Cytoprotective activities of kinetin purine isosteres.

Abstract

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.

• Authors: Barbara Maková, Václav Mik, Barbora Lišková, Gabriel Gonzalez, Dominik Vítek, Martina Medvedíková, Beata Monfort, Veronika Ručilová, Alena Kadlecová, Prashant Khirsariya, Zoila Gándara Barreiro, Libor Havlíček, Marek Zatloukal, Miroslav Soural, Kamil Paruch, Benoit D'Autréaux, Marián Hajdúch, Miroslav Strnad, Jiří Voller
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 33 Pg. 115993 (03 01 2021) ISSN: 1464-3391 [Electronic] England
• PMID: 33497938 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021. Published by Elsevier Ltd.

Chemical References

• Purines
• Kinetin
• purine

Topics

• Cell Survival (drug effects)
• Cells, Cultured
• Cytoprotection
• Dose-Response Relationship, Drug
• Humans
• Kinetin (chemical synthesis, chemistry, pharmacology)
• Molecular Structure
• Oxidative Stress (drug effects)
• Purines (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship