Oxidative stress is constantly involved in the etiopathogenesis of an ever-widening range of neurodegenerative diseases. As a consequence, effective repression of cellular oxidative stress to a redox homeostatic condition is a promising and feasible strategy to treat, or at least retard the progression of, such disorders. Nrf2, a primary orchestrator of cellular antioxidant response machine, is responsible for detoxifying and compensating for deleterious oxidative stress via transcriptional activation of a diverse array of antioxidant biomolecules. In the framework of our persistent interest in disclosing small molecules that interfere with cellular redox-regulating machinery, we report herein the synthesis, optimization, and biological assessment of 47 vinyl sulfone scaffold-bearing small molecules, most of which exhibit robust neuroprotective effect against H 2 O 2 -mediated lesions to PC12 cells. After initial screening, the most potent neuroprotective compounds 9b and 9c with marginal cytotoxicity were selected for the follow-up studies. Our results demonstrate that their neuroprotective effects are attributed to the up-regulation of a panel of antioxidant genes and corresponding gene products. Further mechanistic studies indicate that Nrf2 is indispensable for the cellular performances of 9b and 9c , arising from the fact that silence of Nrf2 gene drastically nullifies their protective action. Taken together, 9b and 9c discovered in this work merit further development as neuroprotective candidates for the treatment of oxidative stress-mediated pathological conditions.
Wang Hanqi,Cheng Fang,He Wei,Zhu Jiaohui,Cheng Gang,Qu Jingping
This paper reported a facile strategy for the one-pot synthesis of vinyl sulfone (VS) group terminated hydrogel precursors [poly(ethylene) glycol (PEG)-VS] and PEG hydrogels via catalytic oxa-Michael reaction. Nine potential catalysts were investigated for the reaction between PEG and divinyl sulfone, among which 4-dimethylaminopyridine (DMAP) prevailed for its high catalytic activity. DMAP produced PEG-VS with a conversion of more than 90% in 2 h under a solvent-free condition at room temperature, which significantly simplifies the synthesis of PEG-VS. The preparation of PEG hydrogels was realized by adding glycerol as a crosslinker, and the physical and the mechanical properties were easily controlled by changing the crosslinker concentration as well as the PEG chain length. This strategy can also be applied to other polyhydroxy compounds as crosslinkers, and thus, a library of hydrogels with designed structures and desired properties could be prepared. The PEG hydrogels showed good antifouling properties, low cytotoxicity, and ability to release drugs at a tunable rate, indicating versatile potential bioapplications.
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