Synthesis and antiproliferative properties of new hydrophilic esters of triterpenic acids

Eur J Med Chem. 2017 Nov 10:140:403-420. doi: 10.1016/j.ejmech.2017.09.041. Epub 2017 Sep 21.


To improve the properties of cytotoxic triterpenoid acids 1-5, a large set of hydrophilic esters was synthesized. We choose betulinic acid (1), dihydrobetulinic acid (2), 21-oxoacid 3 along with highly active des-E lupane acids 4 and 5 as a model set of compounds for esterification of which the properties needed to be improved. As ester moieties were used - methoxyethanol and 2-(2-methoxyethoxy)ethanol and glycolic unit (type a-d), pyrrolidinoethanol, piperidinoethanol and morpholinoethanol (type f-h), and monosaccharide groups (type i-l). As a result, 56 triterpenic esters (49 new compounds) were obtained and their cytotoxicity on four cancer cell lines and normal human fibroblasts was tested. All new compounds were fully soluble at all tested concentrations, which used to be a problem of the parent compounds 1 and 2. 16 compounds had IC50 < 10 μM on at least one cancer cell line, 12 compounds had cytotoxicity of <10 μM against at least three of four tested cancer cell lines. The highest activity was found for compound 3c (1.8 μM on MCF7, 2.8 μM on HeLa, and 1.6 μM on G-361 cells) which also had no toxicity on non-cancerous BJ fibroblasts at the highest tested concentration (50 μM). High selective cytotoxicity was also found in compounds 1k, 2k, 3c, and 3i that are ideal candidates for drug development. Therefore, more studies to identify the mechanism of action were performed in case of 1k, 3c, and 3g such as effects on cell cycle and apoptosis. It was found that compounds 3c and 3g can induce apoptosis via caspase-3 activation and modulation of protein Bcl-2 in G-361 cells. In conclusion, compounds 1k, 3c, and 3g show high and selective cytotoxicity, therefore they are significantly better candidates for anti-cancer drug development than the parent acids 1-5.

Keywords: Apoptosis; Betulinic acid; Cell cycle; Cytotoxicity; Hydrophilic ester; Prodrug; Triterpenic acids.

MeSH terms

  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Drug Screening Assays, Antitumor
  • Esters / chemistry
  • Humans
  • Spectrum Analysis / methods
  • Triterpenes / chemical synthesis*
  • Triterpenes / chemistry
  • Triterpenes / pharmacology*


  • Esters
  • Triterpenes