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. Issue 12 (23rd July 2018)

• Record Type: Journal Article
• Authors: Stevenson, Ralph J.; Azimi, Iman; Flanagan, Jack U.; Inserra, Marco; Vetter, Irina; Monteith, Gregory R.; Denny, William A.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 26:Issue 12(2018)
• Page Start: 3406
• Page End: 3413
• Publication Date: 2018-07-23
• Subjects: FLIPR Fluorescence Imaging Plate Reader -- STIM1 stromal interaction molecule 1 -- ER endoplasmic reticulum -- TNBC triple negative breast cancer -- SAR structure activity relationship -- LHS left hand side -- RHS right hand side -- THF tetrahydrofuran -- i-PrOH isopropanol; Orai1 -- Store-operated Ca2+entry (SOCE) -- Ca2+ release-activated Ca2+ (CRAC) channel -- Triple negative breast cancer -- Inhibitor -- Hydroxy-trifluoromethylpyrazoline -- Structure-activity relationship (SAR); Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2018.05.012
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: The proteins Orai1 and STIM1 control store-operated Ca 2+ 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) Ca 2+ 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.