scholarly journals Design, synthesis and evaluation of belinostat analogs as histone deacetylase inhibitors

2019 ◽  
Vol 11 (21) ◽  
pp. 2765-2778
Author(s):  
Jie-Huan Zhang ◽  
Madhusoodanan Mottamal ◽  
Hai-Shan Jin ◽  
Shanchun Guo ◽  
Yan Gu ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Active Compound ◽  
Histone Deacetylase Inhibitors ◽  
Hdac Inhibitors ◽  
Antitumor Therapy ◽  
Design Synthesis ◽  
Inhibitory Activities ◽  
Antiproliferative Activities

Aim: Histone deacetylase (HDAC) is an attractive target for antitumor therapy. Therefore, the development of novel HDAC inhibitors is warranted. Materials & methods: A series of HDAC inhibitors based on N-hydroxycinnamamide fragment was designed as the clinically used belinostat analog using amide as the connecting unit. All target compounds were evaluated for their in vitro HDAC inhibitory activities and some selected compounds were tested for their antiproliferative activities. Conclusion: Among them, compound 7e showed an IC50 value of 11.5 nM in inhibiting the HDAC in a pan-HDAC assay, being the most active compound of the series.

scholarly journals Ex VivoActivity of Histone Deacetylase Inhibitors against Multidrug-Resistant Clinical Isolates ofPlasmodium falciparumandP. vivax

2010 ◽  
Vol 55 (3) ◽  
pp. 961-966 ◽  
Author(s):  
Jutta Marfurt ◽  
Ferryanto Chalfein ◽  
Pak Prayoga ◽  
Frans Wabiser ◽  
Enny Kenangalem ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Ex Vivo ◽  
Hdac Inhibitors ◽  
Multidrug Resistant ◽  
Clinical Isolates ◽  
Antimalarial Therapy ◽  
Susceptibility Profiles ◽  
Antimalarial Compounds

ABSTRACTHistone acetylation plays an important role in regulating gene transcription and silencing inPlasmodium falciparum. Histone deacetylase (HDAC) inhibitors, particularly those of the hydroxamate class, have been shown to have potentin vitroactivity against drug-resistant and -sensitive laboratory strains ofP. falciparum, raising their potential as a new class of antimalarial compounds. In the current study, stage-specificex vivosusceptibility profiles of representative hydroxamate-based HDAC inhibitors suberoylanilide hydroxamic acid (SAHA), 2-ASA-9, and 2-ASA-14 (2-ASA-9 and 2-ASA-14 are 2-aminosuberic acid-based HDAC inhibitors) were assessed in multidrug-resistant clinical isolates ofP. falciparum(n= 24) andP. vivax(n= 25) from Papua, Indonesia, using a modified schizont maturation assay. Submicromolar concentrations of SAHA, 2-ASA-9, and 2-ASA-14 inhibited the growth of bothP. falciparum(median 50% inhibitory concentrations [IC50s] of 310, 533, and 266 nM) andP. vivax(median IC50s of 170, 503, and 278 nM). Inverse correlation patterns between HDAC inhibitors and chloroquine forP. falciparumand mefloquine forP. vivaxindicate species-specific susceptibility profiles for HDAC inhibitors. These HDAC inhibitors were also found to be potentex vivoagainstP.vivaxschizont maturation, comparable to that inP. falciparum, suggesting that HDAC inhibitors may be promising candidates for antimalarial therapy in geographical locations where both species are endemic. Further studies optimizing the selectivity andin vivoefficacy of HDAC inhibitors inPlasmodiumspp. and defining drug interaction with common antimalarial compounds are warranted to investigate the role of HDAC inhibitors in antimalarial therapy.

scholarly journals Histone deacetylase inhibitors with high in vitro activities against Plasmodium falciparum isolates collected from Gabonese children and adults

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Erik Koehne ◽  
Andrea Kreidenweiss ◽  
Rella Zoleko Manego ◽  
Matthew McCall ◽  
Ghyslain Mombo-Ngoma ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Hdac Inhibitors ◽  
Drug Efficacy ◽  
Human Cells ◽  
Drug Candidates ◽  
Lower Drug ◽  
Reduced Toxicity

AbstractHistone deacetylase (HDAC) enzymes are targets for the development of antimalarial drugs with a different mode of action to established antimalarials. Broad-spectrum HDAC-inhibitors show high potency against Plasmodium falciparum, but displayed some toxicity towards human cells. Inhibitors of human HDAC6 are new drug candidates with supposed reduced toxicity to human cells and favorable activities against laboratory P. falciparum strains. We investigated the potency of 12 peptoid-based HDAC-inhibitors against asexual stages of P. falciparum clinical isolates. Parasites representing different genetic backgrounds were isolated from adults and children with uncomplicated malaria in Gabon. Clinical studies on (non-HDAC-inhibitors) antimalarials, moreover, found lower drug efficacy in children, mainly attributed to acquired immunity with age in endemic areas. Therefore, we compared the in vitro sensitivity profiles of adult- and child-derived isolates to antimalarials (HDAC and standard drugs). All HDAC-inhibitors showed 50% inhibitory concentrations at nanomolar ranges with higher activities than the FDA approved reference HDAC-inhibitor SAHA. We propose peptoid-based HDAC6-inhibitors to be lead structures for further development as antimalarial chemotherapeutics. Our results further suggest no differences in activity of the tested antimalarials between P. falciparum parasites isolated from children and adults.

scholarly journals Design, Synthesis, and Biological Evaluation of Dual c-Met/HDAC Inhibitors Bearing 2-Aminopyrimidine Scaffold

2020 ◽  
Vol 02 (03) ◽  
pp. e143-e149
Author(s):  
Qingwei Zhang ◽  
Guili Xu ◽  
Ya Bao ◽  
Minru Jiao ◽  
Jianqi Li
Keyword(s):  
Histone Deacetylase ◽  
Cell Lines ◽  
Hdac Inhibitors ◽  
Biological Evaluation ◽  
Antitumor Drugs ◽  
Design Synthesis ◽  
Ic50 Values ◽  
Hct 116 ◽  
Synthesis And Biological Evaluation ◽  
Antiproliferative Activities

AbstractA series of c-Met/histone deacetylase (HDAC) bifunctional inhibitors was designed and synthesized by merging pharmacophores of c-Met and HDAC inhibitors. Among them, the most potent compound, 2o, inhibited c-Met kinase and HDACs, with IC50 values of 9.0 and 31.6 nM, respectively, and showed efficient antiproliferative activities against both A549 and HCT-116 cancer cell lines with greater potency than an equimolar mixture of the respective inhibitors of the two enzymes: crizotinib and vorinostat (SAHA). Our study provided an efficient strategy for the discovery of multitargeted antitumor drugs.

scholarly journals Histone Deacetylase Inhibitors and Antioxidants From the Root of Gluta usitata

2019 ◽  
Vol 14 (12) ◽  
pp. 1934578X1989537
Author(s):  
Pakit Kumboonma ◽  
Somprasong Saenglee ◽  
Thanaset Senawong ◽  
Chanokbhorn Phaosiri
Keyword(s):  
Molecular Docking ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Antioxidant Activities ◽  
Hdac Inhibitors ◽  
Docking Studies ◽  
Resonance Spectroscopy ◽  
In Vitro Experiments ◽  
Magnetic Resonance Spectroscopy Data

A new glycoside, glutacoside (1), as well as 6 known compounds was isolated and identified from the root of Gluta usitata. Their structures were determined by Infrared spectroscopy, Mass spectroscopy, and 1-Dimensional and 2-dimensional nuclear magnetic resonance spectroscopy data. The histone deacetylase (HDAC) inhibitory and antioxidant activities of the obtained compounds were evaluated. Molecular docking experiments of the selected compound with representatives of class I (HDAC2 and HDAC8) and class II (HDAC4 and HDAC7) HDAC isoforms displayed potential isoform-selective HDAC inhibitors. Molecular docking data showed consistent results to the in vitro experiments with the highest potency against HDAC8. The docking studies suggested that the phenolic and carbonyl group can be favorably accommodated at the gorge region of the binding site. Furthermore, the phenolic groups also acted as major roles for antioxidant activities.

scholarly journals Design, Synthesis, and Biological Evaluation of Dual c-Met/HDAC Inhibitors Bearing 2-Aminopyrimidine Scaffold

2020 ◽  
Vol 02 (02) ◽  
pp. e117-e123
Author(s):  
Qingwei Zhang ◽  
Guili Xu ◽  
Ya Bao ◽  
Minru Jiao ◽  
Jianqi Li
Keyword(s):  
Histone Deacetylase ◽  
Cell Lines ◽  
Hdac Inhibitors ◽  
Biological Evaluation ◽  
Antitumor Drugs ◽  
Design Synthesis ◽  
Ic50 Values ◽  
Hct 116 ◽  
Synthesis And Biological Evaluation ◽  
Antiproliferative Activities

AbstractA series of c-Met/histone deacetylase (HDAC) bifunctional inhibitors was designed and synthesized by merging pharmacophores of c-Met and HDAC inhibitors. Among them, the most potent compound, 2o, inhibited c-Met kinase and HDACs, with IC50 values of 9.0 and 31.6 nM, respectively, and showed efficient antiproliferative activities against both A549 and HCT-116 cancer cell lines with greater potency than an equimolar mixture of the respective inhibitors of the two enzymes: crizotinib and vorinostat (SAHA). Our study provided an efficient strategy for the discovery of multitargeted antitumor drugs.

scholarly journals Improved development of mouse SCNT embryos by chlamydocin analogues, class I and IIa histone deacetylase inhibitors†

2021 ◽  
Author(s):  
Satoshi Kamimura ◽  
Kimiko Inoue ◽  
Eiji Mizutani ◽  
Jin-Moon Kim ◽  
Hiroki Inoue ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Trichostatin A ◽  
Hdac Inhibitors ◽  
Class I ◽  
Cell Stage ◽  
Inhibitory Spectrum ◽  
Developmental Block

Abstract In mammalian cloning by somatic cell nuclear transfer (SCNT), treatment of reconstructed embryos with histone deacetylase (HDAC) inhibitors improves efficiency. So far, most of those used for SCNT are hydroxamic acid derivatives—such as trichostatin A—characterized by their broad inhibitory spectrum. Here, we examined whether mouse SCNT efficiency could be improved using chlamydocin analogues, a family of newly designed agents that specifically inhibit Class I and IIa HDACs. Development of SCNT-derived embryos in vitro and in vivo revealed that four out of five chlamydocin analogues tested could promote the development of cloned embryos. The highest pup rates (7.1 to 7.2%) were obtained with Ky-9, similar to those achieved with trichostatin A (7.2 to 7.3%). Thus, inhibition of Class I and/or IIa HDACs in SCNT-derived embryos is enough for significant improvements in full-term development. In mouse SCNT, the exposure of reconstructed oocytes to HDAC inhibitors is limited to 8–10 h because longer inhibition with Class I inhibitors causes a 2-cell developmental block. Therefore, we used Ky-29, with higher selectivity for Class IIa than Class I HDACs for longer treatment of SCNT-derived embryos. As expected, 24-h treatment with Ky-29 up to the 2-cell stage did not induce a developmental block, but the pup rate was not improved. This suggests that the 1-cell stage is a critical period for improving SCNT cloning using HDAC inhibitors. Thus, chlamydocin analogues appear promising for understanding and improving the epigenetic status of mammalian SCNT-derived embryos through their specific inhibitory effects on HDACs.

scholarly journals Design and Synthesis of New Quinoxaline Derivatives as Potential Histone Deacetylase Inhibitors Targeting Hepatocellular Carcinoma: In Silico, In Vitro, and SAR Studies

2021 ◽  
Vol 9 ◽  
Author(s):  
Chao Ma ◽  
Mohammed S. Taghour ◽  
Amany Belal ◽  
Ahmed B. M. Mehany ◽  
Naglaa Mostafa ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Cell Lines ◽  
In Silico ◽  
Histone Deacetylase Inhibitors ◽  
Hdac Inhibitors ◽  
Binding Mode ◽  
Cytotoxic Activities ◽  
Reference Drug ◽  
The Future

Guided by the structural optimization principle and the promising anticancer effect of the quinoxaline nucleus, a new series of novel HDAC inhibitors were designed and synthesized. The synthesized compounds were designed to bear the reported pharmacophoric features of the HDAC inhibitors in addition to an extra moiety to occupy the non-used vacant deep pocket of the HDAC receptor. The newly prepared compounds were evaluated for their in vitro anti-proliferative activities against HepG-2 and HuH-7 liver cancer cell lines. The tested compounds showed promising anti-proliferative activities against both cell lines. The most active ten candidates (6c, 6d, 6f, 6g, 6k, 6l, 7b, 8, 10h, and 12) were further evaluated for their effect on the gene expression levels of Bax as an apoptotic marker and Bcl-2 as an anti-apoptotic one. Moreover, they were evaluated for their ability to inhibit histone deacetylase (HDAC1, HDAC4, and HDAC6) activities. Compound 6c achieved the best cytotoxic activities on both HepG-2 and HuH-7 cell lines with IC50 values of 1.53 and 3.06 µM, respectively, and also it showed the most inhibitory activities on HDAC1, HDAC4, and HDAC6 with IC50 values of 1.76, 1.39, and 3.46 µM, respectively, compared to suberoylanilide hydroxamic acid (SAHA) as a reference drug (IC50 = 0.86, 0.97, and 0.93 µM, respectively). Furthermore, it achieved a more characteristic arrest in the growth of cell population of HepG-2 at both G0/G1 and S phases with 1.23-, and 1.18-fold, respectively, compared to that of the control, as determined by cell cycle analysis. Also, compound 6c showed a marked elevation in the AnxV-FITC apoptotic HepG-2 cells percentage in both early and late phases increasing the total apoptosis percentage by 9.98-, and 10.81-fold, respectively, compared to the control. Furthermore, docking studies were carried out to identify the proposed binding mode of the synthesized compounds towards the prospective target (HDAC4). In silico ADMET and toxicity studies revealed that most of the synthesized compounds have accepted profiles of drug-likeness with low toxicity. Finally, an interesting SAR analysis was concluded to help the future design of more potent HDACIs in the future by medicinal chemists.

Design, synthesis and in vitro evaluation of amidoximes as histone deacetylase inhibitors for cancer therapy

2016 ◽  
Vol 26 (19) ◽  
pp. 4679-4683 ◽  
Author(s):  
Peifu Jiao ◽  
Peng Jin ◽  
Chencan Li ◽  
Lechao Cui ◽  
Lihua Dong ◽  
...  
Keyword(s):  
Cancer Therapy ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Design Synthesis ◽  
In Vitro Evaluation

scholarly journals Design, Synthesis and Biological Evaluation of Novel Coumarin-Based Hydroxamate Derivatives as Histone Deacetylase (Hdac) Inhibitors with Antitumor Activities

Molecules ◽  
2019 ◽  
Vol 24 (14) ◽  
pp. 2569 ◽  
Author(s):  
Feifei Yang ◽  
Na Zhao ◽  
Jiali Song ◽  
Kongkai Zhu ◽  
Cheng-shi Jiang ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Hdac Inhibitors ◽  
A549 Cells ◽  
Docking Studies ◽  
Biological Evaluation ◽  
Hdac Inhibition ◽  
Design Synthesis ◽  
M Phase ◽  
Ic50 Values

A series of novel coumarin-based hydroxamate derivatives were designed and synthesized as histone deacetylase inhibitors (HDACis). Selective compounds showed a potent HDAC inhibition with nM IC50 values, with the best compound (10e) being nearly 90 times more active than vorinostat (SAHA) against HDAC1. Compounds 10e and 11d also increased the levels of acetylated histone H3 and H4, which is consistent with their strong HDAC inhibition. In addition, 10e and 11d displayed a higher potency toward human A549 and Hela cancer cell lines compared with SAHA. Moreover, 10e and 11d significantly arrested A549 cells at the G2/M phase and enhanced apoptosis. Molecular docking studies revealed the possible mode of interaction of compounds 10e and 12a with HDAC1. Our findings suggest that these novel coumarin-based HDAC inhibitors provide a promising scaffold for the development of new potential cancer chemotherapies.

scholarly journals Design, synthesis, molecular docking, and in vitro α-glucosidase inhibitory activities of novel 3-amino-2,4-diarylbenzo[4,5]imidazo[1,2-a]pyrimidines against yeast and rat α-glucosidase

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Fariba Peytam ◽  
Ghazaleh Takalloobanafshi ◽  
Toktam Saadattalab ◽  
Maryam Norouzbahari ◽  
Zahra Emamgholipour ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Docking Study ◽  
Rat Small Intestine ◽  
Molecular Docking Study ◽  
Design Synthesis ◽  
Mild Conditions ◽  
Glucosidase Inhibitors ◽  
Inhibitory Activities

AbstractIn an attempt to find novel, potent α-glucosidase inhibitors, a library of poly-substituted 3-amino-2,4-diarylbenzo[4,5]imidazo[1,2-a]pyrimidines 3a–ag have been synthesized through heating a mixture of 2-aminobenzimidazoles 1 and α-azidochalcone 2 under the mild conditions. This efficient, facile protocol has been resulted into the desirable compounds with a wide substrate scope in good to excellent yields. Afterwards, their inhibitory activities against yeast α-glucosidase enzyme were investigated. Showing IC50 values ranging from 16.4 ± 0.36 µM to 297.0 ± 1.2 µM confirmed their excellent potency to inhibit α-glucosidase which encouraged us to perform further studies on α-glucosidase enzymes obtained from rat as a mammal source. Among various synthesized 3-amino-2,4-diarylbenzo[4,5]imidazo[1,2-a]pyrimidines, compound 3k exhibited the highest potency against both Saccharomyces cerevisiae α-glucosidase (IC50 = 16.4 ± 0.36 μM) and rat small intestine α-glucosidase (IC50 = 45.0 ± 8.2 μM). Moreover, the role of amine moiety on the observed activity was studied through substituting with chlorine and hydrogen resulted into a considerable deterioration on the inhibitory activity. Kinetic study and molecular docking study have confirmed the in-vitro results.

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