Journal
BIOORGANIC CHEMISTRY
Volume 105, Issue -, Pages -Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bioorg.2020.104371
Keywords
4-Phenoxypyridine derivatives; c-Met inhibitors; Antitumor activity; Apoptosis; Migration
Funding
- General Project of Education Department of Liaoning Province [LJC201907]
- Natural Science Foundation of Liaoning Provincial Department of Science and Technology [2019-ZD-0191]
- Shenyang Science & Technology Project [18-013-0-03]
- National College Students' innovation and entrepreneurship training program [D201912311824318027]
Ask authors/readers for more resources
Blocking c-Met kinase activity by small-molecule inhibitors has been identified as a promising approach for the treatment of cancers. Herein, we described the design, synthesis, and biological evaluation of a series of 4-phenoxypyridine-based 3-oxo-3,4-dihydroquinoxaline derivatives as c-Met kinase inhibitors. Inhibitory activitives against c-Met kinase evaluation indicated that most of compounds showed excellent c-Met kinase activity in vitro, and IC50 values of ten compounds (23a, 23e, 23f, 23l, 23r, 23s, 23v, 23w, 23x and 23y) were less than 10.00 nM. Notably, three of them (23v, 23w and 23y) showed remarkable potency with IC50 values of 2.31 nM, 1.91 nM and 2.44 nM, respectively, and thus they were more potent than positive control drug foretinib (c-Met, IC50 = 2.53 nM). Cytotoxic evaluation indicated the most promising compound 23w showed remarkable cytotoxicity against A549, H460 and HT-29 cell lines with IC50 values of 1.57 mu M, 0.94 mu M and 0.65 mu M, respectively. Furthermore, the acridine orange/ethidium bromide (AO/EB) staining, cell apoptosis assays by flow cytometry, wound-healing assays and transwell migration assays on HT-29 and/or A549 cells of 23w were performed. Especially compound 23w, which displayed potent antitumor, apoptosis induction and antimetastatic activity, could be used as a promising lead for further development. Meanwhile, their preliminary structure-activity relationships (SARs) were also discussed.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available