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

Khatir, Z. Z., Di Sotto, A., Percaccio, E., Kucukkilinc, T. T., Ercan, A., Chippindale, A. M. ORCID: https://orcid.org/0000-0002-5918-8701, Valipour, M. and Irannejad, H. (2024) 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. Archiv de Pharmazie, 2024. e2300704. ISSN 1521-4184 doi: 10.1002/ardp.202300704

Abstract/Summary

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 CH2NH-linked pyridine for use as dual c-Met/MDR inhibitors. The compound 12g with IC50 of 3.06 μM on HepG2 cells showed more potency than crizotinib (IC50 = 5.15 μM) in MTT assay. In addition, 12g inhibited c-Met kinase at low micromolar level (IC50 = 0.052 μM). 12g significantly inhibited Pgp 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 the anticancer agents.

Item Type	Article
URI	https://reading-clone.eprints-hosting.org/id/eprint/115649
Identification Number/DOI	10.1002/ardp.202300704
Refereed	Yes
Divisions	Interdisciplinary centres and themes > Chemical Analysis Facility (CAF) Interdisciplinary centres and themes > Chemical Analysis Facility (CAF) > Xray (CAF)
Publisher	Wiley
Download/View statistics	View download statistics for this item