5778-84-7Relevant articles and documents
Functionalized acridin-9-yl phenylamines protected neuronal HT22 cells from glutamate-induced cell death by reducing intracellular levels of free radical species
Nguyen, Thuy,Yang, Tianming,Go, Mei-Lin
, p. 1830 - 1838 (2015/03/14)
The in vitro neuronal cell death model based on the HT22 mouse hippocampal cell model is a convenient means of identifying compounds that protect against oxidative glutamate toxicity which plays a role in the development of certain neurodegenerative diseases. Functionalized acridin-9-yl-phenylamines were found to protect HT22 cells from glutamate challenge at submicromolar concentrations. The Aryl1-NHAryl2 scaffold that is embedded in these compounds was the minimal pharmacophore for activity. Mechanistically, protection against the endogenous oxidative stress generated by glutamate did not involve up-regulation of glutathione levels but attenuation of the late stage increases in mitochondrial ROS and intracellular calcium levels. The NH residue in the pharmacophore played a crucial role in this regard as seen from the loss of neuroprotection when it was structurally modified or replaced. That the same NH was essential for radical scavenging in cell-free and cell-based systems pointed to an antioxidant basis for the neuroprotective activities of these compounds.
Functionalized acridin-9-yl phenylamines protected neuronal HT22 cells from glutamate-induced cell death by reducing intracellular levels of free radical species
Nguyen, Thuy,Yang, Tianming,Go, Mei-Lin
, p. 1830 - 1838 (2014/04/17)
The in vitro neuronal cell death model based on the HT22 mouse hippocampal cell model is a convenient means of identifying compounds that protect against oxidative glutamate toxicity which plays a role in the development of certain neurodegenerative diseases. Functionalized acridin-9-yl-phenylamines were found to protect HT22 cells from glutamate challenge at submicromolar concentrations. The Aryl1-NH-Aryl2 scaffold that is embedded in these compounds was the minimal pharmacophore for activity. Mechanistically, protection against the endogenous oxidative stress generated by glutamate did not involve up-regulation of glutathione levels but attenuation of the late stage increases in mitochondrial ROS and intracellular calcium levels. The NH residue in the pharmacophore played a crucial role in this regard as seen from the loss of neuroprotection when it was structurally modified or replaced. That the same NH was essential for radical scavenging in cell-free and cell-based systems pointed to an antioxidant basis for the neuroprotective activities of these compounds.
A novel hybrid of 6-chlorotacrine and metal-amyloid-β modulator for inhibition of acetylcholinesterase and metal-induced amyloid-β aggregation
Kochi, Akiko,Eckroat, Todd J.,Green, Keith D.,Mayhoub, Abdelrahman S.,Lim, Mi Hee,Garneau-Tsodikova, Sylvie
, p. 4137 - 4145 (2013/10/22)
The number of people suffering from Alzheimer's disease (AD) is expected to increase dramatically in the coming decades. Currently, acetylcholinesterase inhibitors (AChEis) provide some relief of cognitive symptoms, while newer approaches, such as amyloid-β (Aβ)-targeted metal chelation, offer potential hope for slowing and/or reversing disease progression. This work details the synthesis and biochemical evaluation of a novel hybrid of 6-chlorotacrine and a metal-Aβ modulator that chemically combines an AChEi and an Aβ-targeted metal chelator into a single molecule. This hybrid shows potent inhibition of AChE under various conditions, interaction with Cu 2+ and Zn2+, control of metal-free and metal-induced Aβ aggregate assembly, and disaggregation of preformed metal-free and metal-associated Aβ aggregates. As such, the hybrid described herein represents a promising, new multifunctional compound for AD studies. The Royal Society of Chemistry 2013.
