4-{3-[(Pyridin-4-ylmethyl)amino]-[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl}phenol: An improved anticancer agent in hepatocellular carcinoma and a selective MDR1/MRP modulator.

Autor: Khatir ZZ; Department of Medicinal Chemistry, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran., Di Sotto A; Department of Physiology and Pharmacology 'V. Erspamer', Sapienza University of Rome, Rome, Italy., Percaccio E; Department of Physiology and Pharmacology 'V. Erspamer', Sapienza University of Rome, Rome, Italy., Tuylu Kucukkilinc T; Department of Biochemistry, Faculty of Pharmacy, Hacettepe University, Sihhiye, Ankara, Turkey., Ercan A; Department of Biochemistry, Faculty of Pharmacy, Hacettepe University, Sihhiye, Ankara, Turkey., Chippindale AM; Department of Chemistry, University of Reading, Reading, UK., Valipour M; Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran., Irannejad H; Department of Medicinal Chemistry, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran.
Jazyk: angličtina
Zdroj: Archiv der Pharmazie [Arch Pharm (Weinheim)] 2024 Jun; Vol. 357 (6), pp. e2300704. Date of Electronic Publication: 2024 Mar 05.
DOI: 10.1002/ardp.202300704
Abstrakt: Hepatocellular carcinoma is the most common type of primary liver cancer. However, multidrug resistance (MDR) is a major obstacle to the effective chemotherapy of cancer cells. This report documents the rational design, synthesis, and biological evaluation of a novel series of triazolotriazines substituted with CH 2 NH-linked pyridine for use as dual c-Met/MDR inhibitors. Compound 12g with IC 50 of 3.06 μM on HepG2 cells showed more potency than crizotinib (IC 50  = 5.15 μM) in the MTT assay. In addition, 12g inhibited c-Met kinase at a low micromolar level (IC 50  = 0.052 μM). 12g significantly inhibited P-gp and MRP1/2 efflux pumps in both cancerous HepG2 and BxPC3 cells starting from the lower concentrations of 3 and 0.3 µM, respectively. 12g did not inhibit MDR1 and MRP1/2 in noncancerous H69 cholangiocytes up to the concentration of 30 and 60 µM, respectively. Current results highlighted that cancerous cells were more susceptible to the effect of 12g than normal cells, in which the inhibition occurred only at the highest concentrations, suggesting a further interest in 12g as a selective anticancer agent. Overall, 12g, as a dual c-Met and P-gp/MRP inhibitor, is a promising lead compound for developing a new generation of anticancer agents.
(© 2024 Deutsche Pharmazeutische Gesellschaft.)
Databáze: MEDLINE
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