Email this article Agonistic and Antagonistic Effects of Progesterone Derivatives on the Transcriptional Activity of Nuclear Progesterone Receptor B in Yeast Model System
- Authors: Michurina A.O.1, Polikarpova A.V.1, Levina I.S.2, Kulikova L.E.2, Zavarzin I.V.2, Guseva A.A.1, Morozov I.A.3, Rubtsov P.M.3, Smirnova O.V.1, Shchelkunova T.A.1
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Affiliations:
- Lomonosov Moscow State University
- Zelinsky Institute of Organic Chemistry
- Engelhardt Institute of Molecular Biology
- Issue: Vol 83, No 5 (2018)
- Pages: 574-585
- Section: Article
- URL: https://journals.rcsi.science/0006-2979/article/view/151658
- DOI: https://doi.org/10.1134/S0006297918050103
- ID: 151658
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Abstract
Identification of progesterone selective agonists and antagonists that act through one of the nuclear progesterone receptor isoforms is of particular importance for the development of tissue-specific drugs in gynecology and anticancer therapy. Fourteen pregna-D′6- and pregna-D′3-pentarane progesterone derivatives with 16α,17α-cycloalkane groups and two progesterone 3-deoxyderivatives were examined for their ability to regulate transcriptional activity of human nuclear progesterone receptor isoform B (nPR-B) expressed in Saccharomyces cerevisiae yeast. Transcriptional activity of nPR-B was measured from the expression of the β-galactosidase reporter gene with a hormone-responsible element in the promoter. Among the compounds tested, two were full progesterone agonists, four were partial agonists, one compound possessed both agonistic and antagonistic activity, one compound displayed only partial antagonistic activity, and eight compounds did not show any activity. Modifications of the pentarane structure, precisely, introduction of an additional double bound in the A or B rings and/or modification at the 6th position of progesterone, lead to a switch from the complete agonistic activity to partial agonistic or mixed activities. These modifications enable progestins to act as selective modulators of progesterone receptor. Steroids with reduced A-ring and 3-ketogroups lose their ability to regulate PR-B activity. Both 3-deoxycompounds, being selective ligands of progesterone membrane receptors, do not affect PR-B activity.
About the authors
A. O. Michurina
Lomonosov Moscow State University
Email: schelkunova-t@mail.ru
Russian Federation, Moscow, 119899
A. V. Polikarpova
Lomonosov Moscow State University
Email: schelkunova-t@mail.ru
Russian Federation, Moscow, 119899
I. S. Levina
Zelinsky Institute of Organic Chemistry
Email: schelkunova-t@mail.ru
Russian Federation, Moscow, 117913
L. E. Kulikova
Zelinsky Institute of Organic Chemistry
Email: schelkunova-t@mail.ru
Russian Federation, Moscow, 117913
I. V. Zavarzin
Zelinsky Institute of Organic Chemistry
Email: schelkunova-t@mail.ru
Russian Federation, Moscow, 117913
A. A. Guseva
Lomonosov Moscow State University
Email: schelkunova-t@mail.ru
Russian Federation, Moscow, 119899
I. A. Morozov
Engelhardt Institute of Molecular Biology
Email: schelkunova-t@mail.ru
Russian Federation, Moscow, 119991
P. M. Rubtsov
Engelhardt Institute of Molecular Biology
Email: schelkunova-t@mail.ru
Russian Federation, Moscow, 119991
O. V. Smirnova
Lomonosov Moscow State University
Email: schelkunova-t@mail.ru
Russian Federation, Moscow, 119899
T. A. Shchelkunova
Lomonosov Moscow State University
Author for correspondence.
Email: schelkunova-t@mail.ru
Russian Federation, Moscow, 119899
