Synthesis and biological evaluation of novel histone deacetylases inhibitors with nitric oxide releasing activity

Duan, Wenwen; Hou, Jinjun; Chu, Xiaojing; Li, Xiaoqian; Zhang, Jian; Li, Jin; Xu, Wenjian; Zhang, Yingjie

doi:10.1016/j.bmc.2015.06.015

Cited by 19 publications

(16 citation statements)

References 26 publications

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“…Additionally, the hybrid of a nitric oxide (NO) donor and an histone deacetylase inhibitor has been developed and displayed outstanding antiproliferative activity in tumor cells (Duan et al 2015). …”

Section: Anticancer Effect Of Hdac Inhibitorsmentioning

confidence: 99%

HDACs and HDAC Inhibitors in Cancer Development and Therapy

Seto

2016

Cold Spring Harb Perspect Med

957

765

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Over the last several decades, it has become clear that epigenetic abnormalities may be one of the hallmarks of cancer. Post-translational modifications of histones, for example, may play a crucial role in cancer development and progression by modulating gene transcription, chromatin remodeling and nuclear architecture. Histone acetylation, a well-studied post-translational histone modification, is controlled by the opposing activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs). By removing acetyl groups, HDACs reverse chromatin acetylation and alter transcription of oncogenes and tumor suppressor genes. In addition, HDACs deacetylate numerous non-histone cellular substrates that govern a wide array of biological processes including cancer initiation and progression. This review will discuss the role of HDACs in cancer and the therapeutic potential of HDAC inhibitors (HDACi) as emerging drugs in cancer treatment.

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Section: Anticancer Effect Of Hdac Inhibitorsmentioning

confidence: 99%

HDACs and HDAC Inhibitors in Cancer Development and Therapy

Seto

2016

Cold Spring Harb Perspect Med

957

765

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“…Epigenetic modifications represent a link between the regulation of gene expression and environmental factors. Epigenetic regulation is mediated by histone posttranslational modifications, known as epigenetic marks, which are involved in a number of different processes such as cellular proliferation, differentiation, and repair of DNA damage …”

Section: Introductionmentioning

confidence: 99%

“…HATs attach acetyl groups to lysine residues in histone and nonhistone proteins which provoke transcriptional activities, while HDACs catalyze the removal of acetyl groups causing chromatin to become highly packaged and, therefore, resulting in repressed gene expression . Overexpression of these enzymes correlate with several diseases including cancer, inflammation, neurodegenerative, and metabolic disorders .…”

Section: Introductionmentioning

confidence: 99%

Enantioselective synthesis and biological investigation of tetrahydro‐β‐carboline‐based HDAC6 inhibitors with improved solubility

Grünstein

Sellmer

Mahboobi

2019

Archiv der Pharmazie

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Aberrant epigenetic changes in DNA methylation and histone modification by acetylation or deacetylation regulate the pathogenesis of many diseases. Especially selective inhibitors are getting more and more attention. We recently reported on a new class of potent and selective anti-inflammatory and antirheumatic histone deacetylase 6 (HDAC6) inhibitors (e.g., Marbostat-100). The attachment of a morpholinoethoxy part to the head group dramatically enhances the solubility, in particular the solubility in aqueous solutions, of the lead compound Marbostat-100.Here, we present the enantioselective synthesis of small-molecule compounds based on the tetrahydro-β-carboline core system with improved solubility, and the influence of the stereochemistry on the biological activity. The enantiomers were synthesized in good enantiomeric excess (ee) purity and were potent and selective HDAC6 inhibitors, whereas the S-derivative S-21 is clearly the eutomer. The potency of our selective HDAC6 inhibitors is demonstrated by K i values in the range of 0.5-2 nM toward HDAC6, and the selectivity was proved in cellular assays by Western blot analysis taking ac-tubulin as surrogate parameter.

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“…Nitric oxide (NO), one of the simplest, odorless, colorless, highly reactive, and biological molecules in nature, is a free radical and a key mediator involved in diverse physiological and pathological processes [16][17][18][19][20]. NO-donating compounds have recently come into focus for the treatment of tumors because NO plays a central role in cell regulatory pathways and is a key signaling molecule involved in the death and apoptosis of tumor cells [21][22][23][24][25][26][27][28][29][30][31][32]. Generally, high levels of NO (above 400 nM [33]) produced from NO donors can induce apoptosis, inhibit metastasis of tumor cells, and sensitize tumor cells to radiation, immunotherapy, and chemotherapy.…”

Section: Introductionmentioning

confidence: 99%

“…Generally, high levels of NO (above 400 nM [33]) produced from NO donors can induce apoptosis, inhibit metastasis of tumor cells, and sensitize tumor cells to radiation, immunotherapy, and chemotherapy. Some synthesized NO-releasing compounds have already shown antitumor activity against human carcinoma cells in vitro and in vivo [21][22][23][24][25][26][27][28][29][30][31][32]. Due to the highly reactive nature of NO, it is difficult to predict its biological effects on a given system from single doses even if provided by the longer action of inducible nitric oxide synthase (iNOS).…”

Section: Introductionmentioning

confidence: 99%

NO-Releasing Enmein-Type Diterpenoid Derivatives with Selective Antiproliferative Activity and Effects on Apoptosis-Related Proteins

Han

et al. 2016

Molecules

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A series of nine enmein-type ent-kaurane diterpenoid and furoxan-based nitric oxide (NO) donor hybrids (10a-i) were designed and synthesized from commercially available oridonin (1). These hybrids were evaluated for their antiproliferative activity against Bel-7402, K562, MGC-803, and CaEs-17 human cancer cell lines and L-02 normal liver cells. The antiproliferative activity against tumor cells was stronger than the lead compound 1 and parent molecule 9 in most cases. Especially, compound 10f showed the strongest activity against human hepatocarcinoma Bel-7402 cell line with an IC 50 of 0.81 µM and could also release 33.7 µmol/L NO at the time point of 60 min. Compounds 10a-i also showed cytotoxic selectivity between tumor and normal liver cells with IC 50 ranging from 22.1 to 33.9 µM. Furthermore, the apoptotic properties on Bel-7402 cells revealed that 10f could induce S phase cell cycle arrest and apoptosis at low micromolar concentrations. The effects of 10f on apoptosis-related proteins were also investigated. The potent antiproliferative activities and mechanistic studies warrant further preclinical investigations.

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Synthesis and biological evaluation of novel histone deacetylases inhibitors with nitric oxide releasing activity

Cited by 19 publications

References 26 publications

HDACs and HDAC Inhibitors in Cancer Development and Therapy

HDACs and HDAC Inhibitors in Cancer Development and Therapy

Enantioselective synthesis and biological investigation of tetrahydro‐β‐carboline‐based HDAC6 inhibitors with improved solubility

NO-Releasing Enmein-Type Diterpenoid Derivatives with Selective Antiproliferative Activity and Effects on Apoptosis-Related Proteins

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