Hybrids of oxoisoaporphine-tetrahydroisoquinoline: novel multi-target inhibitors of inflammation and amyloid-ß aggregation in Alzheimer's disease.

A series of 8- and 11-substituted hybrids of oxoisoaporphine-tetrahydroisoquinoline have been designed and synthesized. The new derivatives strongly suppressed NO and iNOS production and modulated the production of cytokines by decreasing TNF-α and IL-1ß formation in lipopolysaccharide-activated BV-2 microglia and RAW 264.7 macrophages. Meanwhile, incubation of these derivatives with SH-SY5Y cells that were transfected with human APP containing the Swedish mutations significantly decreased the secretion of Aß42. Moreover, these hybrids could strongly inhibit the activity of acetylcholinesterase and butyrylcholinesterase. Further investigations in vivo indicated that the 8-substituted hybrid 3b significantly delayed paralysis caused by Aß1-42 toxicity in GMC101. In sum, these new hybrids could target multiple pathogenetic factors in Alzheimer's disease and merit further investigation.

Assessment of novel azaanthraquinone derivatives as potent multi-target inhibitors of inflammation and amyloid-ß aggregation in Alzheimer's disease.

A series of 6-substituted azaanthraquinone derivatives have been designed, synthesized, and their anti-inflammatory activities, antiaggregation effects on ß-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-1ß 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 Aß 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 Aß42 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.

Synthesis of derivatives of cleistopholine and their anti-acetylcholinesterase and anti-ß-amyloid aggregation activity.

A series of 6- and 9-substituted cleistopholine derivatives has been designed, synthesized and investigated to inhibit the aggregation of acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and ß-myloid (A ß). Results showed that these synthetic compounds had excellent AChE inhibitory activity and a significant in vitro inhibitory potency toward the self-induced A ß aggregation. When SH-SY5Y cells were treated with these substituted cleistopholine derivatives during they overexpressed the Swedish mutant form of human ß -amyloid precursor protein (APPsw), A ß 42 secretion levels were significantly reduced. According to a parallel artificial membrane permeation assay for BBB, seven out of these sixteen synthetic compounds probably could cross the blood-brain barrier (BBB) to reach their targets in the central nervous system (CNS).

Multitarget-directed oxoisoaporphine derivatives: Anti-acetylcholinesterase, anti-ß-amyloid aggregation and enhanced autophagy activity against Alzheimer's disease.

A series of 8- and 11-substituted oxoisoaporphine derivatives have been designed, synthesized, and tested for their ability to inhibit cholinesterase (ChE) in vitro and in vivo, and self-induced ß-amyloid (Aß) aggregation. Their autophagy activity and blood-brain barrier (BBB) permeability were also assessed. The new derivatives exhibited high AChE inhibitory activity in vivo and in intro. Over half the derivatives exhibited a significant in vitro inhibitory activity toward the self-induced Aß aggregation. While, treatment of SH-SY5Y cells overexpressing the Swedish mutant form of human ß-amyloid precursor protein (APPsw) with derivatives was associated with significant reduction of Aß secretion levels. Moreover, one-third of the synthetic compounds were predicted to be able to cross the BBB to reach their targets in the central nervous system (CNS) according to a parallel artificial membrane permeation assay for BBB. Compounds 5b and 6b were chosen for assessing their autophagy activity. The fluorescence intensity of the BC12921 was decreased significantly after treatment with compounds. The result encourages us to study such compounds thoroughly and systematically.