Para to ortho repositioning of the arsenical moiety of the angiogenesis inhibitor 4-(N-(S-glutathionylacetyl)amino)phenylarsenoxide results in a markedly increased cellular accumulation and antiproliferative activity.
The synthetic tripeptide arsenical 4-(N-(S-glutathionylacetyl)amino)p-phenylarsenoxide (p-GSAO) is an angiogenesis inhibitor that inactivates mitochondrial adenine nucleotide translocase (ANT) by cross-linking a pair of matrix-facing cysteine residues. This causes an increase in superoxide levels and proliferation arrest of endothelial cells followed by mitochondrial depolarization and apoptosis. p-GSAO induces proliferation arrest in endothelial cells and is a selective inhibitor of endothelial cells compared with tumor cells. An analogue of p-GSAO has been made in which the arsenical moiety is at the ortho instead of the para position on the phenyl ring. o-GSAO, like p-GSAO, bound to ANT in a dithiol-dependent manner but was approximately 8-fold more efficient than p-GSAO at triggering the mitochondria permeability transition in isolated mitochondria. o-GSAO was an approximately 50-fold more potent inhibitor of endothelial and tumor cell proliferation than p-GSAO. The mechanism of this effect was a consequence of approximately 300-fold faster rate of accumulation of o-GSAO in the cells, which is due, at least in part, to impaired export by the multidrug resistance-associated protein 1. Administration of o-GSAO to tumor-bearing mice delayed tumor growth by inhibiting tumor angiogenesis but there were side effects not observed with p-GSAO administration.
Dilda
Pierre J
PJ
Centre for Vascular Research, University of New South Wales.
Decollogne
Stephanie
S
Rossiter-Thornton
Michael
M
Hogg
Philip J
PJ
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D001152:Arsenicals / Q000627:therapeutic use*; D002417:Cattle; D049109:Cell Proliferation / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D005978:Glutathione / Q000031:analogs & derivatives* / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008928:Mitochondria / Q000201:enzymology; D000226:Mitochondrial ADP, ATP Translocases / Q000037:antagonists & inhibitors / Q000378:metabolism; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000188:drug therapy*; D013237:Stereoisomerism; D013481:Superoxides / Q000378:metabolism; D014050:Toluene / Q000031:analogs & derivatives / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D001152:Arsenicals; D005978:Glutathione; D000226:Mitochondrial ADP, ATP Translocases; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D013481:Superoxides; D014050:Toluene; C426645:4-(N-(S-glutathionylacetyl)amino)phenylarsenoxide; C004848:dithiol; C421109:multidrug resistance-associated protein 1