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Open AccessArticle

Synthesis and Pharmacological Characterization of 2-Aminoethyl Diphenylborinate (2-APB) Derivatives for Inhibition of Store-Operated Calcium Entry (SOCE) in MDA-MB-231 Breast Cancer Cells

1
Institute of Biochemistry and Molecular Medicine, University of Bern, Bühlstrasse 28, 3012 Bern, Switzerland
2
Department of BioMedical Research, University of Bern, Murtenstrasse 35, 3008 Bern, Switzerland
*
Authors to whom correspondence should be addressed.
These two authors have equally contributed to the study.
Int. J. Mol. Sci. 2020, 21(16), 5604; https://doi.org/10.3390/ijms21165604
Received: 24 June 2020 / Revised: 31 July 2020 / Accepted: 3 August 2020 / Published: 5 August 2020
(This article belongs to the Special Issue STIMulating Ca2+ Homeostasis)
Calcium ions regulate a wide array of physiological functions including cell differentiation, proliferation, muscle contraction, neurotransmission, and fertilization. The endoplasmic reticulum (ER) is the major intracellular Ca2+ store and cellular events that induce ER store depletion (e.g., activation of inositol 1,4,5-triphosphate (IP3) receptors) trigger a refilling process known as store-operated calcium entry (SOCE). It requires the intricate interaction between the Ca2+ sensing stromal interaction molecules (STIM) located in the ER membrane and the channel forming Orai proteins in the plasma membrane (PM). The resulting active STIM/Orai complexes form highly selective Ca2+ channels that facilitate a measurable Ca2+ influx into the cytosol followed by successive refilling of the ER by the sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA). STIM and Orai have attracted significant therapeutic interest, as enhanced SOCE has been associated with several cancers, and mutations in STIM and Orai have been linked to immunodeficiency, autoimmune, and muscular diseases. 2-Aminoethyl diphenylborinate (2-APB) is a known modulator and depending on its concentration can inhibit or enhance SOCE. We have synthesized several novel derivatives of 2-APB, introducing halogen and other small substituents systematically on each position of one of the phenyl rings. Using a fluorometric imaging plate reader (FLIPR) Tetra-based calcium imaging assay we have studied how these structural changes of 2-APB affect the SOCE modulation activity at different compound concentrations in MDA-MB-231 breast cancer cells. We have discovered 2-APB derivatives that block SOCE at low concentrations, at which 2-APB usually enhances SOCE. View Full-Text
Keywords: store-operated calcium entry; inhibitors; synthetic chemistry; 2-APB; structure–activity relationship; breast cancer cells; calcium imaging assay; patch-clamp electrophysiology store-operated calcium entry; inhibitors; synthetic chemistry; 2-APB; structure–activity relationship; breast cancer cells; calcium imaging assay; patch-clamp electrophysiology
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MDPI and ACS Style

Schild, A.; Bhardwaj, R.; Wenger, N.; Tscherrig, D.; Kandasamy, P.; Dernič, J.; Baur, R.; Peinelt, C.; Hediger, M.A.; Lochner, M. Synthesis and Pharmacological Characterization of 2-Aminoethyl Diphenylborinate (2-APB) Derivatives for Inhibition of Store-Operated Calcium Entry (SOCE) in MDA-MB-231 Breast Cancer Cells. Int. J. Mol. Sci. 2020, 21, 5604.

AMA Style

Schild A, Bhardwaj R, Wenger N, Tscherrig D, Kandasamy P, Dernič J, Baur R, Peinelt C, Hediger MA, Lochner M. Synthesis and Pharmacological Characterization of 2-Aminoethyl Diphenylborinate (2-APB) Derivatives for Inhibition of Store-Operated Calcium Entry (SOCE) in MDA-MB-231 Breast Cancer Cells. International Journal of Molecular Sciences. 2020; 21(16):5604.

Chicago/Turabian Style

Schild, Achille; Bhardwaj, Rajesh; Wenger, Nicolas; Tscherrig, Dominic; Kandasamy, Palanivel; Dernič, Jan; Baur, Roland; Peinelt, Christine; Hediger, Matthias A.; Lochner, Martin. 2020. "Synthesis and Pharmacological Characterization of 2-Aminoethyl Diphenylborinate (2-APB) Derivatives for Inhibition of Store-Operated Calcium Entry (SOCE) in MDA-MB-231 Breast Cancer Cells" Int. J. Mol. Sci. 21, no. 16: 5604.

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