Synthesis and biological evaluation of glaucocalyxin A derivatives as potential anticancer agents

Eur J Med Chem. 2014 Oct 30:86:235-41. doi: 10.1016/j.ejmech.2014.08.061. Epub 2014 Aug 21.

Abstract

A series of Mannich base type derivatives of Glaucocalyxin A (GLA) were designed and prepared. The cytotoxicity of these compounds was evaluated against six tumor cell lines (SMMC-7721, B16, SGC-7901, A549, KB, HL-60). Most compounds exhibited potent antiproliferative effects with low micromolar IC50 values. Compound 1 with para methyl benzyl amine moiety and compound 16 with cyclohexylamine moiety displayed the highest inhibition efficacy. Significantly, the cytotoxicity of compound 1 was much lower than GLA against the normal human liver cell (HL-7702). The in vitro stability assay revealed that transformation of GLA to Mannich base type derivatives improved the compound stability in rat plasma. Finally, decomposition product analysis supported that compound 1 could act as a prodrug and release GLA in the intracellular environment.

Keywords: Antitumor; Glaucocalyxin A; Glaucocalyxin A derivatives; Prodrug; Structure activity relationship.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Cell Proliferation / drug effects
  • Diterpenes, Kaurane / chemical synthesis
  • Diterpenes, Kaurane / chemistry
  • Diterpenes, Kaurane / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Humans
  • KB Cells
  • Models, Molecular
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Diterpenes, Kaurane
  • glaucocalyxin A