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

Sana Kouba, Julien Braire, Romain Félix, Aurélie Chantôme, Paul Alain Jaffrès, Jacques Lebreton, Didier Dubreuil, Muriel Pipelier, Xuexin Zhang, Mohamed Trebak, Christophe Vandier, Monique Mathé-Allainmat, Marie Potier-Cartereau

Research output: Contribution to journalArticle

Abstract

Small Conductance Calcium (Ca2+)-activated potassium (K+) channels (SKCa) are now proved to be involved in many cancer cell behaviors such as proliferation or migration. The SK3 channel isoform was particularly described in breast cancer where it can be associated with the Orai1 Ca2+ channel to form a complex that regulates the Ca2+ homeostasis during tumor development and acts as a potent mediator of bone metastases development in vivo. Until now, very few specific blockers of Orai1 and/or SK3 have been developed as potential anti-metastatic compounds. In 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 10c) demonstrated a significant decrease in the SK3 channel-dependent migration as well as the SK3/Orai1-related Ca2+ 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.

Original languageEnglish (US)
Article number111854
JournalEuropean Journal of Medicinal Chemistry
Volume186
DOIs
StatePublished - Jan 15 2020

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Alkaloids
Modulators
Cells
Breast Neoplasms
Derivatives
Molecules
Electric current measurement
Toxicity
Calcium-Activated Potassium Channels
Tumors
Potassium
Protein Isoforms
Bone
Potassium Channels
Bone Development
Calcium
Neoplasms
Homeostasis
Pharmaceutical Preparations
Neoplasm Metastasis

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

Kouba, Sana ; Braire, Julien ; Félix, Romain ; Chantôme, Aurélie ; Jaffrès, Paul Alain ; Lebreton, Jacques ; Dubreuil, Didier ; Pipelier, Muriel ; Zhang, Xuexin ; Trebak, Mohamed ; Vandier, Christophe ; Mathé-Allainmat, Monique ; Potier-Cartereau, Marie. / Lipidic synthetic alkaloids as SK3 channel modulators. Synthesis and biological evaluation of 2-substituted tetrahydropyridine derivatives with potential anti-metastatic activity. In: European Journal of Medicinal Chemistry. 2020 ; Vol. 186.
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abstract = "Small Conductance Calcium (Ca2+)-activated potassium (K+) channels (SKCa) are now proved to be involved in many cancer cell behaviors such as proliferation or migration. The SK3 channel isoform was particularly described in breast cancer where it can be associated with the Orai1 Ca2+ channel to form a complex that regulates the Ca2+ homeostasis during tumor development and acts as a potent mediator of bone metastases development in vivo. Until now, very few specific blockers of Orai1 and/or SK3 have been developed as potential anti-metastatic compounds. In 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 10c) demonstrated a significant decrease in the SK3 channel-dependent migration as well as the SK3/Orai1-related Ca2+ 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.",
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Lipidic synthetic alkaloids as SK3 channel modulators. Synthesis and biological evaluation of 2-substituted tetrahydropyridine derivatives with potential anti-metastatic activity. / Kouba, Sana; Braire, Julien; Félix, Romain; Chantôme, Aurélie; Jaffrès, Paul Alain; Lebreton, Jacques; Dubreuil, Didier; Pipelier, Muriel; Zhang, Xuexin; Trebak, Mohamed; Vandier, Christophe; Mathé-Allainmat, Monique; Potier-Cartereau, Marie.

In: European Journal of Medicinal Chemistry, Vol. 186, 111854, 15.01.2020.

Research output: Contribution to journalArticle

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T1 - Lipidic synthetic alkaloids as SK3 channel modulators. Synthesis and biological evaluation of 2-substituted tetrahydropyridine derivatives with potential anti-metastatic activity

AU - Kouba, Sana

AU - Braire, Julien

AU - Félix, Romain

AU - Chantôme, Aurélie

AU - Jaffrès, Paul Alain

AU - Lebreton, Jacques

AU - Dubreuil, Didier

AU - Pipelier, Muriel

AU - Zhang, Xuexin

AU - Trebak, Mohamed

AU - Vandier, Christophe

AU - Mathé-Allainmat, Monique

AU - Potier-Cartereau, Marie

PY - 2020/1/15

Y1 - 2020/1/15

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AB - Small Conductance Calcium (Ca2+)-activated potassium (K+) channels (SKCa) are now proved to be involved in many cancer cell behaviors such as proliferation or migration. The SK3 channel isoform was particularly described in breast cancer where it can be associated with the Orai1 Ca2+ channel to form a complex that regulates the Ca2+ homeostasis during tumor development and acts as a potent mediator of bone metastases development in vivo. Until now, very few specific blockers of Orai1 and/or SK3 have been developed as potential anti-metastatic compounds. In 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 10c) demonstrated a significant decrease in the SK3 channel-dependent migration as well as the SK3/Orai1-related Ca2+ 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.

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