Hybrids of 1-deoxynojirimycin and aryl-1,2,3-triazoles and biological studies related to angiogenesis.
Hybrids of 1-deoxynojirimycin (DNJ) and aryl-1,2,3-triazole have been synthesized with a view to identifying an inhibitor of both alpha-glucosidase and methionine aminopeptidase 2 (MetAP2). One compound was a potent inhibitor of alpha-glucosidase at both the enzyme and cellular level, and this agent also inhibited bovine aortic endothelial cell (BAEC) growth and tube formation. The anti-proliferative activity of this hybrid is due to its ability to induce cell-cycle arrest in the G(1) phase. The novel agent caused a reduction in the expression of cyclin D1 but did not promote apoptosis or inhibit the phosphorylation of ERK1/2. These observations indicate that its mechanism of action is distinct from fumagillin and its analogues, which inhibit MetAP2. Stress-fibre assembly in BAECs was abolished by the novel agent indicating that the inhibition of BAEC tube formation observed is partially a result of a reduction in cell motility.
Zhao
Yunxue
Y
UCD School of Biomolecular and Biomedical Science and the UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.
Zhou
Ying
Y
O'Boyle
Kathy M
KM
Murphy
Paul V
PV
D017485:1-Deoxynojirimycin / Q000737:chemistry*; D000626:Aminopeptidases / Q000037:antagonists & inhibitors; D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000166:cytology; D017209:Apoptosis; D002417:Cattle; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D065089:Glycoside Hydrolase Inhibitors; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000201:enzymology; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D022502:Stress Fibers / Q000187:drug effects / Q000378:metabolism; D014230:Triazoles / Q000737:chemistry*
D020533:Angiogenesis Inhibitors; D004791:Enzyme Inhibitors; D065089:Glycoside Hydrolase Inhibitors; D014230:Triazoles; D019938:Cyclin D1; D017485:1-Deoxynojirimycin; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D000626:Aminopeptidases; C106541:methionine aminopeptidase 2; D008666:Metalloendopeptidases