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Novel quercetin derivatives in treatment of peroxynitrite-oxidized SERCA1

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Abstract

Sarco/endoplasmic reticulum calcium ATP-ase (SERCA) is regulated by low concentrations of peroxynitrite and inhibited by high levels, as indicated in human diseases. We studied quercetin (Q) and its novel derivatives monochloropivaloylquercetin (MPQ) and chloronaphthoquinonequercetin (CHQ) as agents with expected preventive properties against peroxynitrite-induced SERCA impairment. Q and MPQ protected the SERCA1 against peroxynitrite induced activity decrease, while CHQ potentiated the inhibitory effect of peroxynitrite. Quercetin derivatives were found to be weaker antioxidants compared with Q, as indicated by their ability to scavenge peroxynitrite and prevent of SERCA1 carbonylation, both decreasing in the order (Q > MPQ > CHQ). Quantum-chemical values of theoretical parameter E HOMO also indicated lower antioxidant capacities for MPQ and CHQ. Prooxidant properties estimated by calculations of frontier molecular orbitals (E LUMO) correlated with experimentally determined SH-group decrease induced by the compounds studied. Both methods showed a decrease of prooxidant properties as follows: CHQ > MPQ > Q. In addition, experimentally measured half-wave potentials indicated stronger prooxidant properties of quercetin derivatives as compared to Q. More expressive alterations of conformation in the transmembrane region of SERCA1 induced by quercetin derivatives, as compared with Q, may at least partially correlate with their higher lipophilicities. The protective effects of Q and MPQ on different isoforms of SERCA activity may be useful in prevention and treatment of inflammation or muscle diseases. The inhibitory effect of CHQ on SERCA isoforms may be beneficial in therapeutic approaches aimed at anti-tumor treatment.

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Abbreviations

Ca2+-ATPase of SR:

SERCA

CV:

Cyclic voltammetry

Cys-SO3H:

Cysteine sulfonic acid

DMSO:

Dimethylsulfoxide

DNPH:

2,4-dinitrophenylhydrazine

DTNB:

5,5′-dithio-bis(2-nitrobenzoic acid)

EDTA:

Ethylenediaminetetraacetic acid

FITC:

Fluorescein-5-isothiocyanate

CHQ:

Chloronaphthoquinonequercetin

MPQ:

Monochloropivaloylquercetin

NADH:

Nicotinamide adenine dinucleotide

NCD-4:

N-cyclohexyl-N′-(4-dimethylamino-l-naphthyl) carbodiimide

PBS:

Phosphate buffered saline

PIGE:

Paraffine impregnated graphite electrode

PVDF:

Polyvinylidene fluoride

Q :

Quercetin

SDS:

Sodium dodecyl sulfate

SDS-PAGE:

Sodium dodecyl sulfate–polyacrylamide gel electrophoresis

SERCA1:

SERCA from fast-twitch skeletal muscle, isoform 1

SR:

Sarcoplasmic reticulum

ThioGlo1:

10-(2,5-dihydro-2,5-dioxo-1 h-pyrrol-1-yl)-9-methoxy-3-oxo-, methyl ester

TEA:

Triethylenamine

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Acknowledgments

Supported by the Agency of the Ministry of Education, Science, Research and Sport of the Slovak Republic for the Structural Funds of EU, OP R&D of ERDF in the frame of the Project, Evaluation of natural substances and their selection for prevention and treatment of lifestyle diseases (ITMS 26240220040), by VEGA Grants 2/0038/11, 1/0051/13, and COST ACTION CM1001.

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Authors and Affiliations

  1. Institute of Experimental Pharmacology and Toxicology, Slovak Academy of Sciences, Bratislava, Slovak Republic

    Petronela Žižková, Dušan Blaškovič, Magdaléna Májeková, Lucia Račková & L’ubica Horáková

  2. EUROFINS BEL/NOVAMANN s.r.o., Bratislava, Slovak Republic

    L’ubica Ratkovská & Miroslav Veverka

  3. Institute of Analytical Chemistry, Faculty of Chemical and Food Technology, Slovak University of Technology in Bratislava, Bratislava, Slovak Republic

    L’ubomír Švorc

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  1. Petronela Žižková
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  2. Dušan Blaškovič
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  8. L’ubica Horáková
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Correspondence to L’ubica Horáková.

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Žižková, P., Blaškovič, D., Májeková, M. et al. Novel quercetin derivatives in treatment of peroxynitrite-oxidized SERCA1. Mol Cell Biochem 386, 1–14 (2014). https://doi.org/10.1007/s11010-013-1839-8

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