Benzimidazole and imidazole inhibitors of histone deacetylases: Synthesis and biological activity

Bressi, Jerome C.; Jong, Ron de; Wu, Yun; Jennings, Andy; Brown, Jason W.; O’Connell, Shawn M.; Tari, Leslie W.; Skene, R.J.; Vu, Phong; Navre, Marc; Cao, Xiaodong; Gangloff, Anthony R.

doi:10.1016/j.bmcl.2010.03.092

Cited by 46 publications

(19 citation statements)

References 13 publications

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“…9B). A simulation suggests that the transiently bound forms can be converted to the tightly bound, pseudoirreversible form over time, providing a basis for a time-dependent inhibition by this class of inhibitors (Bressi et al 2010). Long-lasting effects on cellular histone acetylation levels after removal of MS-275 also suggest tight binding to the enzymes (Ito et al 2011).…”

Section: Mechanisms Of Hdac Inhibitionmentioning

confidence: 99%

“…Another class of clinically important HDAC inhibitors is benzamides, which includes CI-994 and MS-275 (Entinostat). MS-275, a synthetic benzamide derivative with HDAC inhibitory activity (Saito et al 1999), showed moderate in vitro inhibitory activity, but the activity in cells was relatively strong because of the slow binding and time-dependent inhibition by the benzamide class of inhibitors (Bressi et al 2010). Figure 8 shows the large number of structurally diverse HDAC inhibitors.…”

Section: Discovery Of Hdac Inhibitorsmentioning

confidence: 99%

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Erasers of Histone Acetylation: The Histone Deacetylase Enzymes

Seto

Yoshida

2014

Cold Spring Harbor Perspectives in Biology

1,492

1,212

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SUMMARYHistone deacetylases (HDACs) are enzymes that catalyze the removal of acetyl functional groups from the lysine residues of both histone and nonhistone proteins. In humans, there are 18 HDAC enzymes that use either zinc-or NAD + -dependent mechanisms to deacetylate acetyl lysine substrates. Although removal of histone acetyl epigenetic modification by HDACs regulates chromatin structure and transcription, deacetylation of nonhistones controls diverse cellular processes. HDAC inhibitors are already known potential anticancer agents and show promise for the treatment of many diseases.

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Section: Mechanisms Of Hdac Inhibitionmentioning

confidence: 99%

Section: Discovery Of Hdac Inhibitorsmentioning

confidence: 99%

Erasers of Histone Acetylation: The Histone Deacetylase Enzymes

Seto

Yoshida

2014

Cold Spring Harbor Perspectives in Biology

1,492

1,212

View full text Add to dashboard Cite

show abstract

“…The BNT is a directed graphical model based on the study of Bayes probability and network cluster in MATLAB. Fifty compounds [52] were divided randomly into the predictive models as a training set of ten compounds and test set for the other compounds. These compounds were drawn by ChemBioOffice and modified using the prepare ligand module in DS 2.5.…”

Section: Methodsmentioning

confidence: 99%

In SilicoInvestigation of Traditional Chinese Medicine Compounds to Inhibit Human Histone Deacetylase 2 for Patients with Alzheimer’s Disease

Hung

Chen

Chan

et al. 2014

BioMed Research International

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Human histone deacetylase 2 (HDAC2) has been identified as being associated with Alzheimer's disease (AD), a neuropathic degenerative disease. In this study, we screen the world's largest Traditional Chinese Medicine (TCM) database for natural compounds that may be useful as lead compounds in the search for inhibitors of HDAC2 function. The technique of molecular docking was employed to select the ten top TCM candidates. We used three prediction models, multiple linear regression (MLR), support vector machine (SVM), and the Bayes network toolbox (BNT), to predict the bioactivity of the TCM candidates. Molecular dynamics simulation provides the protein-ligand interactions of compounds. The bioactivity predictions of pIC50 values suggest that the TCM candidatesm, (−)-Bontl ferulate, monomethylcurcumin, and ningposides C, have a greater effect on HDAC2 inhibition. The structure variation caused by the hydrogen bonds and hydrophobic interactions between protein-ligand interactions indicates that these compounds have an inhibitory effect on the protein.

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“…All the studies were implemented on a series of benzimidazole and imidazole cinnamoyl hydroxamates reported by Bressi's group (4). Three racemic mixtures were excluded from the original data set, and 50 compounds were investigated.…”

Section: Data Setmentioning

confidence: 99%

Pharmacophore and QSAR Studies to Design Novel Histone Deacetylase 2 Inhibitors

2012

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One pharmacophore model and three quantitative structure-activity relationship models were developed on a series of benzimidazole and imidazole inhibitors of histone deacetylase 2. The goodness of hit score value of the best pharmacophore model was 0.756, which indicated that it is reliable to be used for virtual screening. The built pharmacophore model was used to search the NCI database. The hit compounds were subjected to molecular docking. The results showed that 25 compounds had high scores and strong interactions with histone deacetylase 2. In three-dimensional quantitative structure-activity relationship studies, good predictive models were obtained using comparative molecular field analysis, comparative molecular similarity indices analysis, and Topomer comparative molecular field analysis. Some putative active compounds were proposed based on compound no. 41. Twenty-six compounds had high scores and good interactions when they were docking into histone deacetylase 2.

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Benzimidazole and imidazole inhibitors of histone deacetylases: Synthesis and biological activity

Cited by 46 publications

References 13 publications

Erasers of Histone Acetylation: The Histone Deacetylase Enzymes

Erasers of Histone Acetylation: The Histone Deacetylase Enzymes

In SilicoInvestigation of Traditional Chinese Medicine Compounds to Inhibit Human Histone Deacetylase 2 for Patients with Alzheimer’s Disease

Pharmacophore and QSAR Studies to Design Novel Histone Deacetylase 2 Inhibitors

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