Design, synthesis and biological evaluation of dual-function inhibitors targeting NMDAR and HDAC for Alzheimer’s disease

He, Feng; Ran, Yingying; Li, Xiaoyang; Wang, Defeng; Zhang, Qiuqiong; Lv, Jiahui; Yu, Chenggong; Qu, Ying; Zhang, Xiangna; Xu, Ana; Wei, Chao; Chou, C. James; Wu, Jingde

doi:10.1016/j.bioorg.2020.104109

Cited by 18 publications

(7 citation statements)

References 25 publications

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“…Studies from AD mice suggest that reduced HDAC6 is beneficial to the AD animal; reducing HDAC6 level in the APP/PS1‐21 mice showed improvement of memory in the water maze and fear conditioning experiment 19 . Many HDAC6 inhibitors have been developed to improve the cognitive function of AD 49–51 . On the contrary, there are also studies showing that increased HDAC6 is beneficial to maintain a cell's function 20,21 .…”

Section: Discussionmentioning

confidence: 99%

“…19 Many HDAC6 inhibitors have been developed to improve the cognitive function of AD. [49][50][51] On the contrary, there are also studies showing that increased HDAC6 is beneficial to maintain a cell's function. 20,21 Previous studies showed that instead of the second DAC domain, the Nterminal DAC domain of HDAC6 is critical for Drosophila olfactory memory retention.…”

Section: Aβ-induced Pathologiesmentioning

confidence: 99%

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The double‐edged sword effect of HDAC6 in Aβ toxicities

2021

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Alzheimer's disease (AD) is the most common form of dementia and is marked with cognitive impairment, cell loss, and reduction of life expectancy. Pathologically, senile plaque, beta-amyloid (Aβ) aggregates, and neurofibrillary tangle, tau aggregates, are the hallmark of the disease. Although genetics studies provide a causative link between the disease and Aβ accumulation, the interaction between Aβ and tau and its contribution to the

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Section: Discussionmentioning

confidence: 99%

Section: Aβ-induced Pathologiesmentioning

confidence: 99%

The double‐edged sword effect of HDAC6 in Aβ toxicities

2021

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“…According to current knowledge, HDAC inhibitors usually have several structural subunits: a zinc chelating group, a hydrophobic linker, and a hydrophobic (usually aromatic) cap [1,2,5]. One of the most commonly used zinc chelating groups in HDACs inhibitors is a hydroxamic acid moiety (-CONHOH) [6][7][8][9][10][11][12][13][14][15]. The ability of hydroxamic acids to form chelates with various metal cations, including the Zn 2+ ion found in the catalytic center of most HDAC proteins, gives them good biological activity in inhibiting these proteins.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and HDAC inhibitory activity of pyrimidine-based hydroxamic acids

Jakubkienė

Valiulis

Schweipert

et al. 2022

Beilstein J. Org. Chem.

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Histone deacetylases (HDACs) play an essential role in the transcriptional regulation of cells through the deacetylation of nuclear histone and non-histone proteins and are promising therapeutic targets for the treatment of various diseases. Here, the synthesis of new compounds in which a hydroxamic acid residue is attached to differently substituted pyrimidine rings via a methylene group bridge of varying length as potential HDAC inhibitors is described. The target compounds were obtained by alkylation of 2-(alkylthio)pyrimidin-4(3H)-ones with ethyl 2-bromoethanoate, ethyl 4-bromobutanoate, or methyl 6-bromohexanoate followed by aminolysis of the obtained esters with hydroxylamine. Oxidation of the 2-methylthio group to the methylsulfonyl group and following treatment with amines resulted in the formation of the corresponding 2-amino-substituted derivatives, the ester group of which reacted with hydroxylamine to give the corresponding hydroxamic acids. The synthesized hydroxamic acids were tested as inhibitors of the HDAC4 and HDAC8 isoforms. Among the synthesized pyrimidine-based hydroxamic acids N-hydroxy-6-[6-methyl-2-(methylthio)-5-propylpyrimidin-4-yloxy]hexanamide was found to be the most potent inhibitor of both the HDAC4 and HDAC8 isoforms, with an IC50 of 16.6 µM and 1.2 µM, respectively.

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“…designed the first-in-class GSK-3β-HDAC dual inhibitor showing disease-modifying effects in vitro for AD . The Wu group recently published memantine-based HDAC-NMDAR and tacrine-based HDAC-ChEs multitarget inhibitors, which exhibit potent neuroprotection, antioxidant, and anti-Aβ - aggregation activities. , Tseng et al designed HDAC-AChE multitarget inhibitors that enhance neurite outgrowth and show significant anti-Aβ - aggregation activity …”

Section: Introductionmentioning

confidence: 99%

“…25 The Wu group recently published memantine-based HDAC-NMDAR and tacrine-based HDAC-ChEs multitarget inhibitors, which exhibit potent neuroprotection, antioxidant, and anti-Aβ-aggregation activities. 26,27 Tseng et al designed HDAC-AChE multitarget inhibitors that enhance neurite outgrowth and show significant anti-Aβ-aggregation activity. 28 Natural products melatonin and ferulic acid have shown promising pharmacological effects potentially beneficial for AD treatment, such as antioxidant effects, neuroprotection, and neurogenesis promotion.…”

Section: ■ Introductionmentioning

confidence: 99%

Melatonin- and Ferulic Acid-Based HDAC6 Selective Inhibitors Exhibit Pronounced Immunomodulatory Effects In Vitro and Neuroprotective Effects in a Pharmacological Alzheimer’s Disease Mouse Model

Chou

Scheiner

et al. 2021

J. Med. Chem.

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The structures of melatonin and ferulic acid were merged into tertiary amide-based histone deacetylase 6 (HDAC6) inhibitors to develop multi-target-directed inhibitors for neurodegenerative diseases to incorporate antioxidant effects without losing affinity and selectivity at HDAC6. Structure-activity relationships led to compound 10b as a hybrid molecule showing pronounced and selective inhibition of HDAC6 (IC50 = 30.7 nM, > 25-fold selectivity over other subtypes). This compound shows comparable DPPH radical scavenging ability to ferulic acid, comparable ORAC value to melatonin and comparable Cu2+ chelating ability to EDTA. It also lacks neurotoxicity on HT-22 cells, exhibits a pronounced immunomodulatory effect, and is active in vivo showing significantly higher efficacy in an AD mouse model to prevent both Aβ25−35-induced spatial working and long-term memory dysfunction at lower dose (0.3 mg/kg) compared to positive control HDAC6 inhibitor ACY1215 and an equimolar mixture of the three entities ACY1215, melatonin and ferulic acid, suggesting potentially disease-modifying properties.

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Design, synthesis and biological evaluation of dual-function inhibitors targeting NMDAR and HDAC for Alzheimer’s disease

Cited by 18 publications

References 25 publications

The double‐edged sword effect of HDAC6 in Aβ toxicities

The double‐edged sword effect of HDAC6 in Aβ toxicities

Synthesis and HDAC inhibitory activity of pyrimidine-based hydroxamic acids

Melatonin- and Ferulic Acid-Based HDAC6 Selective Inhibitors Exhibit Pronounced Immunomodulatory Effects In Vitro and Neuroprotective Effects in a Pharmacological Alzheimer’s Disease Mouse Model

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