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Molecular design of fluorescence probes for cell bio-imaging from a new “Store Operated Calcium Entry/Orai1” inhibitor of pancreatic cancer: the delikine DAD3.473.
* 1, 2 , 2, 3 , 2 , 1 , 1 , 4 , 2 , 2 , 5 , 5, 6 , 1, 7
1  Institut des Sciences Chimiques de Rennes ISCR UMR CNRS 6226, Université de Rennes 1, Campus de Beaulieu, Bât. 10A, CS 74205, 263 Avenue du Général Leclerc, 35042 Rennes Cédex, France
2  Laboratoire de Chimie Bio-Organique & de Substances Naturelles LCBOSN, Université Nangui-Abrogoua, Voie Express d’Abobo-Adjamé, 02 BP 801, Abidjan 02, Côte d’Ivoire
3  Institut des Sciences Chimiques de Rennes ISCR UMR CNRS 6226, Université de Rennes 1, Campus de Beaulieu, Bât. 10A, CS 74205, 263 Avenue du Général Leclerc, 35042 Rennes Cédex, France.
4  Lymphocytes B et Auto-Immunité LBAI, Inserm U1227, CHU Morvan, Université de Bretagne Occidentale, 22 Avenue Camille Desmoulins, 29200 Brest Cedex, France
5  ImPACcell platform, SFR Biosit, Inserm U018, Université de Rennes 1’, Campus de Villejean, Bât. 08, 2 Avenue du Prof. Léon Bernard, CS 34317, 35043 Rennes Cedex, France
6  Institut de recherche en santé, environnement et travail, IRSET S_Inserm 1085, Université de Rennes 1, 9 Avenue du Prof. Léon Bernard, 35000 Rennes, France
7  S2 Wave platform, ScanMAT UAR 2025 CNRS, Université de Rennes 1, Campus de Beaulieu, Bât. 10A, CS 74205, 263 Avenue du Général Leclerc, 35042 Rennes Cédex, France
Academic Editor: Maria Emília Sousa

https://doi.org/10.3390/ECMC2022-13436 (registering DOI)
Abstract:

Calcium channel Orai1 is currently considered as an emerging and relevant target in cancer due to its indirect contribution, particularly in cell migration/invasion and metastatic spread. Therefore, the calcium channel Orai1 represents a promising therapeutic lead and accessibility to a selective inhibitor is a challenge for preventive treatment of metastases. During a Structure Activity Relationship study around SKF-96365 (a molecule used as reference for measuring calcium influx since 1991), delikine molecules were identified as a new family of selective inhibitors targeting SOCE calcium influx controlled by the membrane protein Orai1. Thus, the delikine DAD3.4733 was identified and patented in 2020 as an active "hit" on pancreatic carcinoma cells PANC1 and on breast carcinoma cells MDA-H321 during the RSA study. To date, the mechanism of action of industrial SOCE/Orai1 inhibitors (GSK-96365 and CM4620) in clinical studies, is not or is poorly controlled. In this context and to try to build proof of concept around this new SOCE/Orai1 inhibitor, we decided to develop fluorescence probes derived from the delikine DAD3.473. To achieve this objective, we opted for the use of a short linker (3 or 4 carbon atoms) so as not to disturb the intrinsic character of this SOCE inhibitor, and to graft it onto the West, East or North of this inhibitor. The terminal part of the linker comprises the fluorophore NBD (7-nitro-1,2,3-benzoxadiazole). For this 8th ECMC presentation, the results of the multi-step syntheses of these fluorescence probes will be presented as well as the cell bio-imaging works.

Keywords: calcium channel; store-operated calcium entry (SOCE); Orai1 protein; pancreatic cancer; Orai1 inhibitor; delikine; fluorescence probe; NBD.

 
 
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