期刊
EUROPEAN JOURNAL OF PHARMACOLOGY
卷 894, 期 -, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.ejphar.2021.173850
关键词
Anticancer drug; Kinase inhibitor; Scaffold hopping; Drug design; Molecular modeling
资金
- Shiraz University of Medical Sciences, Shiraz, Iran [8950]
- National Institute for Medical Research Development (NIMAD), Tehran, Iran [957652]
- Shiraz University of Medical Sciences [1396-01-106-15688]
The study synthesized 27 3,4-dihydropyrimidin-2(1H)-one C5 amide derivatives and found that some of them displayed considerable anti-proliferative effects against breast cancer, colon cancer, and leukemia cell lines, with relatively sparing non-cancer cells. Some derivatives bearing benzothiazolyl carboxamide moiety at the C5 position showed the highest activities.
Cancer continues to be the second leading cause of death worldwide. Discovery of novel therapeutic agents has crucial importance for improvement of our medical management capabilities. Dysregulation of the MET receptor tyrosine kinase pathway plays an important role in cancer progression, making this receptor an attractive molecular target for anticancer drug discovery. In this study, twenty-seven 3,4-dihydropyrimidin-2(1H)-one C5 amide derivatives were synthesized and their cancer cell growth inhibitory activity was examined against MCF-7, HT-29 and MOLT-4 cells and also NIH/3T3 non-cancer cells by MTT assay. The antipmliferative effect of the most potent derivatives were tested against MET-dependent EBC-1 and MKN-45, lung and gastric cancer cell lines, respectively. MET kinase inhibition was measured by a Homogenous Time Resolved Fluorescence (HTRF) Assay. The influence of the test compounds on cell cycle was examined by RNase/PI flow cytometric assay. A number of compounds exhibited considerable antiproliferative effects against breast and colon cancer and leukemia cell lines, relatively sparing non-cancer cells. Some derivatives bearing benzothiazolyl carboxamide moiety at C5 position (15, 21, 23, 31, and 37) showed the highest activities with IC50 values as low as 10.9 mu M. These compounds showed antiproliferative effects also against MET-amplified cells and dose-dependently inhibited MET kinase activity. They also induced G0/G1 cell cycle arrest at lower doses and apoptosis at higher doses. Molecular docking and dynamics simulation studies confirmed the interaction of compound 23 with the active site of the MET receptor. These findings demonstrate that 3,4-dihydropyrimidin-2(1H)-one analogues may represent promising targeted anticancer agents.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据