title: Substituted oxines inhibit endothelial cell proliferation and angiogenesis.
abstract: Two substituted oxines, nitroxoline (5) and 5-chloroquinolin-8-yl phenylcarbamate (22), were identified as hits in a high-throughput screen aimed at finding new anti-angiogenic agents. In a previous study, we have elucidated the molecular mechanism of antiproliferative activity of nitroxoline in endothelial cells, which comprises of a dual inhibition of type 2 human methionine aminopeptidase (MetAP2) and sirtuin 1 (SIRT1). Structure-activity relationship study (SAR) of nitroxoline offered many surprises where minor modifications yielded oxine derivatives with increased potency against human umbilical vein endothelial cells (HUVEC), but with entirely different as yet unknown mechanisms. For example, 5-nitrosoquinolin-8-ol (33) inhibited HUVEC growth with sub-micromolar IC(50), but did not affect MetAP2 or MetAP1, and it only showed weak inhibition against SIRT1. Other sub-micromolar inhibitors were derivatives of 5-aminoquinolin-8-ol (34) and 8-sulfonamidoquinoline (32). A sulfamate derivative of nitroxoline (48) was found to be more potent than nitroxoline with the retention of activities against MetAP2 and SIRT1. The bioactivity of the second hit, micromolar HUVEC and MetAP2 inhibitor carbamate 22 was improved further with an SAR study culminating in carbamate 24 which is a nanomolar inhibitor of HUVEC and MetAP2.
authors.affiliation: Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA.
authors.forename: Shridhar
authors.initials: S
authors.lastname: Bhat
authors.forename: Joong Sup
authors.initials: JS
authors.lastname: Shim
authors.forename: Feiran
authors.initials: F
authors.lastname: Zhang
authors.forename: Curtis Robert
authors.initials: CR
authors.lastname: Chong
authors.forename: Jun O
authors.initials: JO
authors.lastname: Liu
mesh_terms: D000626:Aminopeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006023:Glycoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D057166:High-Throughput Screening Assays; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D006912:Hydroxyquinolines / Q000138:chemical synthesis* / Q000494:pharmacology; D063208:Methionyl Aminopeptidases; D009600:Nitroquinolines / Q000138:chemical synthesis* / Q000494:pharmacology; D048448:Phenylcarbamates / Q000138:chemical synthesis* / Q000494:pharmacology; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D020533:Angiogenesis Inhibitors; D004791:Enzyme Inhibitors; D006023:Glycoproteins; D006912:Hydroxyquinolines; D009600:Nitroquinolines; D048448:Phenylcarbamates; C005308:nitroxoline; D000626:Aminopeptidases; C506619:METAP1 protein, human; C081311:METAP2 protein, human; D063208:Methionyl Aminopeptidases; C447939:SIRT1 protein, human; D056564:Sirtuin 1