0545890 - ÚEB 2022 RIV GB eng J - Journal Article
Maková, B. - Mik, V. - Lišková, B. - Gonzalez, G. - Vítek, D. - Medvedíková, M. - Monfort, B. - Ručilová, V. - Kadlecová, A. - Khirsariya, P. - Gándara Barreiro, Z. - Havlíček, Libor - Zatloukal, M. - Soural, M. - Paruch, K. - D'Autréaux, B. - Hajdúch, M. - Strnad, M. - Voller, Jiří
Cytoprotective activities of kinetin purine isosteres.
Bioorganic & Medicinal Chemistry. Roč. 33, MAR 1 (2021), č. článku 115993. ISSN 0968-0896. E-ISSN 1464-3391
Institutional support: RVO:61389030
Keywords : bioisostery – Friedreich́s ataxia * Cytokinin * Kinetin * Mitoprotection – familial dysautonomia * Neuroprotection
OECD category: Pharmacology and pharmacy
Impact factor: 3.461, year: 2021
Method of publishing: Open access
http://doi.org/10.1016/j.bmc.2021.115993

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.
Permanent Link: http://hdl.handle.net/11104/0322516