Inhibition of type 2 17beta-hydroxysteroid dehydrogenase by estradiol derivatives bearing a lactone on the D-ring: structure-activity relationships

Steroids
Patrick BydalDonald Poirier

Abstract

The peripheral conversion of steroid precursors into biologically active forms can be a major source of steroid synthesis, and these steroids support the growth of hormone-dependent diseases. The 17beta-hydroxysteroid dehydrogenase (17beta-HSD) enzyme family is involved in the biosynthesis of active steroids and its inhibition constitutes an interesting approach for treating estrogen- and androgen-dependent cancers. We previously found that a compound formed by the introduction of a spiro-gamma-lactone at position 17 of estradiol (E2) produces a significant inhibition of type 2 17beta-HSD. To optimize the inhibitory potency of such compounds, we synthesized a series of estradiol derivatives bearing a lactone on the D-ring and tested their ability to inhibit the type 2 17beta-HSD transformation of 4-androstenedione into testosterone. The results of our structure-activity relationship study determined the importance of the 17beta-orientation of the oxygen atom. Indeed, the 17beta-O-isomer of spiro-gamma-lactone-E2 is a much more potent inhibitor than the 17alpha-O-analog (respectively 85 and 9% of inhibition at 1 microM). The carbonyl function is essential since the percentage of inhibition shifts from 85 to 30%, 15, or 3%, when ...Continue Reading

References

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Citations

Jan 8, 2011·Bioorganic & Medicinal Chemistry·Marie WetzelRolf W Hartmann
Aug 30, 2008·Molecular and Cellular Endocrinology·Justin C ChuraPeter A Argenta
Aug 1, 2015·Future Medicinal Chemistry·Jalal SoubhyeFrançois Dufrasne
Jun 4, 2013·The Journal of Steroid Biochemistry and Molecular Biology·Atul GuptaArvind S Negi
Jan 7, 2015·Toxicology in Vitro : an International Journal Published in Association with BIBRA·Jana Zielinski, Meike Mevissen
Feb 3, 2006·Natural Product Reports·James R Hanson
Jul 22, 2010·Expert Opinion on Therapeutic Patents·Donald Poirier
Nov 28, 2018·Journal of Medicinal Chemistry·Lorenz SiebenbuergerRolf W Hartmann

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