Lipidic synthetic alkaloids as SK3 channel modulators. Synthesis and biological evaluation of 2-substituted tetrahydropyridine derivatives with potential anti-metastatic activity

Autor: Sana Kouba, Monique Mathé-Allainmat, Paul-Alain Jaffrès, Christophe Vandier, Muriel Pipelier, Aurélie Chantôme, Jacques Lebreton, Didier Dubreuil, Xuexin Zhang, Marie Potier-Cartereau, Mohamed Trebak, Romain Félix, Julien Braire
Přispěvatelé: Nutrition, croissance et cancer (U 1069) (N2C), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Chimie Et Interdisciplinarité : Synthèse, Analyse, Modélisation (CEISAM), Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Chimie, Electrochimie Moléculaires et Chimie Analytique (CEMCA), Université de Brest (UBO)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Department of Cellular and Molecular Physiology (DCMP), Pennylvania State University College of Medicine, This work has been developed with technical (ImPACcell platform, Rennes (F) R. Le Guével) and financial supports from the 'Réseau Canaux Ioniques' of the 'Cancéropôle Grand Ouest'. We are also deeply grateful to the 'Ligue Contre le Cancer' for financial supports (interregional grants: CSIRGO 2015). This work was supported by 'University of Tours', 'Région Centre Val de Loire', 'INSERM', and Sana Kouba held her fellowship from the 'Ministère de l'enseignement supérieur et de la recherche'., Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Tours, Institut des Sciences Chimiques de Rennes (ISCR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes-Centre National de la Recherche Scientifique (CNRS), Université de Nantes - Faculté des Sciences et des Techniques, Université de Nantes (UN)-Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université de Nantes (UN)-Université de Nantes (UN)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), MATHE-ALLAINMAT, Monique, Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM)
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Pyrrolidines
cell migration
Small-Conductance Calcium-Activated Potassium Channels
[SDV]Life Sciences [q-bio]
[CHIM.THER]Chemical Sciences/Medicinal Chemistry
01 natural sciences
Drug Discovery
Cells
Cultured
ComputingMilieux_MISCELLANEOUS
amphiphiles
0303 health sciences
Molecular Structure
tetrahydropyridine derivatives
ORAI1
[CHIM.ORGA]Chemical Sciences/Organic chemistry
amphiphilic compounds
Cell migration
General Medicine
Lipids
3. Good health
Gene isoform
[CHIM.THER] Chemical Sciences/Medicinal Chemistry
chemistry.chemical_element
Antineoplastic Agents
[SDV.CAN]Life Sciences [q-bio]/Cancer
Calcium
Structure-Activity Relationship
03 medical and health sciences
Alkaloids
breast cancer
Breast cancer
SK3
Mediator
medicine
Humans
[CHIM]Chemical Sciences
Ca2+ -activated K + channels
Cell Proliferation
030304 developmental biology
Pharmacology
Dose-Response Relationship
Drug
010405 organic chemistry
Organic Chemistry
canaux ioniques
medicine.disease
0104 chemical sciences
HEK293 Cells
chemistry
Cancer cell
Cancer research
Drug Screening Assays
Antitumor
Zdroj: European Journal of Medicinal Chemistry
European Journal of Medicinal Chemistry, Elsevier, 2020, 186, pp.111854. ⟨10.1016/j.ejmech.2019.111854⟩
European Journal of Medicinal Chemistry, 2020, 186, pp.111854. ⟨10.1016/j.ejmech.2019.111854⟩
ISSN: 0223-5234
1768-3254
DOI: 10.1016/j.ejmech.2019.111854⟩
Popis: International audience; Small Conductance Calcium (Ca 2-)-activated potassium (K-) channels (SKCa) are now proved to be involved in many cancer cell behaviors such as proliferation or migration. The SIG channel isoform was particularly described in breast cancer where it can be associated with the Orai 1 Ca 2-channel to form a complex that regulates the ca 2-homeostasis during tumor development and acts as a potent mediator of bone metastases development in vivo. Until now, very few specific blockers of Orail and/or SIG have been developed as potential anti-metastatic compounds. ln this study, we illustrated the synthesis of new families of lipophilic pyridine and tetrahydropyridine derivatives designed as potential modulators of SK3 channel. The toxicity of the newly synthesized compounds and their migration effects were evaluated on the breast cancer cell line MDA-MB-435s. Two molecules (7a and toc) demonstrated a significant decrease in the SK3 channel-dependent migration as well as the SK3/Orai1-related Ca 2-entry. Current measurements showed that these compounds are more likely SK3-selective. Taken all together these results suggest that such molecules could be considered as promising anti-metastatic drugs in breast cancer.
Databáze: OpenAIRE
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