Development of the “hidden” multifunctional agents for Alzheimer's disease

Huang, Wenhai; Liang, Meihao; Li, Qin; Zheng, Xiaoliang; Zhang, Chixiao; Wang, Qiao; Tang, Li; Zhang, Zhimin; Wang, Beibei; Shen, Zhengrong

doi:10.1016/j.ejmech.2019.05.051

Cited by 25 publications

(11 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Aβ oligomers can lead to neuronal death and recognition dysfunction and are believed to be the major neurotoxic aggregates in AD . Aβ oligomer-induced hyperphosphorylation of tau could disrupt the organization of microtubules and lead to neurotoxicity.…”

Section: Resultsmentioning

confidence: 99%

“…However, the level of hyperphosphorylated tau in Aβ oligomer-treated group was significantly higher when compared with control group Aβ oligomers can lead to neuronal death and recognition dysfunction and are believed to be the major neurotoxic aggregates in AD. 53 Aβ oligomer-induced hyperphosphorylation of tau could disrupt the organization of microtubules and lead to neurotoxicity. It was believed that the prevention of tau hyperphosphorylation could effectively protect neurons and ameliorate dementia.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Fascaplysin Derivatives Are Potent Multitarget Agents against Alzheimer’s Disease: in Vitro and in Vivo Evidence

Pan

Qiu

Zhang

et al. 2019

ACS Chem. Neurosci.

View full text Add to dashboard Cite

Alzheimer’s disease (AD) is characterized by progressive neurodegeneration and impaired cognitive functions. Fascaplysin is a β-carboline alkaloid isolated from marine sponge Fascaplysinopsis bergquist in 1988. Previous studies have shown that fascaplysin might act on acetylcholinesterase and β-amyloid (Aβ) 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 Aβ 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 Aβ-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.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: ■ Results and Discussionmentioning

confidence: 99%

Fascaplysin Derivatives Are Potent Multitarget Agents against Alzheimer’s Disease: in Vitro and in Vivo Evidence

Pan

Qiu

Zhang

et al. 2019

ACS Chem. Neurosci.

View full text Add to dashboard Cite

show abstract

“…The supernatant from the samples was separated and analyzed using LC/MS. The complete experimental procedure is described in our previous publication …”

Section: Methodsmentioning

confidence: 99%

Design, Synthesis, and Bioactivity of Novel Bifunctional Small Molecules for Alzheimer’s disease

Liang

Zhang

et al. 2022

ACS Omega

Self Cite

View full text Add to dashboard Cite

The abnormal phosphorylation of the τ-protein is a typical early pathological feature of Alzheimer’s disease (AD). The excessive phosphorylation of the τ-protein in the brain causes the formation of neurofibrillary tangles (NFTs) and increases the neurotoxicity of amyloid-β (Aβ). Thus, targeting the τ-protein is considered a promising strategy for treating AD. Herein, we designed and synthesized a series of molecules containing bifunctional groups to recognize the τ-protein and the E3 ligase. The molecules were examined in vitro , and their effects were tested on PC12 cells. In addition, we further studied the pharmacokinetics of compound I3 in healthy rats. Our data showed that compound I3 could effectively degrade τ-protein, reduce Aβ-induced cytotoxicity, and regulate the uneven distribution of mitochondria, which may open a new therapeutic strategy for the treatment of AD.

show abstract

“…In order to study the possibility of interactions with AChE, we performed molecular docking simulations using AutoDockTools-1.5.6 using the crystal structure of the AChE-Rivastigmine complex (PDB ID:1GQR) as a template [59,60]. We analyzed all metal chelators Hbpq, H2dqpyca, H2bqch and H2bqen in terms of interactions and bond distances with critical amino acids of AChE that interact also with rivastigmine [23,59]. Docking and the subsequent calculation of scores and free energies were performed using default parameters and are shown in Table S1.…”

Section: Molecular Docking Studies Suggest Possible Interaction Of Th...mentioning

confidence: 99%

“…Currently, several research groups have focused on the synthesis and evaluation of metal chelators as a basis of multifunctional compounds [20][21][22][23][24]. Previous studies have described quinoline derivatives as promising compounds with positive results in preclinical models.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, characterization and pharmacological evaluation of quinoline derivatives and their complexes with copper(ΙΙ) in in vitro cell models of Alzheimer's disease

Pavlidis

Kofinas

Papanikolaou

et al. 2021

Journal of Inorganic Biochemistry

View full text Add to dashboard Cite

Development of the “hidden” multifunctional agents for Alzheimer's disease

Cited by 25 publications

References 31 publications

Fascaplysin Derivatives Are Potent Multitarget Agents against Alzheimer’s Disease: in Vitro and in Vivo Evidence

Fascaplysin Derivatives Are Potent Multitarget Agents against Alzheimer’s Disease: in Vitro and in Vivo Evidence

Design, Synthesis, and Bioactivity of Novel Bifunctional Small Molecules for Alzheimer’s disease

Synthesis, characterization and pharmacological evaluation of quinoline derivatives and their complexes with copper(ΙΙ) in in vitro cell models of Alzheimer's disease

Contact Info

Product

Resources

About