Journal
BIOORGANIC CHEMISTRY
Volume 83, Issue -, Pages 477-486Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bioorg.2018.10.073
Keywords
Azaanthraquinone derivatives; Inflammation; Amyloid-beta aggregation; Neuroprotection
Funding
- National Natural Science Foundation of China [81260471]
- Program for Changjiang Scholars and Innovative Research Team in University of Ministry of Education of China [IRT1225]
- Guangxi Provincial Natural Science Foundation of China [2013GXNSFAA019132]
- State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Guangxi Normal University [CMEMR-C28]
- Innovation Project of Guangxi Graduate Education [XYCSZ2017056]
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A series of 6-substituted azaanthraquinone derivatives have been designed, synthesized, and their anti-inflammatory activities, antiaggregation effects on beta-amyloid proteins, anticholinesterase and neuroprotective activity were tested. The new derivatives strongly suppressed NO and iNOS production and modulate the production of cytokines by decreasing TNF-a, IL-1 beta and IL-6 formation in lipopolysaccharide (LPS)-activated RAW 264.7 macrophages. Meanwhile, the derivatives exhibited a significant in vitro inhibitory activity toward the self-induced A beta aggregation. While, treatment of SH-SY5Y cells overexpressing the Swedish mutant form of human b-amyloid precursor protein (APPsw) with derivatives was associated with significant reduction of A beta 42 secretion levels. Moreover, the derivatives exhibited moderate inhibitory potency toward acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Further investigations indicated that compound 7b could attenuate H2O2-induced neurotoxicity toward SH-SY5Y neuroblastoma cells and half of the synthetic compounds were predicted to be able to cross the blood-brain barrier (BBB) to reach their targets in the central nervous system (CNS) according to a parallel artificial membrane permeation assay for BBB. Taken together, azaanthraquinone derivatives targeting multiple pathogenetic factors deserves further investigation for prevention and treatment of AD.
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