Design, synthesis and antiproliferative activities of novel benzamides derivatives as HDAC inhibitors

Li, Yanyang; Wang, Yongzhen; Xie, Ning; Xu, Ming; Qian, Pengyu; Zhao, Yuqin; Li, Shuxin

doi:10.1016/j.ejmech.2015.05.045

Cited by 22 publications

(11 citation statements)

References 15 publications

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“…Biological data have shown that the inhibitory activities of bicyclic heterocycle substituted compounds were better than pyridinyl compounds, especially the imidazo[1,2-b] pyridazine ring (Table XVI). 89 While in the precedent series, the introduction of the fluoro group on the benzamide portion did not affect the antitumor activity, the acrylamide derivatives with the fluoro substituent at the metaand para-position (46i,j) exhibited lower antitumor activities against HCT-116, MCF-7, and A549 cancer cell lines than others. According to the precedent series, elongation of the linker from 1 to 2 carbons led to lower antiproliferative activities (46b,d,f,h).…”

Section: B Benzamidesmentioning

confidence: 92%

“…To increase the physicochemical stability and bioactivities, the bicyclic heterocycle ( E )‐3‐(1 H ‐indol‐3‐yl)acrylamide derivatives were also synthesized. Biological data have shown that the inhibitory activities of bicyclic heterocycle substituted compounds were better than pyridinyl compounds, especially the imidazo[1,2‐ b ] pyridazine ring (Table ) . While in the precedent series, the introduction of the fluoro group on the benzamide portion did not affect the antitumor activity, the acrylamide derivatives with the fluoro substituent at the meta ‐ and para ‐position ( 46i , j ) exhibited lower antitumor activities against HCT‐116, MCF‐7, and A549 cancer cell lines than others.…”

Section: Chemical Classes Of Histone Deacetylases Inhibitorsmentioning

confidence: 99%

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The Search for Potent, Small‐Molecule HDACIs in Cancer Treatment: A Decade After Vorinostat

Zagni

Floresta

Monciino

et al. 2017

Medicinal Research Reviews

110

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Histone deacetylases (HDACs) play a crucial role in the remodeling of chromatin, and are involved in the epigenetic regulation of gene expression. In the last decade, inhibition of HDACs came out as a target for specific epigenetic changes associated with cancer and other diseases. Until now, more than 20 HDAC inhibitors (HDACIs) have entered clinical studies, and some of them (e.g., vorinostat, romidepsin) have been approved for the treatment of cutaneous T-cell lymphoma. This review provides an overview of current knowledge, progress, and molecular mechanisms of HDACIs, covering a period from 2011 until 2015.

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Section: B Benzamidesmentioning

confidence: 92%

Section: Chemical Classes Of Histone Deacetylases Inhibitorsmentioning

confidence: 99%

The Search for Potent, Small‐Molecule HDACIs in Cancer Treatment: A Decade After Vorinostat

Zagni

Floresta

Monciino

et al. 2017

Medicinal Research Reviews

110

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“…A comprehensive set of HDAC1 inhibitors characterized by the 2-aminophenylbenzamide scaffold with known IC 50 values that vary over a wide range was collected from the literature [66,67,[79][80][81][82][83][84][85][86][87][88][89][90][91][92] and the bindingDB database [93]. The selection criterion for the compounds to be included in the set was that their HDAC1 inhibition was evaluated using the same fluorescent assay based on the fluorogenic substrate Fluor-de-Lys.…”

Section: Ligands and Data Set Preparationmentioning

confidence: 99%

“…After the generation of the 3D-QSAR model, a preliminary in silico validation was performed using a large external test set of compounds (113 molecules) selected from the literature [83,84,89,[103][104][105][106] ( Table S2 in the Supplementary Materials) that have not been used for generating and cross validating the model. These compounds were prepared by using Maestro, LigPrep, and MacroModel, adopting the same procedure for preparing the molecules used to derive the model.…”

Section: In Silico 3d-qsar Model Validationmentioning

confidence: 99%

Computer-Driven Development of an in Silico Tool for Finding Selective Histone Deacetylase 1 Inhibitors

et al. 2020

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Histone deacetylases (HDACs) are a class of epigenetic modulators overexpressed in numerous types of cancers. Consequently, HDAC inhibitors (HDACIs) have emerged as promising antineoplastic agents. Unfortunately, the most developed HDACIs suffer from poor selectivity towards a specific isoform, limiting their clinical applicability. Among the isoforms, HDAC1 represents a crucial target for designing selective HDACIs, being aberrantly expressed in several malignancies. Accordingly, the development of a predictive in silico tool employing a large set of HDACIs (aminophenylbenzamide derivatives) is herein presented for the first time. Software Phase was used to derive a 3D-QSAR model, employing as alignment rule a common-features pharmacophore built on 20 highly active/selective HDAC1 inhibitors. The 3D-QSAR model was generated using 370 benzamide-based HDACIs, which yielded an excellent correlation coefficient value (R 2 = 0.958) and a satisfactory predictive power (Q 2 = 0.822; Q 2 F3 = 0.894). The model was validated (r 2 ext_ts = 0.794) using an external test set (113 compounds not used for generating the model), and by employing a decoys set and the receiver-operating characteristic (ROC) curve analysis, evaluating the Güner-Henry score (GH) and the enrichment factor (EF). The results confirmed a satisfactory predictive power of the 3D-QSAR model. This latter represents a useful filtering tool for screening large chemical databases, finding novel derivatives with improved HDAC1 inhibitory activity.Molecules 2020, 25, 1952 2 of 20 chromatin structure which concomitantly restricts the accessibility of related transcriptional factors to their target genes, thereby suppressing gene expression including tumor suppressor genes [6][7][8]. The abnormal regulation of this process culminates with the high expression level of HDACs. This event has been observed in the development of several human cancers. Consequently, effective inhibition of HDACs has recently gained importance as a valid therapeutic strategy to reverse aberrant epigenetic changes associated with cancer [9][10][11]. HDAC inhibitors (HDACIs) induce histone hyperacetylation and subsequent transcriptional re-activation of suppressed genes which are correlated with a variety of effects on tumor cells including apoptosis, differentiation, cell cycle arrest, inhibition of proliferation and cytostasis [12,13].The HDAC family comprises 18 isoforms in mammalian cells which are categorized into four main classes (class I-IV) based on their structural and functional characteristics. HDACs belonging to class I (HDAC1-3 and 8), II (HDACs 4-7, 9 and 10) and IV (HDAC11) are all zinc-dependent metalloenzymes, while class III HDACs, also known as the sirtuins (SIRT1-7), requires NAD + as a cofactor for their catalytic function [6,14].Extensive efforts over recent decades have led to the identification of four chemically diverse classes of HDACIs as potent antineoplastic agents including, hydroxamates, benzamides, cyclic peptides, and short-chain fatty acids [3]. The main...

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“…HDAC inhibitors (HDACI) can affect tumour cell growth and survival by blocking the deacetylation of histone or nonhistone proteins (such as α-tubulin, Hsp90, and transcription factors p53 and NF-κB), inducing cell cycle arrest, angiogenesis suppression, tumor cell antigenicity enhancement, and apoptosis [30] . Recently immense efforts have been made to develop novel HDAC inhibitors [31][32][33][34][35][36][37][38] .…”

mentioning

confidence: 99%

Hybrids from 4-anilinoquinazoline and hydroxamic acid as dual inhibitors of vascular endothelial growth factor receptor-2 and histone deacetylase

Peng

Ren

et al. 2015

Bioorganic & Medicinal Chemistry Letters

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Design, synthesis and antiproliferative activities of novel benzamides derivatives as HDAC inhibitors

Cited by 22 publications

References 15 publications

The Search for Potent, Small‐Molecule HDACIs in Cancer Treatment: A Decade After Vorinostat

The Search for Potent, Small‐Molecule HDACIs in Cancer Treatment: A Decade After Vorinostat

Computer-Driven Development of an in Silico Tool for Finding Selective Histone Deacetylase 1 Inhibitors

Hybrids from 4-anilinoquinazoline and hydroxamic acid as dual inhibitors of vascular endothelial growth factor receptor-2 and histone deacetylase

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