Journal
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
Volume 37, Issue 1, Pages 431-444Publisher
TAYLOR & FRANCIS LTD
DOI: 10.1080/14756366.2021.2018685
Keywords
Chromone; nitrogen mustard; breast cancer; apoptosis
Funding
- General Scientific Research Projects of Department of Education in Liaoning Province [2019LJC11]
- Career Development Support Plan for Young and Middle-aged Teachers in Shenyang Pharmaceutical University
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In this study, a series of nitrogen mustard derivatives of chromone were designed and synthesized, among which one compound showed the most potent antiproliferative activity against breast tumor cells and exhibited certain selectivity between tumor cells and normal cells. This compound possibly induced G2/M phase arrest and apoptosis in tumor cells by generating intracellular ROS and activating DNA damage, leading to inhibition of tumor cell metastasis, invasion, and adhesion.
Chromone has emerged as one of the most important synthetic scaffolds for antitumor activity, which promotes the development of candidate drugs with better activity. In this study, a series of nitrogen mustard derivatives of chromone were designed and synthesised, in order to discover promising anti-breast tumour candidates. Almost all target derivatives showed antiproliferative activity against MCF-7 and MDA-MB-231 cell lines. In particular, methyl (S)-3-(4-(bis(2-chloroethyl)amino)phenyl)-2-(5-(((6-methoxy-4-oxo-4H-chromen-3-yl)methyl)amino)-5-oxopentanamido)propanoate showed the most potent antiproliferative activity with IC50 values of 1.83 and 1.90 mu M, respectively, and it also exhibited certain selectivity between tumour cells and normal cells. Further mechanism exploration against MDA-MB-231 cells showed that it possibly induced G2/M phase arrest and apoptosis by generating intracellular ROS and activating DNA damage. In addition, it also inhibited MDA-MB-231 cells metastasis, invasion and adhesion. Overall, methyl (S)-3-(4-(bis(2-chloroethyl)amino)phenyl)-2-(5-(((6-methoxy-4-oxo-4H-chromen-3-yl)methyl)amino)-5-oxopentanamido)propanoate showed potent antitumor activities and relatively low side effects, and deserved further investigation.
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