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
Dec 26, 2001·Cytokine & Growth Factor Reviews·Gautam MaulikRavi Salgia
Dec 7, 2007·The Journal of Biological Chemistry·Steven F BellonIsabelle Dussault
Apr 23, 2008·Journal of Medicinal Chemistry·Brian K AlbrechtSteven F Bellon
Jun 10, 2011·Investigational New Drugs·Yu KataokaHironobu Minami
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
Mar 12, 2016·Bioorganic & Medicinal Chemistry·Wufu ZhuPengwu Zheng
Apr 5, 2016·European Journal of Medicinal Chemistry·Fei LeiWufu Zhu
Jul 30, 2017·European Journal of Medicinal Chemistry·Li ZhangYadong Chen
Sep 25, 2017·European Journal of Medicinal Chemistry·Daowei HuangJianqi Li
Dec 5, 2017·European Journal of Medicinal Chemistry·Haoliang YuanTao Lu
Dec 6, 2017·Bioorganic & Medicinal Chemistry·Linxiao WangWufu Zhu
Jan 15, 2018·European Journal of Medicinal Chemistry·Wenhui WangWufu Zhu
Jun 29, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Xiaobo LiuWufu Zhu
Sep 25, 2018·European Journal of Medicinal Chemistry·Wei ShiHai Qian
Dec 12, 2018·European Journal of Medicinal Chemistry·Bingbing ZhaoWufu Zhu
Apr 24, 2019·Cytotherapy·Ha-Ram ParkDae Seog Heo
Nov 5, 2019·European Journal of Medicinal Chemistry·Bingbing ZhaoPengwu Zheng
Nov 26, 2019·European Journal of Medicinal Chemistry·Zefeng ZhaoXiaohui Zheng
Jan 12, 2020·European Journal of Medicinal Chemistry·Prabodh Chander SharmaAakash Deep