title: 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 IC50against 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 IC50around 24 nM against the PAK1-dependent growth of A549 cancer cells, inactivating PAK1 in cell culture with the apparent IC50around 65 nM, and inhibiting COX-2 in vitro with the IC50around 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.affiliation: PAK Research Center (Lab), Okinawa, Japan; Kagoshima University, Kagoshima, Japan.
authors.forename: Binh Cao Quan
authors.initials: BCQ
authors.lastname: Nguyen
authors.affiliation: Tokushima University, Tokushima, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Takahashi
authors.affiliation: Tokushima University, Tokushima, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Uto
authors.affiliation: PAK Research Center (Lab), Okinawa, Japan; Kagoshima University, Kagoshima, Japan.
authors.forename: M D
authors.initials: MD
authors.lastname: Shahinozzaman
authors.affiliation: PAK Research Center (Lab), Okinawa, Japan.
authors.forename: Shinkichi
authors.initials: S
authors.lastname: Tawata
authors.affiliation: PAK Research Center (Lab), Okinawa, Japan; PAK Research Center (Office), Melbourne, Australia. Electronic address: maruta20420@yahoo.co.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Maruta
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001692:Biological Transport; D045744:Cell Line, Tumor; D057930:Click Chemistry; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D004952:Esters / Q000737:chemistry*; D006801:Humans; D020910:Ketorolac / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D014230:Triazoles / Q000737:chemistry*; D054462:p21-Activated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D052246:Cyclooxygenase 2 Inhibitors; D004952:Esters; D047428:Protein Kinase Inhibitors; D014230:Triazoles; C515903:PAK1 protein, human; D054462:p21-Activated Kinases; D020910:Ketorolac
keywords: COX-2; Cancer; Click chemistry; Ketorolac; PAK1; Triazole ring