Mou C

References (2)

Title : Design and synthesis of novel tacrine-dipicolylamine dimers that are multiple-target-directed ligands with potential to treat Alzheimer's disease - Zhang_2021_Bioorg.Chem_116_105387
Author(s) : Zhang P , Wang Z , Mou C , Zou J , Xie Y , Liu Z , Benjamin Naman C , Mao Y , Wei J , Huang X , Dong J , Yang M , Wang N , Jin H , Liu F , Lin D , Liu H , Zhou F , He S , Zhang B , Cui W
Ref : Bioorg Chem , 116 :105387 , 2021
Abstract : Alzheimer's disease (AD) is a prevalent neurodegenerative disorder that has multiple causes. Therefore, multiple-target-directed ligands (MTDLs), which act on multiple targets, have been developed as a novel strategy for AD therapy. In this study, novel drug candidates were designed and synthesized by the covalent linkings of tacrine, a previously used anti-AD acetylcholinesterase (AChE) inhibitor, and dipicolylamine, an beta-amyloid (Abeta) aggregation inhibitor. Most tacrine-dipicolylamine dimers potently inhibited AChE and Abeta(1-42) aggregation in vitro, and 13a exhibited nanomolar level inhibition. Molecular docking analysis suggested that 13a could interact with the catalytic active sites and the peripheral anion site of AChE, and bind to Abeta(1-42) pentamers. Moreover, 13a effectively attenuated Abeta(1-42) oligomers-induced cognitive dysfunction in mice by activating the cAMP-response element binding protein/brain-derived neurotrophic factor signaling pathway, decreasing tau phosphorylation, preventing synaptic toxicity, and inhibiting neuroinflammation. The safety profile of 13a in mice was demonstrated by acute toxicity experiments. All these results suggested that novel tacrine-dipicolylamine dimers, especially 13a, have multi-target neuroprotective and cognitive-enhancing potentials, and therefore might be developed as MTDLs to combat AD.
ESTHER : Zhang_2021_Bioorg.Chem_116_105387
PubMedSearch : Zhang_2021_Bioorg.Chem_116_105387
PubMedID: 34628225

Title : Fascaplysin Derivatives Are Potent Multitarget Agents against Alzheimer's Disease: in Vitro and in Vivo Evidence - Pan_2019_ACS.Chem.Neurosci_10_4741
Author(s) : Pan H , Qiu H , Zhang K , Zhang P , Liang W , Yang M , Mou C , Lin M , He M , Xiao X , Zhang D , Wang H , Liu F , Li Y , Jin H , Yan X , Liang H , Cui W
Ref : ACS Chem Neurosci , 10 :4741 , 2019
Abstract : Alzheimer's disease (AD) is characterized by progressive neurodegeneration and impaired cognitive functions. Fascaplysin is a beta-carboline alkaloid isolated from marine sponge Fascaplysinopsis bergquist in 1988. Previous studies have shown that fascaplysin might act on acetylcholinesterase and beta-amyloid (Abeta) to produce anti-AD properties. In this study, a series of fascaplysin derivatives were synthesized. The cholinesterase inhibition activities, the neuronal protective effects, and the toxicities of these compounds were evaluated in vitro. Compounds 2a and 2b, the two most powerful compounds in vitro, were further selected to evaluate their cognitive-enhancing effects in animals. Both 2a and 2b could ameliorate cognitive dysfunction induced by scopolamine or Abeta oligomers without affecting locomotor functions in mice. We also found that 2a and 2b could prevent cholinergic dysfunctions, decrease pro-inflammatory cytokine expression, and inhibit Abeta-induced tau hyperphosphorylation in vivo. Most importantly, pharmacodynamics studies suggested that 2b could penetrate the blood-brain barrier and be retained in the central nervous system. All these results suggested that fascaplysin derivatives are potent multitarget agents against AD and might be clinical useful for AD treatment.
ESTHER : Pan_2019_ACS.Chem.Neurosci_10_4741
PubMedSearch : Pan_2019_ACS.Chem.Neurosci_10_4741
PubMedID: 31639294