Synthesis and biological evaluation of phenothiazine derivative-containing hydroxamic acids as potent class II histone deacetylase inhibitors

Hsu, Kai‐Cheng; Chu, Jung-Chun; Tseng, Hui-Ju; Liu, Chia-I; Wang, Hao Ching; Lin, Tony Eight; Lee, Hong-Sheng; Hsin, Ling‐Wei; Wang, Andrew H.J.; Lin, Chang‐Ping; Huang, Wei‐Jan

doi:10.1016/j.ejmech.2021.113419

Cited by 11 publications

(3 citation statements)

References 47 publications

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“…Compound 85, a selective HDAC6 inhibitor (IC50 = 4.6 nM) with a phenothiazine scaffold and hydroxamic acid as ZBG, was reported as it can stimulate neurite development without damage to nerve cells [122].…”

Section: Class Iib Selective Inhibitors 2221 Hdac6 Selective Inhibitorsmentioning

confidence: 99%

Recent review on selective histone deacetylase inhibitors in cancer therapy

Abd El-hameed,

Mohamed,

Beshr

2023

Octahedron Drug Research

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Cancer is the most serious disease afflicting humans and a primary cause of death on a global scale. Chemotherapy continues to be one of the most essential cancer treatments, in addition to surgery and radiotherapy. Recently, the use of targeted anticancer medications as an approach for optimizing antitumor therapy has been advocated. One of the most wellestablished cancer targets is histone deacetylases (HDACs). HDAC inhibitors (HDACis) have evolved as one of the most effective anticancer medications due to their capacity to destroy cancer cells aggressively via alteration of the chromatin structure or inhibition of their activity. The discovery of selective HDACs has recently garnered considerable interest for their diverse biological activities and potential therapeutic agents with fewer adverse effects than approved pan inhibitors. This review provides an overview of isoform-and class-selective HDAC inhibitors, including the IC50 values and biological effects on various types of cancer.

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Section: Class Iib Selective Inhibitors 2221 Hdac6 Selective Inhibitorsmentioning

confidence: 99%

Recent review on selective histone deacetylase inhibitors in cancer therapy

Abd El-hameed,

Mohamed,

Beshr

2023

Octahedron Drug Research

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“…Histone deacetylase (HDAC) inhibitor is proved to inhibit oxidative stress and inflammation in the brain to improve cerebral damage (121,122) and interfere with pro-inflammatory skewing (51) as well as oxidative damage of proteins (123) in X-ALD. SAHA, the pan-HDAC inhibitor in clinical practice, has been found to restore mitochondrial integrity and function in ABCD1 silenced oligodendrocytes and astrocytes (124) and reduce the expression of proinflammatory cytokines, iNOS, as well as the activation of NF-κB in ABCD1/ABCD2-silenced mice primary astrocytes (125).…”

Section: Preclinical Studies Of X-linked Adrenoleukodystrophy For New...mentioning

confidence: 99%

The Role of Oxidative Stress and Inflammation in X-Link Adrenoleukodystrophy

Chen

Guo

et al. 2022

Front. Nutr.

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X-linked adrenoleukodystrophy (X-ALD) is an inherited disease caused by a mutation in the ABCD1 gene encoding a peroxisomal transmembrane protein. It is characterized by the accumulation of very-long-chain fatty acids (VLCFAs) in body fluids and tissues, leading to progressive demyelination and adrenal insufficiency. ALD has various phenotypes, among which the most common and severe is childhood cerebral adrenoleukodystrophy (CCALD). The pathophysiological mechanisms of ALD remain unclear, but some in vitro/in vivo research showed that VLCFA could induce oxidative stress and inflammation, leading to damage. In addition, the evidence that oxidative stress and inflammation are increased in patients with X-ALD also proves that it is a potential mechanism of brain and adrenal damage. Therefore, normalizing the redox balance becomes a critical therapeutic target. This study focuses on the possible predictors of the severity and progression of X-ALD, the potential mechanisms of pathogenesis, and the promising targeted drugs involved in oxidative stress and inflammation.

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“…The reported HDAC inhibitors can be structurally divided into three moieties, which include a zinc-binding group (ZBG), a hydrophobic carbon linker, and a capping group also in hydrophobic nature. Previously, we have incorporated various commercially available phenothiazines, which have different C-3 substituents, as the cap group into ZBG hydroxamic acid using a benzyl linker 22 ( Scheme 1 ). Several resulting compounds exhibited more potent class II HDAC-inhibiting activities than did the clinically used HDAC inhibitor SAHA.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and biological evaluation of C-4 substituted phenoxazine-bearing hydroxamic acids with potent class II histone deacetylase inhibitory activities

Chu

Tseng

Lee

et al. 2023

Journal of Enzyme Inhibition and Medicinal Chemistry

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Class II histone deacetylases (HDACs) are considered as potential targets to treat Alzheimer’s disease (AD). Previously, C-3 substituted phenothiazine-containing compounds with class II HDAC-inhibiting activities was found to promote neurite outgrowth. This study replaced phenothiazine moiety with phenoxazine that contains many C-3 and C-4 substituents. Some resulting compounds bearing the C-4 substituent on a phenoxazine ring displayed potent class II HDAC inhibitory activities. Structure-activity relationship (SAR) of these compounds that inhibited HDAC isoenzymes was disclosed. Molecular modelling analysis demonstrates that the potent activities of C-4 substituted compounds probably arise from π-π stacked interactions between these compounds and class IIa HDAC enzymes. One of these, compound 7d exhibited the most potent class II HDAC inhibition (IC 50 = 3–870 nM). Notably, it protected neuron cells from H 2 O 2 -induced neuron damage at sub-μM concentrations, but with no significant cytotoxicity. These findings show that compound 7d is a lead compound for further development of anti-neurodegenerative agents.

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Synthesis and biological evaluation of phenothiazine derivative-containing hydroxamic acids as potent class II histone deacetylase inhibitors

Cited by 11 publications

References 47 publications

Recent review on selective histone deacetylase inhibitors in cancer therapy

Recent review on selective histone deacetylase inhibitors in cancer therapy

The Role of Oxidative Stress and Inflammation in X-Link Adrenoleukodystrophy

Synthesis and biological evaluation of C-4 substituted phenoxazine-bearing hydroxamic acids with potent class II histone deacetylase inhibitory activities

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