Premium
Biological study of the Angiogenesis Inhibitor N ‐(8‐(3‐ethynylphenoxy)octyl‐1‐deoxynojirimycin
Author(s) -
Zhao Yunxue,
Zhou Ying,
O’ Boyle Kathy M.,
Murphy Paul V.
Publication year - 2010
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/j.1747-0285.2010.00968.x
Subject(s) - chemistry , angiogenesis inhibitor , angiogenesis , pharmacology , stereochemistry , combinatorial chemistry , computational biology , biology , medicine
The α‐glucosidase inhibitors N‐ methyl‐1‐deoxynojirimycin (MDNJ) and castanospermine have been shown to inhibit angiogenesis. A hybrid of 1‐deoxynojirimycin (DNJ) and an aryl‐1,2,3‐triazole, which inhibits both an α‐glucosidase and methionine aminopeptidase‐2 (MetAP2), displayed properties associated with inhibition of angiogenesis ( Bioorg. Med. Chem. , 16 , 2008 , 6333–7). The biological evaluation of a structural analogue N ‐(8‐(3‐ethynylphenoxy)octyl‐1‐deoxynojirimycin is described herein. Although this alkyne derivative did not inhibit MetAP2, it inhibited a bacterial α‐glucosidase, altered bovine aortic endothelial cell (BAEC) surface oligosaccharide expression and inhibited BAEC proliferation by inducing G1 phase cell cycle arrest. Experiments showed G1 arrest was attributable to the α‐glucosidase inhibitor inducing an increase in p27 Kip1 expression and high phosphorylation of ERK1/2 without a reduction in cyclin D1. The DNJ derivative (0.1 m m ) prevented capillary tube formation from bovine aortic endothelial cells, whereas DNJ or other analogues were unable to inhibit tube formation at the same concentration. Stress fiber assembly in bovine aortic endothelial cells was abolished, and BAEC migration was inhibited indicating the inhibition of tube formation by this derivative is partially a result of a reduction in cell motility. The agent also caused a reduction in secretion of MMP‐2 from bovine aortic endothelial cells. Therefore, the new α‐glucosidase inhibitor has a different mechanism by which it inhibits angiogenesis in vitro when compared with deoxynojirimycin, the deoxynojirimycin ‐triazole hybrid, N ‐methyl‐1‐deoxynojirimycin and castanospermine.