A novel compound T7 (N-{4'-[(1E)-N-hydroxyethanimidoyl]-3',5,6-trimethoxybiphenyl-3-yl}-N'-[4-(3-morpholin-4-ylpropoxy)phenyl]urea) screened by tissue angiogenesis model and its activity evaluation on anti-angiogenesis.

Abstract

A tissue model for angiogenesis that imitated new blood vessels formation in vivo had been established in the previous study. Here, it was used to screen and evaluate a series of synthesized compounds and the results indicated that compound T7 (N-{4'-[(1E)-N-hydroxyethanimidoyl]-3',5,6-trimethoxybiphenyl-3-yl}-N'-[4-(3-morpholin-4-ylpropoxy)phenyl]urea) could effectively inhibit the blood vessels formation. Then the anti-angiogenic potential of T7 and its related molecular mechanisms against lung carcinoma in vitro and in vivo were investigated. Treatment with T7 significantly inhibited human umbilical vein endothelial cells and A549 cells proliferation and migration. T7 reduced human umbilical vein endothelial cells tube formation as well. Western blotting analysis of cell signaling molecules indicated that T7 reduced phosphorylation of KDR and its downstream signaling players AKT and ERK1/2 activation in endothelial cells and A549 cells. Moreover, T7 inhibited tumor growth in A549 xenografted model of athymic mice and reduced CD34 expression levels in tumor-bearing mice by immunohistochemistry. In sum, our findings showed that T7 was a candidate of tumor angiogenesis inhibitors, and it functioned by interrupting the autophosphorylation of KDR, AKT and ERK1/2.

• Authors: Bingling Dai, Junpeng Qi, Rui Liu, Jie Zhang, Yingzhuan Zhan, Yanmin Zhang
• Journal: Phytomedicine : international journal of phytotherapy and phytopharmacology (Phytomedicine) Vol. 21 Issue 12 Pg. 1675-83 (Oct 15 2014) ISSN: 1618-095X [Electronic] Germany
• PMID: 25442276 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier GmbH. All rights reserved.

Chemical References

• Angiogenesis Inhibitors
• N-(4'-(N-hydroxyethanimidoyl)-3',5,6-trimethoxybiphenyl-3-yl)-N'-(4-(3-morpholin-4-ylpropoxy)phenyl)urea
• Oximes
• Phenylurea Compounds
• Vascular Endothelial Growth Factor Receptor-2
• Oncogene Protein v-akt
• Mitogen-Activated Protein Kinases

Topics

• Angiogenesis Inhibitors (chemical synthesis, pharmacology)
• Animals
• Cell Line, Tumor
• Human Umbilical Vein Endothelial Cells (drug effects)
• Humans
• Male
• Mice, Inbred BALB C
• Mice, Nude
• Mitogen-Activated Protein Kinases (metabolism)
• Oncogene Protein v-akt (metabolism)
• Oximes (pharmacology)
• Phenylurea Compounds (chemical synthesis, pharmacology)
• Phosphorylation
• Signal Transduction (drug effects)
• Vascular Endothelial Growth Factor Receptor-2 (metabolism)
• Xenograft Model Antitumor Assays