Discovery of new fluorescent thiazole-pyrazoline derivatives as autophagy inducers by inhibiting mTOR activity in A549 human lung cancer cells.

Abstract

A series of fluorescent thiazole-pyrazoline derivatives was synthesized and their structures were characterized by 1H NMR, 13C NMR, and HRMS. Biological evaluation demonstrated that these compounds could effectively inhibit the growth of human non-small cell lung cancer (NSCLC) A549 cells in a dose- and time-dependent manner in vitro and inhibit tumor growth in vivo. The structure-activity relationship (SAR) of the compounds was analyzed. Further mechanism research revealed they could induce autophagy and cell cycle arrest while had no influence on cell necrosis. Compound 5e inhibited the activity of mTOR via FKBP12, which could be reversed by 3BDO, an mTOR activator and autophagy inhibitor. Compound 5e inhibited growth, promoted autophagy of A549 cells in vivo. Moreover, compound 5e showed good selectivity with no influence on normal vascular endothelial cell growth and the normal chick embryo chorioallantoic membrane (CAM) capillary formation. Therefore, our research provides potential lead compounds for the development of new anticancer drugs against human lung cancer.

• Authors: ZhaoMin Lin, ZhaoYang Wang, XueWen Zhou, Ming Zhang, DongFang Gao, Lu Zhang, Peng Wang, Yuan Chen, YuXing Lin, BaoXiang Zhao, JunYing Miao, Feng Kong
• Journal: Cell death & disease (Cell Death Dis) Vol. 11 Issue 7 Pg. 551 (07 20 2020) ISSN: 2041-4889 [Electronic] England
• PMID: 32686662 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Pyrazoles
• Thiazoles
• TOR Serine-Threonine Kinases
• Tacrolimus Binding Protein 1A
• Fluorouracil

Topics

• A549 Cells
• Animals
• Autophagy (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Chick Embryo
• Fluorescence
• Fluorouracil (pharmacology)
• Humans
• Inhibitory Concentration 50
• Lung Neoplasms (metabolism, pathology)
• Lysosomes (drug effects, metabolism)
• Pyrazoles (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship
• TOR Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Tacrolimus Binding Protein 1A (metabolism)
• Thiazoles (chemical synthesis, chemistry, pharmacology)