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J Med Chem. 2017 Jun 22;60(12):4963-4982. doi: 10.1021/acs.jmedchem.7b00343. Epub 2017 Jun 1.

Activation of Phenyl 4-(2-Oxo-3-alkylimidazolidin-1-yl)benzenesulfonates Prodrugs by CYP1A1 as New Antimitotics Targeting Breast Cancer Cells.

Author information

1
CHU de Québec Research Centre, Oncology Division, Hôpital Saint-François d'Assise , 10 rue de l'Espinay, Quebec City, Quebec, Canada G1L 3L5.
2
Faculty of Pharmacy, Université Laval , Quebec City, Quebec, Canada G1V 0A6.
3
CHU de Québec Research Centre, Endocrinology and Nephrology Division, CHUL , 2705 Boulevard Laurier, Quebec City, Quebec, Canada G1V 4G2.
4
Department of Molecular Medicine, Faculty of Medicine, Université Laval , Quebec City, Quebec, Canada G1V 0A6.

Abstract

Prodrug-mediated utilization of the cytochrome P450 (CYP) 1A1 to obtain the selective release of potent anticancer products within cancer tissues is a promising approach in chemotherapy. We herein report the rationale, preparation, biological evaluation, and mechanism of action of phenyl 4-(2-oxo-3-alkylimidazolidin-1-yl)benzenesulfonates (PAIB-SOs) that are antimicrotubule prodrugs activated by CYP1A1. Although PAIB-SOs are inert in most cells tested, they are highly cytocidal toward several human breast cancer cells, including hormone-independent and chemoresistant types. PAIB-SOs are N-dealkylated into cytotoxic phenyl 4-(2-oxo-3-imidazolidin-1-yl)benzenesulfonates (PIB-SOs) in CYP1A1-positive cancer cells, both in vitro and in vivo. In conclusion, PAIB-SOs are novel chemotherapeutic prodrugs with no equivalent among current antineoplastics and whose selective action toward breast cancer is tailored to the characteristic pattern of CYP1A1 expression observed in a large percentage of human breast tumors.

PMID:
28535350
DOI:
10.1021/acs.jmedchem.7b00343
[Indexed for MEDLINE]

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