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
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 Ca<sup>2+</sup> store and cellular events that induce ER store...
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MDPI AG
2020-08-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/21/16/5604 |
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| author | Achille Schild Rajesh Bhardwaj Nicolas Wenger Dominic Tscherrig Palanivel Kandasamy Jan Dernič Roland Baur Christine Peinelt Matthias A. Hediger Martin Lochner |
| author_facet | Achille Schild Rajesh Bhardwaj Nicolas Wenger Dominic Tscherrig Palanivel Kandasamy Jan Dernič Roland Baur Christine Peinelt Matthias A. Hediger Martin Lochner |
| author_sort | Achille Schild |
| collection | DOAJ |
| description | 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 Ca<sup>2+</sup> store and cellular events that induce ER store depletion (e.g., activation of inositol 1,4,5-triphosphate (IP<sub>3</sub>) receptors) trigger a refilling process known as store-operated calcium entry (SOCE). It requires the intricate interaction between the Ca<sup>2+</sup> 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 Ca<sup>2+</sup> channels that facilitate a measurable Ca<sup>2+</sup> 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. |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T17:56:55Z |
| publishDate | 2020-08-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-5e40f6c15bbf4406b19eff638db0b2612023-11-20T09:09:28ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-08-012116560410.3390/ijms21165604Synthesis and Pharmacological Characterization of 2-Aminoethyl Diphenylborinate (2-APB) Derivatives for Inhibition of Store-Operated Calcium Entry (SOCE) in MDA-MB-231 Breast Cancer CellsAchille Schild0Rajesh Bhardwaj1Nicolas Wenger2Dominic Tscherrig3Palanivel Kandasamy4Jan Dernič5Roland Baur6Christine Peinelt7Matthias A. Hediger8Martin Lochner9Institute of Biochemistry and Molecular Medicine, University of Bern, Bühlstrasse 28, 3012 Bern, SwitzerlandDepartment of BioMedical Research, University of Bern, Murtenstrasse 35, 3008 Bern, SwitzerlandDepartment of BioMedical Research, University of Bern, Murtenstrasse 35, 3008 Bern, SwitzerlandInstitute of Biochemistry and Molecular Medicine, University of Bern, Bühlstrasse 28, 3012 Bern, SwitzerlandDepartment of BioMedical Research, University of Bern, Murtenstrasse 35, 3008 Bern, SwitzerlandDepartment of BioMedical Research, University of Bern, Murtenstrasse 35, 3008 Bern, SwitzerlandInstitute of Biochemistry and Molecular Medicine, University of Bern, Bühlstrasse 28, 3012 Bern, SwitzerlandInstitute of Biochemistry and Molecular Medicine, University of Bern, Bühlstrasse 28, 3012 Bern, SwitzerlandDepartment of BioMedical Research, University of Bern, Murtenstrasse 35, 3008 Bern, SwitzerlandInstitute of Biochemistry and Molecular Medicine, University of Bern, Bühlstrasse 28, 3012 Bern, SwitzerlandCalcium 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 Ca<sup>2+</sup> store and cellular events that induce ER store depletion (e.g., activation of inositol 1,4,5-triphosphate (IP<sub>3</sub>) receptors) trigger a refilling process known as store-operated calcium entry (SOCE). It requires the intricate interaction between the Ca<sup>2+</sup> 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 Ca<sup>2+</sup> channels that facilitate a measurable Ca<sup>2+</sup> 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.https://www.mdpi.com/1422-0067/21/16/5604store-operated calcium entryinhibitorssynthetic chemistry2-APBstructure–activity relationshipbreast cancer cells |
| spellingShingle | Achille Schild Rajesh Bhardwaj Nicolas Wenger Dominic Tscherrig Palanivel Kandasamy Jan Dernič Roland Baur Christine Peinelt Matthias A. Hediger Martin Lochner 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 store-operated calcium entry inhibitors synthetic chemistry 2-APB structure–activity relationship breast cancer cells |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | store-operated calcium entry inhibitors synthetic chemistry 2-APB structure–activity relationship breast cancer cells |
| url | https://www.mdpi.com/1422-0067/21/16/5604 |
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