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Cytoprotective activities of kinetin purine isosteres

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MAKOVÁ Barbara MIK Václav LIŠKOVÁ Barbora GONZALEZ Gabriel VÍTEK Dominik MEDVEDÍKOVÁ Martina MONFORT Beata RUČILOVÁ Veronika KADLECOVÁ Alena KHIRSARIYA Prashant BARREIRO Zoila Gándara HAVLÍČEK Libor ZATLOUKAL Marek SOURAL Miroslav PARUCH Kamil D'AUTRÉAUX Benoit HAJDÚCH Marián STRNAD Miroslav VOLLER Jiří

Rok publikování 2021
Druh Článek v odborném periodiku
Časopis / Zdroj Bioorganic and Medicinal Chemistry
Fakulta / Pracoviště MU

Přírodovědecká fakulta

Citace
www https://doi.org/10.1016/j.bmc.2021.115993
Doi http://dx.doi.org/10.1016/j.bmc.2021.115993
Klíčová slova Cytokinin; Kinetin; bioisostery - Friedreichs ataxia; Mitoprotection - familial dysautonomia; Neuroprotection
Popis Kinetin (N-6-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 Friedreich's 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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