Novel Phenolic Inhibitors of Small/Intermediate-Conductance Ca2+-Activated K+ Channels, KCa3.1 and KCa2.3

Aida Oliván-Viguera, Marta Sofía Valero, María Divina Murillo, Heike Wulff, Ángel Luis García-Otín, José Miguel Arbonés-Mainar, Ralf Köhler

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Background: KCa3.1 channels are calcium/calmodulin-regulated voltage-independent K+ channels that produce membrane hyperpolarization and shape Ca2+-signaling and thereby physiological functions in epithelia, blood vessels, and white and red blood cells. Up-regulation of KCa3.1 is evident in fibrotic and inflamed tissues and some tumors rendering the channel a potential drug target. In the present study, we searched for novel potent small molecule inhibitors of KCa3.1 by testing a series of 20 selected natural and synthetic (poly)phenols, synthetic benzoic acids, and non-steroidal anti-inflammatory drugs (NSAIDs), with known cytoprotective, anti-inflammatory, and/or cytostatic activities. Methodology/Principal Findings: In electrophysiological experiments, we identified the natural phenols, caffeic acid (EC50 1.3 μM) and resveratrol (EC50 10 μM) as KCa3.1 inhibitors with moderate potency. The phenols, vanillic acid, gallic acid, and hydroxytyrosol had weak or no blocking effects. Out of the NSAIDs, flufenamic acid was moderately potent (EC50 1.6 μM), followed by mesalamine (EC50≥10 μM). The synthetic fluoro-trivanillic ester, 13b ([3,5-bis[(3-fluoro-4-hydroxy-benzoyl)oxymethyl]phenyl]methyl 3-fluoro-4-hydroxy-benzoate), was identified as a potent mixed KCa2/3 channel inhibitor with an EC50 of 19 nM for KCa3.1 and 360 pM for KCa2.3, which affected KCa1.1 and Kv channels only at micromolar concentrations. The KCa3.1/KCa2-activator SKA-31 antagonized the 13b-blockade. In proliferation assays, 13b was not cytotoxic and reduced proliferation of 3T3 fibroblasts as well as caffeic acid. In isometric vessel myography, 13b increased contractions of porcine coronary arteries to serotonin and antagonized endothelium-derived hyperpolarization-mediated vasorelaxation to pharmacological KCa3.1/KCa2.3 activation. Conclusions/Significance: We identified the natural phenols, caffeic acid and resveratrol, the NSAID, flufenamic acid, and the polyphenol 13b as novel KCa3.1 inhibitors. The high potency of 13b with pan-activity on KCa3.1/KCa2 channels makes 13b a new pharmacological tool to manipulate inflammation and cancer growth through KCa3.1/KCa2 blockade and a promising template for new drug design.

Original languageEnglish (US)
Article numbere58614
JournalPLoS One
Volume8
Issue number3
DOIs
StatePublished - Mar 14 2013

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Calcium-Activated Potassium Channels
Phenols
potassium channels
phenols
nonsteroidal anti-inflammatory agents
Anti-Inflammatory Agents
caffeic acid
Flufenamic Acid
calcium
Benzoates
resveratrol
Pharmaceutical Preparations
Myography
Vanillic Acid
Pharmacology
benzoic acids
Mesalamine
Gallic Acid
vanillic acid
neoplasms

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Oliván-Viguera, A., Valero, M. S., Murillo, M. D., Wulff, H., García-Otín, Á. L., Arbonés-Mainar, J. M., & Köhler, R. (2013). Novel Phenolic Inhibitors of Small/Intermediate-Conductance Ca2+-Activated K+ Channels, KCa3.1 and KCa2.3. PLoS One, 8(3), [e58614]. https://doi.org/10.1371/journal.pone.0058614

Novel Phenolic Inhibitors of Small/Intermediate-Conductance Ca2+-Activated K+ Channels, KCa3.1 and KCa2.3. / Oliván-Viguera, Aida; Valero, Marta Sofía; Murillo, María Divina; Wulff, Heike; García-Otín, Ángel Luis; Arbonés-Mainar, José Miguel; Köhler, Ralf.

In: PLoS One, Vol. 8, No. 3, e58614, 14.03.2013.

Research output: Contribution to journalArticle

Oliván-Viguera, A, Valero, MS, Murillo, MD, Wulff, H, García-Otín, ÁL, Arbonés-Mainar, JM & Köhler, R 2013, 'Novel Phenolic Inhibitors of Small/Intermediate-Conductance Ca2+-Activated K+ Channels, KCa3.1 and KCa2.3', PLoS One, vol. 8, no. 3, e58614. https://doi.org/10.1371/journal.pone.0058614
Oliván-Viguera A, Valero MS, Murillo MD, Wulff H, García-Otín ÁL, Arbonés-Mainar JM et al. Novel Phenolic Inhibitors of Small/Intermediate-Conductance Ca2+-Activated K+ Channels, KCa3.1 and KCa2.3. PLoS One. 2013 Mar 14;8(3). e58614. https://doi.org/10.1371/journal.pone.0058614
Oliván-Viguera, Aida ; Valero, Marta Sofía ; Murillo, María Divina ; Wulff, Heike ; García-Otín, Ángel Luis ; Arbonés-Mainar, José Miguel ; Köhler, Ralf. / Novel Phenolic Inhibitors of Small/Intermediate-Conductance Ca2+-Activated K+ Channels, KCa3.1 and KCa2.3. In: PLoS One. 2013 ; Vol. 8, No. 3.
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abstract = "Background: KCa3.1 channels are calcium/calmodulin-regulated voltage-independent K+ channels that produce membrane hyperpolarization and shape Ca2+-signaling and thereby physiological functions in epithelia, blood vessels, and white and red blood cells. Up-regulation of KCa3.1 is evident in fibrotic and inflamed tissues and some tumors rendering the channel a potential drug target. In the present study, we searched for novel potent small molecule inhibitors of KCa3.1 by testing a series of 20 selected natural and synthetic (poly)phenols, synthetic benzoic acids, and non-steroidal anti-inflammatory drugs (NSAIDs), with known cytoprotective, anti-inflammatory, and/or cytostatic activities. Methodology/Principal Findings: In electrophysiological experiments, we identified the natural phenols, caffeic acid (EC50 1.3 μM) and resveratrol (EC50 10 μM) as KCa3.1 inhibitors with moderate potency. The phenols, vanillic acid, gallic acid, and hydroxytyrosol had weak or no blocking effects. Out of the NSAIDs, flufenamic acid was moderately potent (EC50 1.6 μM), followed by mesalamine (EC50≥10 μM). The synthetic fluoro-trivanillic ester, 13b ([3,5-bis[(3-fluoro-4-hydroxy-benzoyl)oxymethyl]phenyl]methyl 3-fluoro-4-hydroxy-benzoate), was identified as a potent mixed KCa2/3 channel inhibitor with an EC50 of 19 nM for KCa3.1 and 360 pM for KCa2.3, which affected KCa1.1 and Kv channels only at micromolar concentrations. The KCa3.1/KCa2-activator SKA-31 antagonized the 13b-blockade. In proliferation assays, 13b was not cytotoxic and reduced proliferation of 3T3 fibroblasts as well as caffeic acid. In isometric vessel myography, 13b increased contractions of porcine coronary arteries to serotonin and antagonized endothelium-derived hyperpolarization-mediated vasorelaxation to pharmacological KCa3.1/KCa2.3 activation. Conclusions/Significance: We identified the natural phenols, caffeic acid and resveratrol, the NSAID, flufenamic acid, and the polyphenol 13b as novel KCa3.1 inhibitors. The high potency of 13b with pan-activity on KCa3.1/KCa2 channels makes 13b a new pharmacological tool to manipulate inflammation and cancer growth through KCa3.1/KCa2 blockade and a promising template for new drug design.",
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AU - Valero, Marta Sofía

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AU - Wulff, Heike

AU - García-Otín, Ángel Luis

AU - Arbonés-Mainar, José Miguel

AU - Köhler, Ralf

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N2 - Background: KCa3.1 channels are calcium/calmodulin-regulated voltage-independent K+ channels that produce membrane hyperpolarization and shape Ca2+-signaling and thereby physiological functions in epithelia, blood vessels, and white and red blood cells. Up-regulation of KCa3.1 is evident in fibrotic and inflamed tissues and some tumors rendering the channel a potential drug target. In the present study, we searched for novel potent small molecule inhibitors of KCa3.1 by testing a series of 20 selected natural and synthetic (poly)phenols, synthetic benzoic acids, and non-steroidal anti-inflammatory drugs (NSAIDs), with known cytoprotective, anti-inflammatory, and/or cytostatic activities. Methodology/Principal Findings: In electrophysiological experiments, we identified the natural phenols, caffeic acid (EC50 1.3 μM) and resveratrol (EC50 10 μM) as KCa3.1 inhibitors with moderate potency. The phenols, vanillic acid, gallic acid, and hydroxytyrosol had weak or no blocking effects. Out of the NSAIDs, flufenamic acid was moderately potent (EC50 1.6 μM), followed by mesalamine (EC50≥10 μM). The synthetic fluoro-trivanillic ester, 13b ([3,5-bis[(3-fluoro-4-hydroxy-benzoyl)oxymethyl]phenyl]methyl 3-fluoro-4-hydroxy-benzoate), was identified as a potent mixed KCa2/3 channel inhibitor with an EC50 of 19 nM for KCa3.1 and 360 pM for KCa2.3, which affected KCa1.1 and Kv channels only at micromolar concentrations. The KCa3.1/KCa2-activator SKA-31 antagonized the 13b-blockade. In proliferation assays, 13b was not cytotoxic and reduced proliferation of 3T3 fibroblasts as well as caffeic acid. In isometric vessel myography, 13b increased contractions of porcine coronary arteries to serotonin and antagonized endothelium-derived hyperpolarization-mediated vasorelaxation to pharmacological KCa3.1/KCa2.3 activation. Conclusions/Significance: We identified the natural phenols, caffeic acid and resveratrol, the NSAID, flufenamic acid, and the polyphenol 13b as novel KCa3.1 inhibitors. The high potency of 13b with pan-activity on KCa3.1/KCa2 channels makes 13b a new pharmacological tool to manipulate inflammation and cancer growth through KCa3.1/KCa2 blockade and a promising template for new drug design.

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