1,2,3-Triazolyl esterization of PAK1-blocking propolis ingredients, artepillin C (ARC) and caffeic acid (CA), for boosting their anti-cancer/anti-PAK1 activities along with cell-permeability

Drug Discov Ther. 2017 May 30;11(2):104-109. doi: 10.5582/ddt.2017.01009. Epub 2017 Apr 24.


Artepillin C (ARC) and caffeic acid (CA) are among the major anti-cancer ingredients of propolis, and block the oncogenic/melanogenic/ageing kinase PAK1. However, mainly due to their COOH moiety, cell-permeability of these herbal compounds is rather limited. Thus, in this study, in an attempt to increase their cell-permeability without any significant loss of their water-solubility, we have esterized both ARC and CA with the water-soluble 1,2,3-triazolyl alcohol through Click Chemistry. We found that this esterization boosts the anti-cancer activity of ARC and CA by 100 and over 400 folds, respectively, against the PAK-dependent growth of A549 lung cells, but show no effect on the PAK1-independent growth of B16F10 melanoma cells. Confirming this "selective" toxicity, these esters are still capable of blocking the kinase PAK1 strongly in cell culture (with IC50 around 5 µM), and the anti-PAK1 activity of 15A (ARC ester) and 15C (CA ester) appears to be 30-fold and 140-fold higher than ARC and CA, respectively. The 15A and 15C are 8-fold and 70-fold more cell-permeable (through the multi-drug resistant cell line EMT6) than ARC and CA, respectively. These data altogether suggest that both 15A and 15C would be far more useful than propolis for the treatment of a wide variety of PAK1-dependent diseases/disorders such as cancers, Alzheimer's diseases (AD), hypertension, diabetes (type 2), and hyper-pigmentation.

Keywords: PAK1; artepillin C; caffeic acid; click chemistry; triazolyl esters.

MeSH terms

  • A549 Cells
  • Animals
  • Anti-Infective Agents
  • Antineoplastic Agents / pharmacology*
  • Caffeic Acids / chemistry
  • Caffeic Acids / pharmacology*
  • Esters / chemistry
  • Esters / pharmacology
  • Humans
  • Melanoma, Experimental
  • Mice
  • Permeability
  • Phenylpropionates / chemistry
  • Phenylpropionates / pharmacology*
  • Propolis / chemistry
  • Propolis / pharmacology*
  • Solubility
  • Triazoles / chemistry
  • Triazoles / pharmacology
  • p21-Activated Kinases / antagonists & inhibitors*


  • Anti-Infective Agents
  • Antineoplastic Agents
  • Caffeic Acids
  • Esters
  • Phenylpropionates
  • Triazoles
  • artepillin C
  • Propolis
  • p21-Activated Kinases
  • caffeic acid