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.

激动素 ( N ⁶ -furfuryladenine) 是细胞分裂素家族的一种植物生长物质，已在动物模型中显示可调节衰老和各种与年龄相关的病症。在这里，我们报告了嘌呤环被其他双环杂环取代的激动素等排体的合成，以及它们在体外几种活性的生物学评价与神经退行性疾病相关的模型。我们的研究结果表明激动素等排体保护 Friedreich 共济失调患者来源的成纤维细胞免受谷胱甘肽耗竭，保护神经元样 SH-SY5Y 细胞免受谷氨酸诱导的氧化损伤，并纠正来自家族性自主神经功能障碍患者的成纤维细胞中 ELP1 基因的异常剪接。尽管激动素衍生物的作用机制尚不清楚，但我们的数据表明某些嘌呤等排体的细胞保护活性是由它们减少氧化应激的能力介导的。此外，对人造膜和模型肠道和血脑屏障的渗透研究表明，这些化合物可口服，并可到达中枢神经系统。总体，