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ACS Chem Neurosci. 2019 Aug 6. doi: 10.1021/acschemneuro.9b00329. [Epub ahead of print]

Gracilin A derivatives target early events in Alzheimer's disease: in vitro effects on neuroinflammation and oxidative stress.


The search for compounds capable of targeting early pathological changes of Alzheimer`s disease (AD), such as oxidative stress and neuroinflammation, is an important challenge. Gracilin A derivatives were recently synthesized, using a pharmacophore-directed retrosynthesis strategy, and found to posses potent neuroprotective effects. In this work, the derivatives 21a, 27a, 27b, 29a, 21b, 22 and 23c (1-7) that had demonstrated mitochondrial-mediated, anti-oxidant effects, were chosen. The ability of compounds to modulate the expression of anti-oxidant genes (CAT, GPx, SOD's and Nrf2) was determined in SH-SY5Y cells, being the simplified derivatives 2 and 3 the most effective compounds. The anti-neuroinflammatory properties of derivatives were assessed in BV2 microglial cells activated with lipopolysaccharide (LPS). Derivatives decreased the release of cytokines (Il-1β, IL-6, GM-CSF and TNF-α) and other damaging molecules (ROS, NO). Compounds also regulated the translocation of Nrf2 and NFκB, and reduced p38 activation. These protective effects were confirmed in a trans-well co-culture with both cell lines, in which derivatives added to BV2 cells increased SH-SY5Y survival. This work provides new results that demonstrate the neuroprotective properties of gracilin A derivatives, making them promising candidate drugs for AD. Particularly, derivatives 2 and 3 showed the greatest potential as lead compounds for further development.

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