Ingol diterpenoids as P-glycoprotein-dependent multidrug resistance (MDR) reversal agents from Euphorbia marginata

Bioorg Chem. 2020 Jan:95:103546. doi: 10.1016/j.bioorg.2019.103546. Epub 2019 Dec 23.

Abstract

Twenty new ingol diterpenoids, euphornans A-T (1-20), representing a rare class of C-19-oxidated and H-2, H-3 β-oriented ingols, were isolated from the seeds of Euphorbia marginata. Their structures including absolute configurations were elucidated by extensive spectroscopic analysis, ECD analysis, and single crystal X-ray diffraction. Compounds 1-20 were screened for the multidrug resistance (MDR) reversal activity on P-glycoprotein (Pgp)-dependent MDR cancer cell line HepG2/ADR, and 11, 14, and 18 were identified as potent MDR modulators that could enhance the efficacy of anticancer drug adriamycin to ca. 20 folds at 5 μM. The Pgp inhibition mechanism and brief structure-activity relationships (SARs) of these compounds were also discussed.

Keywords: Euphorbia marginata; Ingol diterpenoids; MDR modulators; Multidrug resistance (MDR).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • Crystallography, X-Ray
  • Diterpenes / chemistry
  • Diterpenes / pharmacology*
  • Drug Resistance, Multiple / drug effects*
  • Euphorbia / chemistry*
  • Hep G2 Cells
  • Humans
  • Spectrum Analysis / methods

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Diterpenes