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

, : 1,2,3-Triazolyl ester of Ketorolac: A "Click Chemistry"-based highly potent PAK1-blocking cancer-killer. European Journal of Medicinal Chemistry 126(): 270-276

NlmCategory="UNASSIGNED">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.


PMID: 27889630

DOI: 10.1016/j.ejmech.2016.11.038

Other references

Khajeddin, S.J.; Akbari, M.; Karimzadeh, H.R.; Eghbal, M.K., 2008: Detecting desertification processes using TM and ETM+ data, north of Isfahan, Iran. Aims Desertification results in ecological and biological diminution of the earth, and can happen naturally or cause by anthrogenic activities. This process especially affects and and semi-arid regions, such as the Isfahan region, where the sprea...

Kawazu, K.; Yamada, K.; Nakamura, M.; Ota, A., 1999: Characterization of cyclosporin A transport in cultured rabbit corneal epithelial cells: P-glycoprotein transport activity and binding to cyclophilin. Purpose. The purpose of this study was to characterize cyclosporin A (CsA) uptake and transport in cultured rabbit corneal epithelial cells (RCECs). Methods. CsA uptake was evaluated by measuring time-dependent 3H-CsA accumulation in confluent RCE...

Zhdanov, A.P.; Gaifutdinova, G.M., 1954: Metacercariae of Alaria in the muscles of badgers in Bashkir ASSR.. The authors found the muscles of five badgers to be infected with metacercariae of Alaria. When these larvae were feel to a puppy eggs were found 33 days later in the faeces and when the dog was killed 70 specimens of Alaria alata were found in th...

Brown M.S.; Goldstein J.L., 1991: The hyperlipoproteinemias and other disorders of lipid metabolism. Wilson, J D , Et Al (Ed ) Harrison's Principles Of Internal Medicine, Twelfth Edition, Vols 1 And 2 Xxx+1026p (Vol 1); Xxx+1183p (Vol 2) Mcgraw-Hill, Inc : New York, New York, Usa; London, England, Uk Illus Maps 1814-1825

He, Y., 2015: Role of surgery in the treatment of liver metastases from gastric cancer. The development of liver metastases is a fatal event for gastric cancer patients, and remains a major cause of cancer-related death. Many studies showed that the 5-year survival rate is as low as about 10% in these cases. The management of liver m...

Anonymous, 2007: A&WMA Celebrates 100 Years of Environmental Stewardship in 2007. Journal of the Air & Waste Management Association 57(1): 135-135

Ploch, R., 1968: Some pre- and postoperative problems in patients with prostatic adenoma. Polski Przeglad Chirurgiczny 40(4): 461-469

Noeske K., 1971: Problems of quantitative determination of substances in cyto photometry. Fortschritte der Medizin 89(31): 1228-1231

Favorova, L.A., 1965: On the intensity of transmission of diphtheria from clinically normal carriers. 3. Zhurnal Mikrobiologii, Epidemiologii, i Immunobiologii 42(5): 47-50

Dobler, C.C.; Waterer, G., 2014: Healthcare-associated pneumonia: a US disease or relevant to the Asia Pacific, too?. The term healthcare-associated pneumonia (HCAP) was introduced by the American Thoracic Society and the Infectious Diseases Society of America in 2005 to describe a distinct entity of pneumonia that resembles hospital-acquired pneumonia rather tha...