Cytoprotective activities of kinetin purine isosteres

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61989592%3A15110%2F21%3A73605065" target="_blank" >RIV/61989592:15110/21:73605065 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/61389030:_____/21:00545890 RIV/00216224:14310/21:00121382 RIV/61989592:15310/21:73605065 RIV/00098892:_____/21:N0000155

Výsledek na webu

<a href="https://www.sciencedirect.com/science/article/abs/pii/S0968089621000018" target="_blank" >https://www.sciencedirect.com/science/article/abs/pii/S0968089621000018</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.bmc.2021.115993" target="_blank" >10.1016/j.bmc.2021.115993</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Cytoprotective activities of kinetin purine isosteres

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

Cytoprotective activities of kinetin purine isosteres

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30107 - Medicinal chemistry

Projekt

<a href="/cs/project/LTC18078" target="_blank" >LTC18078: Identifikace nových látek pro terapii Friedreichovy ataxie</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2021

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Bioorganic and Medicinal Chemistry

ISSN

0968-0896

e-ISSN

1464-3391

Svazek periodika

33

Číslo periodika v rámci svazku

MAR

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

14

Strana od-do

"115993-1"-"115993-14"

Kód UT WoS článku

000623635000002

EID výsledku v databázi Scopus

2-s2.0-85099708904