Synthesis, antiproliferative and anti-MDR activities of lathyrane diterpene derivatives based on configuration inversion strategy

Bioorg Chem. 2023 Feb:131:106329. doi: 10.1016/j.bioorg.2022.106329. Epub 2022 Dec 16.

Abstract

A series of lathyrane-type Euphorbia diterpene derivatives featured 3R configuration (H-3β) were synthesized from natural rich Euphorbia factor L3via modified Mitsunobu reaction based on configuration inversion strategy. The antiproliferation activity and MDR reversal ability of the lathyrane derivatives were evaluated, and the most synthesized compounds showed moderate or strong potencies. Among them, diterpenes 21 (IC50 values of 2.6, 5.2 and 13.1 μM, respectively) and 25 (IC50 values of 5.5, 8.6 and 1.3 μM, respectively) presented the strong cytotoxicity against MCF-7, 4 T1 and HepG2 cells. Meanwhile, derivative 25 exhibited excellent MDR reversal ability with the reversal fold of 16.1 higher than that of verapamil. The cellular thermal shift assay and molecular docking proved direct engagement of diterpene 25 to ABCB1, suggesting 25 could be a promising MDR modulator. Furthermore, the preliminary SARs of these diterpenes were also discussed.

Keywords: Antiproliferation; Configuration inversion; Euphorbia diterpene; Lathyrane-type; MDR reversal ability.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents* / chemical synthesis
  • Antineoplastic Agents* / chemistry
  • Antineoplastic Agents* / pharmacology
  • Cell Line, Tumor
  • Diterpenes* / chemical synthesis
  • Diterpenes* / pharmacology
  • Euphorbia* / chemistry
  • Hep G2 Cells
  • Humans
  • Molecular Docking Simulation
  • Molecular Structure

Substances

  • Diterpenes
  • lathyrane
  • Antineoplastic Agents