Peer-Reviewed Journal Details
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Zhao, YX,Zhou, Y,Boyle, KMO,Murphy, PV
2010
June
Chemical Biology & Drug Design
Biological study of the Angiogenesis Inhibitor N-(8-(3-ethynylphenoxy)octyl-1-deoxynojirimycin
Published
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Optional Fields
ENDOTHELIAL-CELLS GROWTH 1-DEOXYNOJIRIMYCIN CANCER ARYL-1,2,3-TRIAZOLES IMINOSUGARS SURVIVAL THERAPY
75
570
577
The alpha-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 alpha-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 alpha-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 alpha-glucosidase inhibitor inducing an increase in p27Kip1 expression and high phosphorylation of ERK1/2 without a reduction in cyclin D1. The DNJ derivative (0.1 mm) 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 alpha-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.
DOI 10.1111/j.1747-0285.2010.00968.x
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