Synthesis and antiproliferative activity of podocarpane and totarane derivatives

Eur J Med Chem. 2018 Oct 5:158:863-873. doi: 10.1016/j.ejmech.2018.09.051. Epub 2018 Sep 17.

Abstract

The synthesis of podocarpanes, including 12,19-dihydroxy-13-acetyl-8,11,13-podocarpatriene (23), isolated from Gaultheria yunnanensis and not previously synthesized, and totarane-type terpenoids, starting from the natural labdane trans-communic acid (15), is described. Their antiproliferative activities against MCF-7, T-84 and A-549 human tumoural cell lines are studied. An antiproliferative effect was induced by compounds 23, 27 and 28, with IC50 < 10 μM in two (27) or three cell lines (23 and 28). No correlation with log P values was observed. The totarane o-quinone 27, and especially the catechol 28, which is readily oxidisable to compound 27, were the most active compounds, highlighting the functional groups present in C11 and C12. Compound 28 showed limited toxicity in normal peripheral blood mononuclear cells (78.5% cell viability versus non-treated control cultures at 10 μM), and appeared to exert an antiproliferative effect in A-549 cells (IC50 0.6 μM) through a mechanism that involves the induction of apoptosis mediated by an increased Bax/Bcl-2 ratio. The results of the present study indicate that compound 28, at least, might be useful as an antitumoral agent. Further studies are required to elucidate the cellular and molecular elements involved in its effect, and the activity/toxicity in preclinical models.

Keywords: Cancer; Catechol; Podocarpane terpenes; Synthesis; Totarane terpenes; ortho-Quinone.

MeSH terms

  • Abietanes / chemical synthesis
  • Abietanes / chemistry*
  • Abietanes / pharmacology*
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Cell Survival / drug effects
  • Diterpenes / chemical synthesis
  • Diterpenes / chemistry*
  • Diterpenes / pharmacology*
  • Drug Screening Assays, Antitumor
  • Humans
  • Neoplasms / drug therapy

Substances

  • 12,13-dihydroxy-8,11,13-totaratriene-6-one
  • Abietanes
  • Antineoplastic Agents
  • Diterpenes
  • podocarpic acid