Issue 15, 2012

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 IC50, 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.

Graphical abstract: Substituted oxines inhibit endothelial cell proliferation and angiogenesis

Supplementary files

Article information

Article type
Paper
Submitted
23 Nov 2011
Accepted
08 Feb 2012
First published
08 Feb 2012

Org. Biomol. Chem., 2012,10, 2979-2992

Substituted oxines inhibit endothelial cell proliferation and angiogenesis

S. Bhat, J. S. Shim, F. Zhang, C. R. Chong and J. O. Liu, Org. Biomol. Chem., 2012, 10, 2979 DOI: 10.1039/C2OB06978D

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