Discovery of Triazolo-pyridazine/-pyrimidine Derivatives Bearing Aromatic (Heterocycle)-Coupled Azole Units as Class II c-Met Inhibitors

ACS Omega
Qian ZhangWufu Zhu

Abstract

Two series of novel triazolo-pyridazine/-pyrimidine derivatives were designed, synthesized, and evaluated for their inhibitory activity against c-Met kinase, as well as three c-Met overexpressed cancer cell lines (A549, MCF-7, and HeLa) and one normal human hepatocytes cell line LO2 in vitro. The pharmacological data indicated that most of the tested compounds showed moderate cytotoxicity, and the most promising compound 12e exhibited significant cytotoxicity against A549, MCF-7, and HeLa cell lines with IC50 values of 1.06 ± 0.16, 1.23 ± 0.18, and 2.73 ± 0.33 μM, respectively. Moreover, the inhibitory activity of compound 12e against c-Met kinase (IC50 = 0.090 μM) was equal to that of Foretinib (IC50 = 0.019 μM). The result of the acridine orange (AO) single staining test demonstrated that compound 12e could remarkably induce apoptosis of A549 cells. The results of apoptosis and cycle distribution of cells showed that compound 12e could induce late apoptosis of A549 cells and stimulate A549 cells arresting in the G0/G1 phase. Structure-activity relationships (SARs), pharmacological results, and docking studies indicated that the introduction of 5-methylthiazole fragment to the five-atom moiety was beneficial for the activity. ...Continue Reading

References

Apr 23, 2008·Journal of Medicinal Chemistry·Brian K AlbrechtSteven F Bellon
Feb 11, 2012·Journal of Medicinal Chemistry·Mark H NormanIsabelle Dussault
May 6, 2014·European Journal of Medicinal Chemistry·Wei ZhangYingxia Li
Feb 24, 2015·Journal of Medicinal Chemistry·Emily A PetersonJean-Christophe Harmange
Mar 7, 2015·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Martijn P LolkemaFerry A L M Eskens
Dec 5, 2017·European Journal of Medicinal Chemistry·Haoliang YuanTao Lu
Jun 29, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Xiaobo LiuWufu Zhu
Nov 26, 2019·European Journal of Medicinal Chemistry·Zefeng ZhaoXiaohui Zheng
Jan 12, 2020·European Journal of Medicinal Chemistry·Prabodh Chander SharmaAakash Deep

❮ Previous
Next ❯

Methods Mentioned

BETA
flow cytometry
NMR
Assay

Software Mentioned

AutoDock
PyMOL

Related Concepts

Related Feeds

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis