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An SAR study of hydroxy-trifluoromethylpyrazolines as inhibitors of Orai1-mediated store operated Ca2+ entry in MDA-MB-231 breast cancer cells using a convenient Fluorescence Imaging Plate Reader assay

Citation

Stevenson, RJ and Azimi, I and Flanagan, JU and Inserra, M and Vetter, I and Monteith, GR and Denny, WA, An SAR study of hydroxy-trifluoromethylpyrazolines as inhibitors of Orai1-mediated store operated Ca2+ entry in MDA-MB-231 breast cancer cells using a convenient Fluorescence Imaging Plate Reader assay, Bioorganic & Medicinal Chemistry, 26, (12) pp. 3406-3413. ISSN 0968-0896 (2018) [Refereed Article]

Copyright Statement

Copyright 2018 Elsevier Ltd.

DOI: doi:10.1016/j.bmc.2018.05.012

Abstract

The proteins Orai1 and STIM1 control store-operated Ca2+ entry (SOCE) into cells. SOCE is important for migration, invasion and metastasis of MDA-MB-231 human triple negative breast cancer (TNBC) cells and has been proposed as a target for cancer drug discovery. Two hit compounds from a medium throughput screen, displayed encouraging inhibition of SOCE in MDA-MB-231 cells, as measured by a Fluorescence Imaging Plate Reader (FLIPR) Ca2+ assay. Following NMR spectroscopic analysis of these hits and reassignment of their structures as 5-hydroxy-5-trifluoromethylpyrazolines, a series of analogues was prepared via thermal condensation reactions between substituted acylhydrazones and trifluoromethyl 1,3-dicarbonyl arenes. Structure-activity relationship (SAR) studies showed that small lipophilic substituents at the 2- and 3-positions of the RHS and 2-, 3- and 4-postions of the LHS terminal benzene rings improved activity, resulting in a novel class of potent and selective inhibitors of SOCE.

Item Details

Item Type:Refereed Article
Keywords:Orai1, store-operated calcium entry, breast cancer
Research Division:Biomedical and Clinical Sciences
Research Group:Oncology and carcinogenesis
Research Field:Cancer cell biology
Objective Division:Expanding Knowledge
Objective Group:Expanding knowledge
Objective Field:Expanding knowledge in the biological sciences
UTAS Author:Azimi, I (Dr Iman Azimi)
ID Code:126010
Year Published:2018
Web of Science® Times Cited:6
Deposited By:Pharmacy
Deposited On:2018-05-17
Last Modified:2019-01-21
Downloads:0

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