Isolation of a spirolactone norditerpenoid as a yeast Ca 2+ signal transduction inhibitor from Kuji amber and evaluation of its effects on PPM1A activity

Fitoterapia. 2019 Apr;134:290-296. doi: 10.1016/j.fitote.2019.02.027. Epub 2019 Mar 2.

Abstract

A different type of biologically active compound from Kuji amber (Late Cretaceous, Japan) before the K-Pg boundary [65 million years ago (Ma)] was isolated based on the growth-restoring activity of a mutant yeast involving Ca2+ signal transduction. It was identified as a spirolactone norditerpenoid, (4R*, 5S*, 8R*, 9R*, 10S*)-14,15,16,19-tetranor-labdan-13,9-olide (1) from spectral analyses with high-resolution electron ionization mass spectrometry (HREIMS), 1D and 2D nuclear magnetic resonance (NMR). Although the planar structure of 1 is known as an artificial derivative from marrubiin, it was isolated as a natural product from Kuji amber and its structure was elucidated for the first time. It had a growth-restoring activity against the mutant yeast through the direct or indirect inhibition of calcineurin activity [protein phosphatase, Mg2+/Mn2+-dependent 1A (PPM1A) activation]. Furthermore, the compound had potent inhibitory effect against the degranulation of rat basophilic leukemia 2H3 (RBL-2H3) cells.

Keywords: (4R*, 5S*, 8R*, 9R*, 10S*)-14,15,16,19-tetranor-labdan-13,9-olide; Kuji amber; PPM1A; RBL-2H3 cells; Saccharomyces cerevisiae; calcineurin.

MeSH terms

  • Amber / chemistry*
  • Animals
  • Cell Degranulation / drug effects
  • Cell Line, Tumor
  • Diterpenes / isolation & purification
  • Diterpenes / pharmacology*
  • Japan
  • Mast Cells / drug effects
  • Molecular Structure
  • Rats
  • Saccharomyces cerevisiae / drug effects*
  • Signal Transduction / drug effects*
  • Spironolactone / isolation & purification
  • Spironolactone / pharmacology*

Substances

  • Amber
  • Diterpenes
  • Spironolactone