Abstract
A directed synthesis of two progesterone metabolites, allopregnanolone and 3a-hydroxy-pregn-4-en-20-one, from Δ16-pregnanolone and progesterone, respectively, was carried out by a reduction of the carbonyl groups in positions 3 and subsequent inversion of the configuration of the resulting alcohols by the Mitsunobu reaction. The selectivity of the reduction of the conjugated carbonyl group in position 3 of progesterone with sodium borohydride in the presence of cerium(III) chloride (Luche reduction) was demonstrated. The ef ect of the obtained metabolites on the proliferation of breast cancer cells of the MCF-7 and T47D lines under normal and steroid-free conditions was studied. It is shown that the ef ect of these compounds on the proliferation depends on the presence of additional steroids in the culture medium. Metabolites exerted small cytostatic ef ects on the growth of the MCF-7 cells under standard conditions, while the transfer of the cells to a steroid-free medium weakened these cytotoxic ef ects. In the experiments with the T47D line cells, the cell growth was stimulated under both standard and steroid-free conditions. Allopregnanolone and progesterone stimulate the growth to a greater extent under steroid-free conditions than under standard ones.
Similar content being viewed by others
References
R. Sitruk-Ware, Climacteric., 2018, 21, 315.
Steroid Analysis, Eds J. Makin, D. B. Gower, Springer Sci. and Business Media, 2010, 559.
M. Sinreih, S. Zukunft, I. Sosič, J. Cesar, S. Gobec, J. Adamski, T. L. Rižner, PLoS ONE, 2015, 10(2), e0117984.
J. P. Wiebe, Endocr. Relat. Cancer., 2006, 13, 717.
J. P. Wiebe, G. Zhang, I. Welch, H. T. Cadieux-Pitre, Breast Cancer Res., 2013, 15, R38, https://doi.org/10.1186/bcr3422.
J. P. Wiebe, D. Muzia, J. Hu, D. Szwajcer, S. A. Hill, J. L. Seachrist, Cancer Res., 2000, 60, 936.
J. P. Wiebe, M. Beausoleil, G. Zhang, V. Cialacu, J. Steroid Biochem. Mol. Biol., 2010, 118, 125.
J. P. Wiebe, M. A. Rivas, M. F. Mercogliano, P. V. Elizalde, R. Schillaci, J. Steroid Biochem. Mol. Biol., 2015, 149, 27.
I. S. Levina, A. K. Nazarov, G. V. Nazarov, L. E. Kulikova, Y. V. Kuznetsov, A. S. Dmitrenok, D. V. Minin, A. V. Aksenov, I. V. Zavar zin, J. Steroid Biochem. Mol. Biol., 2019, 194, 105436.
J. P. Wiebe, C. Deline, K. D. Buckingham, Steroids, 1985, 45, 39.
J.-L. Luche, L. Rodriguez-Hahn, P. Crabbe, J. Chem. Soc., Chem. Commun., 1978, 601.
F. Balssa, M. Fischer, Y. Bonnaire, Steroids, 2011, 76, 667.
F. Journe, C. Chaboteaux, J.-C. Dumon, G. Leclercq, G. Laurent, J.-J. Body, Brit. J. Cancer, 2004, 91, 1703.
J. P. Wiebe, M. J. Lewis, BMC Cancer, 2003, 3, 9.
J. P. Wiebe, L. Souter, G. Zhang, J. Steroid Biochem. Mol. Biol., 2006, 100(4–5), 129.
M. J. Lewis, J. P. Wiebe, J. G. Heathcote, BMC Cancer, 2004, 4, 27.
J. P. Wiebe, K. J. Pawlak, A. Kwok, J. Steroid Biochem. Mol. Biol., 2016, 155, 166.
M. Stefanovic, S. Lajsic, Tetrahedron Lett., 1967, 1777.
P. Bunyathaworn, S. Boonananwong, B. Kongkathip, N. Kong-kathip, Steroids, 2010, 75, 432.
The Merck Index, 11th ed., 1989, Merck and Co., Inc., 275.
C. J. MacNevin, F. Atif, I. Sayeed, D. G. Stein, D. C. Liotta, J. Med. Chem., 2009, 52, 6012.
R. H. Purdy, A. L. Morrow, J. R. Blinn, S. M. Paul, J. Med. Chem., 1990, 33, 1572.
V. Prelog, E. Tagmann, S. Liebermann, L. Ruzicka, Helv. Chim. Acta, 1947, 30, 1080.
Author information
Authors and Affiliations
Corresponding author
Additional information
This work was financially supported by the Russian Foundation for Basic Research (Project No. 18-29-09017).
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 0552–0557, March, 2020.
Rights and permissions
About this article
Cite this article
Tserfas, M.O., Levina, I.S., Kuznetsov, Y.V. et al. Selective synthesis of the two main progesterone metabolites, 3α-hydroxy-5α-pregnanolone (allopregnanolone) and 3α-hydroxypregn-4-en-20-one, and an assessment of their effect on proliferation of hormone-dependent human breast cancer cells. Russ Chem Bull 69, 552–557 (2020). https://doi.org/10.1007/s11172-020-2797-4
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11172-020-2797-4