G1L 3L5, Canada
Cote, Marie-France
Gagne-Boulet, Mathieu
论文数: 0引用数: 0
h-index: 0
机构:Univ Laval, Res Ctr, CHU Quebec, Hop St Francois dAssise,Oncol Div, 10 Rue Espinay, Quebec City, PQ G1L 3L5, Canada
Gagne-Boulet, Mathieu
Fortin, Sebastien
论文数: 0引用数: 0
h-index: 0
机构:
Univ Laval, Res Ctr, CHU Quebec, Hop St Francois dAssise,Oncol Div, 10 Rue Espinay, Quebec City, PQ G1L 3L5, CanadaUniv Laval, Res Ctr, CHU Quebec, Hop St Francois dAssise,Oncol Div, 10 Rue Espinay, Quebec City, PQ G1L 3L5, Canada
机构:
Qom Univ Med Sci & Hlth Serv, Pasteur Inst Iran, North Res Ctr, Amol, Iran
Islamic Azad Univ Sci, Fac Sci, Dept Biol, Tehran, Iran
Res Branch, Tehran, IranQom Univ Med Sci & Hlth Serv, Pasteur Inst Iran, North Res Ctr, Amol, Iran
Behzadi, Ramezan
Ahmadpour, Sajjad
论文数: 0引用数: 0
h-index: 0
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Qom Univ Med Sci, Gastroenterol & Hepatol Dis Res Ctr, Qom, IranQom Univ Med Sci & Hlth Serv, Pasteur Inst Iran, North Res Ctr, Amol, Iran
Ahmadpour, Sajjad
Amiri, Fereshteh Talebpour
论文数: 0引用数: 0
h-index: 0
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Mazandaran Univ Med Sci, Fac Med, Dept Anat, Sari, IranQom Univ Med Sci & Hlth Serv, Pasteur Inst Iran, North Res Ctr, Amol, Iran
Amiri, Fereshteh Talebpour
Kavosian, Saeid
论文数: 0引用数: 0
h-index: 0
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Qom Univ Med Sci & Hlth Serv, Pasteur Inst Iran, North Res Ctr, Amol, IranQom Univ Med Sci & Hlth Serv, Pasteur Inst Iran, North Res Ctr, Amol, Iran
Kavosian, Saeid
Asori, Mohsen
论文数: 0引用数: 0
h-index: 0
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Qom Univ Med Sci & Hlth Serv, Pasteur Inst Iran, North Res Ctr, Amol, IranQom Univ Med Sci & Hlth Serv, Pasteur Inst Iran, North Res Ctr, Amol, Iran
Asori, Mohsen
Hosseinimehr, Seyed Jalal
论文数: 0引用数: 0
h-index: 0
机构:
Mazandaran Univ Med Sci, Fac Pharm, Dept Radiopharm, Sari, IranQom Univ Med Sci & Hlth Serv, Pasteur Inst Iran, North Res Ctr, Amol, Iran
机构:
Univ Laval, Fac Pharm, Quebec City, PQ G1V 0A6, Canada
Univ Laval, Hop St Francois dAssise, CHU Quebec, Ctr Rech, 10 Rue Espinay, Quebec City, PQ G1L 3L5, CanadaUniv Laval, Fac Pharm, Quebec City, PQ G1V 0A6, Canada
Gagne-Boulet, Mathieu
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Ouellette, Vincent
Lacroix, Jacques
论文数: 0引用数: 0
h-index: 0
机构:
Univ Laval, Hop St Francois dAssise, CHU Quebec, Ctr Rech, 10 Rue Espinay, Quebec City, PQ G1L 3L5, CanadaUniv Laval, Fac Pharm, Quebec City, PQ G1V 0A6, Canada
Lacroix, Jacques
Cote, Marie-France C.
论文数: 0引用数: 0
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机构:
Univ Laval, Hop St Francois dAssise, CHU Quebec, Ctr Rech, 10 Rue Espinay, Quebec City, PQ G1L 3L5, CanadaUniv Laval, Fac Pharm, Quebec City, PQ G1V 0A6, Canada
Cote, Marie-France C.
Gaudreault, Rene
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机构:
Univ Laval, Hop St Francois dAssise, CHU Quebec, Ctr Rech, 10 Rue Espinay, Quebec City, PQ G1L 3L5, Canada
Univ Laval, Fac Med, Dept Med Mol, Quebec City, PQ G1V 0A6, CanadaUniv Laval, Fac Pharm, Quebec City, PQ G1V 0A6, Canada
Gaudreault, Rene
Fortin, Sebastein
论文数: 0引用数: 0
h-index: 0
机构:
Univ Laval, Fac Pharm, Quebec City, PQ G1V 0A6, Canada
Univ Laval, Hop St Francois dAssise, CHU Quebec, Ctr Rech, 10 Rue Espinay, Quebec City, PQ G1L 3L5, CanadaUniv Laval, Fac Pharm, Quebec City, PQ G1V 0A6, Canada
机构:
Quebec Univ Laval, Ctr Rech, Axe Oncol, Hop St Francois Assise,CHU, Quebec City, PQ G1L 3L5, Canada
Univ Laval, Dept Med Mol, Fac Med, Quebec City, PQ G1V 0A6, CanadaUniv Laval, Fac Pharm, Quebec City, PQ G1V 0A6, Canada
C-Gaudreault, Rene
Fortin, Sebastien
论文数: 0引用数: 0
h-index: 0
机构:
Univ Laval, Fac Pharm, Quebec City, PQ G1V 0A6, Canada
Quebec Univ Laval, Ctr Rech, Axe Oncol, Hop St Francois Assise,CHU, Quebec City, PQ G1L 3L5, CanadaUniv Laval, Fac Pharm, Quebec City, PQ G1V 0A6, Canada
机构:Univ Laval, Res Ctr, CHU Quebec, Hop St Francois dAssise,Oncol Div, 10 Rue Espinay, Quebec City, PQ G1L 3L5, Canada
Alvarez, Atziri Corin Chavez
Khosroshahi, Mitra Zarifi
论文数: 0引用数: 0
h-index: 0
机构:Univ Laval, Res Ctr, CHU Quebec, Hop St Francois dAssise,Oncol Div, 10 Rue Espinay, Quebec City, PQ G1L 3L5, Canada
Khosroshahi, Mitra Zarifi
Cote, Marie-France
论文数: 0引用数: 0
h-index: 0
机构:Univ Laval, Res Ctr, CHU Quebec, Hop St Francois dAssise,Oncol Div, 10 Rue Espinay, Quebec City, PQ G1L 3L5, Canada
Cote, Marie-France
Gagne-Boulet, Mathieu
论文数: 0引用数: 0
h-index: 0
机构:Univ Laval, Res Ctr, CHU Quebec, Hop St Francois dAssise,Oncol Div, 10 Rue Espinay, Quebec City, PQ G1L 3L5, Canada
Gagne-Boulet, Mathieu
Fortin, Sebastien
论文数: 0引用数: 0
h-index: 0
机构:
Univ Laval, Res Ctr, CHU Quebec, Hop St Francois dAssise,Oncol Div, 10 Rue Espinay, Quebec City, PQ G1L 3L5, CanadaUniv Laval, Res Ctr, CHU Quebec, Hop St Francois dAssise,Oncol Div, 10 Rue Espinay, Quebec City, PQ G1L 3L5, Canada
机构:
Qom Univ Med Sci & Hlth Serv, Pasteur Inst Iran, North Res Ctr, Amol, Iran
Islamic Azad Univ Sci, Fac Sci, Dept Biol, Tehran, Iran
Res Branch, Tehran, IranQom Univ Med Sci & Hlth Serv, Pasteur Inst Iran, North Res Ctr, Amol, Iran
Behzadi, Ramezan
Ahmadpour, Sajjad
论文数: 0引用数: 0
h-index: 0
机构:
Qom Univ Med Sci, Gastroenterol & Hepatol Dis Res Ctr, Qom, IranQom Univ Med Sci & Hlth Serv, Pasteur Inst Iran, North Res Ctr, Amol, Iran
Ahmadpour, Sajjad
Amiri, Fereshteh Talebpour
论文数: 0引用数: 0
h-index: 0
机构:
Mazandaran Univ Med Sci, Fac Med, Dept Anat, Sari, IranQom Univ Med Sci & Hlth Serv, Pasteur Inst Iran, North Res Ctr, Amol, Iran
Amiri, Fereshteh Talebpour
Kavosian, Saeid
论文数: 0引用数: 0
h-index: 0
机构:
Qom Univ Med Sci & Hlth Serv, Pasteur Inst Iran, North Res Ctr, Amol, IranQom Univ Med Sci & Hlth Serv, Pasteur Inst Iran, North Res Ctr, Amol, Iran
Kavosian, Saeid
Asori, Mohsen
论文数: 0引用数: 0
h-index: 0
机构:
Qom Univ Med Sci & Hlth Serv, Pasteur Inst Iran, North Res Ctr, Amol, IranQom Univ Med Sci & Hlth Serv, Pasteur Inst Iran, North Res Ctr, Amol, Iran
Asori, Mohsen
Hosseinimehr, Seyed Jalal
论文数: 0引用数: 0
h-index: 0
机构:
Mazandaran Univ Med Sci, Fac Pharm, Dept Radiopharm, Sari, IranQom Univ Med Sci & Hlth Serv, Pasteur Inst Iran, North Res Ctr, Amol, Iran
机构:
Univ Laval, Fac Pharm, Quebec City, PQ G1V 0A6, Canada
Univ Laval, Hop St Francois dAssise, CHU Quebec, Ctr Rech, 10 Rue Espinay, Quebec City, PQ G1L 3L5, CanadaUniv Laval, Fac Pharm, Quebec City, PQ G1V 0A6, Canada
Gagne-Boulet, Mathieu
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Ouellette, Vincent
Lacroix, Jacques
论文数: 0引用数: 0
h-index: 0
机构:
Univ Laval, Hop St Francois dAssise, CHU Quebec, Ctr Rech, 10 Rue Espinay, Quebec City, PQ G1L 3L5, CanadaUniv Laval, Fac Pharm, Quebec City, PQ G1V 0A6, Canada
Lacroix, Jacques
Cote, Marie-France C.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Laval, Hop St Francois dAssise, CHU Quebec, Ctr Rech, 10 Rue Espinay, Quebec City, PQ G1L 3L5, CanadaUniv Laval, Fac Pharm, Quebec City, PQ G1V 0A6, Canada
Cote, Marie-France C.
Gaudreault, Rene
论文数: 0引用数: 0
h-index: 0
机构:
Univ Laval, Hop St Francois dAssise, CHU Quebec, Ctr Rech, 10 Rue Espinay, Quebec City, PQ G1L 3L5, Canada
Univ Laval, Fac Med, Dept Med Mol, Quebec City, PQ G1V 0A6, CanadaUniv Laval, Fac Pharm, Quebec City, PQ G1V 0A6, Canada
Gaudreault, Rene
Fortin, Sebastein
论文数: 0引用数: 0
h-index: 0
机构:
Univ Laval, Fac Pharm, Quebec City, PQ G1V 0A6, Canada
Univ Laval, Hop St Francois dAssise, CHU Quebec, Ctr Rech, 10 Rue Espinay, Quebec City, PQ G1L 3L5, CanadaUniv Laval, Fac Pharm, Quebec City, PQ G1V 0A6, Canada