1,2,3-Triazolyl ester of Ketorolac: A "Click Chemistry"-based highly potent PAK1-blocking cancer-killer.

Abstract

An old anti-inflammatory/analgesic drug called Toradol is a racemic form of Ketorolac (50% R-form and 50% S-form) that blocks the oncogenic RAC-PAK1-COX-2 (cyclooxygenase-2) signaling, through the direct inhibition of RAC by the R-form and of COX-2 by the S-form, eventually down-regulating the production of prostaglandins. However, due to its COOH moiety which is clearly repulsive to negatively-charged phospholipid-based plasma membrane, its cell-permeability is rather poor (the IC50 against the growth of human cancer cells such as A549 is around 13 μM). In an attempt to boost its anti-cancer activity, hopefully by increasing its cell-permeability through abolishing the negative charge, yet keeping its water-solubility, here we synthesized a 1,2,3-triazolyl ester of Toradol through "Click Chemistry". The resultant water-soluble "azo" derivative called "15K" was found to be over 500 times more potent than Toradol with the IC50 around 24 nM against the PAK1-dependent growth of A549 cancer cells, inactivating PAK1 in cell culture with the apparent IC50 around 65 nM, and inhibiting COX-2 in vitro with the IC50 around 6 nM. Furthermore, the Click Chemistry boosts the anti-cancer activity of Ketorolac by 5000 times against the PAK1-independent growth of B16F10 melanoma cells. Using a multi-drug-resistant (MDR) cancer cell line (EMT6), we found that the esterization of Ketorolac boosts its cell-permeability by at least 10 folds. Thus, the Click Chemistry dramatically boosts the anti-cancer activity of Ketorolac, at least in three ways: increasing its cell-permeability, the anti-PAK1 activity of R-form and anti-COX-2 activity of S-form. The resultant "15K" is so far among the most potent PAK1-blockers, and therefore would be potentially useful for the therapy of many different PAK1-dependent diseases/disorders such as cancers.

• Authors: Binh Cao Quan Nguyen, Hideaki Takahashi, Yoshihiro Uto, M D Shahinozzaman, Shinkichi Tawata, Hiroshi Maruta
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 126 Pg. 270-276 (Jan 27 2017) ISSN: 1768-3254 [Electronic] France
• PMID: 27889630 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Chemical References

• Antineoplastic Agents
• Cyclooxygenase 2 Inhibitors
• Esters
• Protein Kinase Inhibitors
• Triazoles
• PAK1 protein, human
• p21-Activated Kinases
• Ketorolac

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, metabolism, pharmacology)
• Biological Transport
• Cell Line, Tumor
• Click Chemistry
• Cyclooxygenase 2 Inhibitors (chemical synthesis, chemistry, metabolism, pharmacology)
• Esters (chemistry)
• Humans
• Ketorolac (chemical synthesis, chemistry, metabolism, pharmacology)
• Protein Kinase Inhibitors (chemical synthesis, chemistry, metabolism, pharmacology)
• Signal Transduction (drug effects)
• Triazoles (chemistry)
• p21-Activated Kinases (antagonists & inhibitors, metabolism)