Substituted Oxines Inhibit Endothelial Cell Proliferation and Angiogenesis

Overview

Journal Org Biomol Chem

Publisher Royal Society of Chemistry

Specialties Biochemistry
Chemistry

Date 2012 Mar 7

PMID 22391578

Citations 9

Authors

Shridhar Bhat

Joong Sup Shim

Feiran Zhang

Curtis Robert Chong

Jun O Liu

Affiliations

Soon will be listed here.

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.

Citing Articles

Organometallic Half-Sandwich Complexes of 8-Hydroxyquinoline-Derived Mannich Bases with Enhanced Solubility: Targeting Multidrug Resistant Cancer.

Pivarcsik T, Toth S, Posa S, May N, Kovats E, Spengler G Inorg Chem. 2024; 63(50):23983-23998.

PMID: 39638428 PMC: 11653257. DOI: 10.1021/acs.inorgchem.4c04398.

Application of nitroxoline in urologic oncology - a review of evidence.

Tomczak W, Krajewski W, Chorbinska J, Nowak L, Laszkiewicz J, Grunwald K Contemp Oncol (Pozn). 2024; 28(1):1-8.

PMID: 38800529 PMC: 11117163. DOI: 10.5114/wo.2024.139584.

Synthesis of Bioactive Aminomethylated 8-Hydroxyquinolines via the Modified Mannich Reaction.

Csuvik O, Szatmari I Int J Mol Sci. 2023; 24(9).

PMID: 37175622 PMC: 10177806. DOI: 10.3390/ijms24097915.

8-Hydroxyquinolines are bactericidal against Mycobacterium tuberculosis.

Odingo J, Early J, Smith J, Johnson J, Bailey M, Files M Drug Dev Res. 2019; 80(5):566-572.

PMID: 30893501 PMC: 6767403. DOI: 10.1002/ddr.21531.

Synthesis and Cytoprotective Characterization of 8-Hydroxyquinoline Betti Products.

Kanizsai I, Madacsi R, Hackler Jr L, Gyuris M, Szebeni G, Huzian O Molecules. 2018; 23(8).

PMID: 30072653 PMC: 6222637. DOI: 10.3390/molecules23081934.

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