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.

Abstract

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.

• Authors: Hideaki Takahashi, Binh Cao Quan Nguyen, Yoshihiro Uto, Md Shahinozzaman, Shinkichi Tawata, Hiroshi Maruta
• Journal: Drug discoveries & therapeutics (Drug Discov Ther) Vol. 11 Issue 2 Pg. 104-109 (May 30 2017) ISSN: 1881-7831 [Print] Japan
• PMID: 28442677 (Publication Type: Journal Article)

Chemical References

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

Topics

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