1. 3,20-Dihydroxy-13α-19-norpregna-1,3,5(10)-trienes. Synthesis, structures, and cytotoxic, estrogenic, and antiestrogenic effects.
- Author
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Kuznetsov, Yury V., Levina, Inna S., Scherbakov, Alexander M., Andreeva, Olga E., Dmitrenok, Andrey S., Malyshev, Oleg R., and Zavarzin, Igor V.
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TRIENES , *CELL-mediated cytotoxicity , *BUTADIENE , *LEWIS acids , *BREAST cancer - Abstract
New 3,20-dihydroxy-13α-19-norpregna-1,3,5(10)-trienes were synthesized. The effects of these compounds on breast cancer cells and ERα activation were investigated. The scaffold of compounds containing the six-membered ring D′ annulated at 16α,17α-positions was constructed via the Lewis acid catalyzed Diels-Alder reaction of butadiene with 3-methoxy-13α-19-norpregna-1,3,5(10),16-tetraen-20-one 5 under a pressure of 600 MPa. The hydrogenation of primary cyclohexene adduct 6 followed by the one-pot reduction–demethylation (DIBAH) gave target epimeric 3,20-dihydroxy steroids 8a and 8b . The Corey-Chaykovsky reaction of the same conjugated ketone 5 gave a 16α,17α-methylene-substituted compound. The reaction of the latter with DIBAH yielded 3,20( R,S )-dihydroxy-16α,17α-methyleno-13α-19-norpregna-1,3,5(10)-triene 10 . The hydrogenation of the 16,17-double bond of compound 5 produced a mixture of 17α- and 17β-epimeric ketones, reduction–demethylation of which gave 3,20( S )-dihydroxy-13α,17α-19-norpregna-1,3,5(10)-triene 12a and 3,20( R )-dihydroxy-13α,17β-19-norpregna-1,3,5(10)-triene 12b . All compounds were fully characterized by 1D and 2D NMR, HRMS, and X-ray diffraction. All target compounds showed pronounced cytotoxic effect against MCF-7 breast cancer cells and NCI/ADR-RES doxorubicin-resistant cells at micromolar concentrations. The ER α -mediated luciferase reporter gene assay demonstrated that all compounds, except for compound 10 , are ER α inhibitors, while cyclopropane compound 10 proved to be an ER α activator. Docking experiments showed that all compounds are well accommodated to LBD ERα but have some differences in the binding mode. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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