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Bioorg Med Chem. 2018 Jul 23;26(12):3406-3413. doi: 10.1016/j.bmc.2018.05.012. Epub 2018 May 9.

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.

Author information

1
Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. Electronic address: r.stevenson@auckland.ac.nz.
2
The School of Pharmacy, The University of Queensland, Brisbane, Queensland, Australia; Mater Research Institute, The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia; Division of Pharmacy, College of Health and Medicine, University of Tasmania, Hobart, Tasmania, Australia.
3
Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
4
Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia; School of Pharmacy, The University of Queensland, Woolloongabba, Queensland 4102, Australia.
5
The School of Pharmacy, The University of Queensland, Brisbane, Queensland, Australia; Mater Research Institute, The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia.
6
Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. Electronic address: b.denny@auckland.ac.nz.

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.

KEYWORDS:

Ca(2+) release-activated Ca(2+) (CRAC) channel; Hydroxy-trifluoromethylpyrazoline; Inhibitor; Orai1; Store-operated Ca(2+)entry (SOCE); Structure-activity relationship (SAR); Triple negative breast cancer

PMID:
29776832
DOI:
10.1016/j.bmc.2018.05.012
[Indexed for MEDLINE]

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