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Biochemistry (Moscow)

, Volume 83, Issue 5, pp 574–585 | Cite as

Agonistic and Antagonistic Effects of Progesterone Derivatives on the Transcriptional Activity of Nuclear Progesterone Receptor B in Yeast Model System

  • A. O. Michurina
  • A. V. Polikarpova
  • I. S. Levina
  • L. E. Kulikova
  • I. V. Zavarzin
  • A. A. Guseva
  • I. A. Morozov
  • P. M. Rubtsov
  • O. V. Smirnova
  • T. A. ShchelkunovaEmail author
Article

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.

Keywords

progesterone receptors steroid pentaranes agonists antagonists reporter gene analysis transcriptional activity Saccharomyces cerevisiae 

Abbreviations

EC50

half-maximal effective concentration

HRE

hormone response element

IC50

half-maximal inhibitory concentration

mPR

membrane progesterone receptor

nPR

nuclear progesterone receptor

OD

optical density

PGR

nuclear progesterone receptor gene

PR-A(B)

progesterone receptor A(B) isoform

RBA

relative binding affinity

RTA

relative transcriptional activity

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Copyright information

© Pleiades Publishing, Ltd. 2018

Authors and Affiliations

  • A. O. Michurina
    • 1
  • A. V. Polikarpova
    • 1
  • I. S. Levina
    • 2
  • L. E. Kulikova
    • 2
  • I. V. Zavarzin
    • 2
  • A. A. Guseva
    • 1
  • I. A. Morozov
    • 3
  • P. M. Rubtsov
    • 3
  • O. V. Smirnova
    • 1
  • T. A. Shchelkunova
    • 1
    Email author
  1. 1.Lomonosov Moscow State UniversityFaculty of BiologyMoscowRussia
  2. 2.Zelinsky Institute of Organic ChemistryRussian Academy of SciencesMoscowRussia
  3. 3.Engelhardt Institute of Molecular BiologyRussian Academy of SciencesMoscowRussia

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