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Cytoprotective activities of kinetin purine isosteres

B. Maková, V. Mik, B. Lišková, G. Gonzalez, D. Vítek, M. Medvedíková, B. Monfort, V. Ručilová, A. Kadlecová, P. Khirsariya, Z. Gándara Barreiro, L. Havlíček, M. Zatloukal, M. Soural, K. Paruch, B. D'Autréaux, M. Hajdúch, M. Strnad, J. Voller

. 2021 ; 33 (-) : 115993. [pub] 20210106

Language English Country Great Britain

Document type Journal Article, Research Support, Non-U.S. Gov't

Persistent link   https://www.medvik.cz/link/bmc21025990

Kinetin (N6-furfuryladenine), a plant growth substance of the cytokinin family, has been shown to modulate aging and various age-related conditions in animal models. Here we report the synthesis of kinetin isosteres with the purine ring replaced by other bicyclic heterocycles, and the biological evaluation of their activity in several in vitro models related to neurodegenerative diseases. Our findings indicate that kinetin isosteres protect Friedreich́s ataxia patient-derived fibroblasts against glutathione depletion, protect neuron-like SH-SY5Y cells from glutamate-induced oxidative damage, and correct aberrant splicing of the ELP1 gene in fibroblasts derived from a familial dysautonomia patient. Although the mechanism of action of kinetin derivatives remains unclear, our data suggest that the cytoprotective activity of some purine isosteres is mediated by their ability to reduce oxidative stress. Further, the studies of permeation across artificial membrane and model gut and blood-brain barriers indicate that the compounds are orally available and can reach central nervous system. Overall, our data demonstrate that isosteric replacement of the kinetin purine scaffold is a fruitful strategy for improving known biological activities of kinetin and discovering novel therapeutic opportunities.

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$a Kinetin (N6-furfuryladenine), a plant growth substance of the cytokinin family, has been shown to modulate aging and various age-related conditions in animal models. Here we report the synthesis of kinetin isosteres with the purine ring replaced by other bicyclic heterocycles, and the biological evaluation of their activity in several in vitro models related to neurodegenerative diseases. Our findings indicate that kinetin isosteres protect Friedreich́s ataxia patient-derived fibroblasts against glutathione depletion, protect neuron-like SH-SY5Y cells from glutamate-induced oxidative damage, and correct aberrant splicing of the ELP1 gene in fibroblasts derived from a familial dysautonomia patient. Although the mechanism of action of kinetin derivatives remains unclear, our data suggest that the cytoprotective activity of some purine isosteres is mediated by their ability to reduce oxidative stress. Further, the studies of permeation across artificial membrane and model gut and blood-brain barriers indicate that the compounds are orally available and can reach central nervous system. Overall, our data demonstrate that isosteric replacement of the kinetin purine scaffold is a fruitful strategy for improving known biological activities of kinetin and discovering novel therapeutic opportunities.
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$a Mik, Václav $u Department of Experimental Biology, Faculty of Science, Palacký University, Šlechtitelů 27, Olomouc CZ-78371, Czech Republic
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$a Lišková, Barbora $u Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 3, Olomouc CZ-77515, Czech Republic $7 xx0267204
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$a Gonzalez, Gabriel $u Department of Experimental Biology, Faculty of Science, Palacký University, Šlechtitelů 27, Olomouc CZ-78371, Czech Republic; Department of Neurology, Palacký University Olomouc, Faculty of Medicine and Dentistry and University Hospital, Olomouc, Czech Republic
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$a Vítek, Dominik $u Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 3, Olomouc CZ-77515, Czech Republic
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$a Medvedíková, Martina $u Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 3, Olomouc CZ-77515, Czech Republic
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$a Monfort, Beata $u Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC), 91198 Gif-sur-Yvette, France
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$a Ručilová, Veronika $u Department of Organic Chemistry, Faculty of Science, Palacký University, 17. listopadu 1192/12, Olomouc CZ-783-71, Czech Republic
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$a Kadlecová, Alena $u Department of Experimental Biology, Faculty of Science, Palacký University, Šlechtitelů 27, Olomouc CZ-78371, Czech Republic
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$a Khirsariya, Prashant $u Department of Chemistry, CZ Openscreen, Faculty of Science, Masaryk University, Brno, Czech Republic
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$a Gándara Barreiro, Zoila $u Department of Experimental Biology, Faculty of Science, Palacký University, Šlechtitelů 27, Olomouc CZ-78371, Czech Republic
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$a Havlíček, Libor $u Isotope Laboratory, The Czech Academy of Science, Institute of Experimental Botany, Vídeňská 1083, Praha 4 CZ-14220, Czech Republic
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$a Zatloukal, Marek $u Department of Chemical Biolology and Genetics, Centre of the Region Hana for Biotechnological and Agricultural Research, Palacký University, Šlechtitelů 27, Olomouc CZ-78371, Czech Republic
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$a Soural, Miroslav $u Department of Organic Chemistry, Faculty of Science, Palacký University, 17. listopadu 1192/12, Olomouc CZ-783-71, Czech Republic
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$a Paruch, Kamil $u Department of Chemistry, CZ Openscreen, Faculty of Science, Masaryk University, Brno, Czech Republic
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$a D'Autréaux, Benoit $u Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC), 91198 Gif-sur-Yvette, France
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$a Hajdúch, Marián $u Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 3, Olomouc CZ-77515, Czech Republic
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$a Strnad, Miroslav $u Department of Experimental Biology, Faculty of Science, Palacký University, Šlechtitelů 27, Olomouc CZ-78371, Czech Republic
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$a Voller, Jiří $u Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 3, Olomouc CZ-77515, Czech Republic; Laboratory of Growth Regulators, Palacký University & Institute of Experimental Botany AS CR, Šlechtitelů 27, Olomouc CZ-78371, Czech Republic. Electronic address: jiri.voller@upol.cz
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