Synthesis and biological evaluation of thiophene-based hydroxamate derivatives as HDACis with antitumor activities

2020 ◽  
Vol 12 (8) ◽  
pp. 655-672 ◽  
Author(s):  
Feifei Yang ◽  
Lina Han ◽  
Na Zhao ◽  
Yang Yang ◽  
Di Ge ◽  
...  
Keyword(s):  
Anticancer Agents ◽  
Histone Deacetylases ◽  
Hdac Inhibitors ◽  
Xenograft Model ◽  
Biological Evaluation ◽  
Anticancer Activities ◽  
Antitumor Activities ◽  
Cancer Treatments

Aim:   Histone deacetylases (HDACs) are one of the validated targets for cancer treatments. In our previous work, we designed a series of bis-substituted aromatic amide HDAC inhibitors (HDACis), among which compounds 7 and 8 showed promising anticancer effects. However, the low solubilities prevented their subsequent developments. We developed additional thiophene-based hydroxamate HDACis in order to improve their physicochemical properties. Materials & methods: In vitro biological evaluations of these analogs revealed potent antiproliferative and antimigrated activities. More importantly, compound 10h exhibited excellent in vivo antitumor activities in MDA-MB-231 xenograft model mice. Furthermore, 10h showed better anticancer activities and drug-like properties than 7. Results & conclusion: Our results proved that thiophene-based hydroxamate HDACis can serve as a promising framework for developing potential anticancer agents.

scholarly journals Upregulation of ERK-EGR1-heparanase axis by HDAC inhibitors provides targets for rational therapeutic intervention in synovial sarcoma

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Cinzia Lanzi ◽  
Enrica Favini ◽  
Laura Dal Bo ◽  
Monica Tortoreto ◽  
Noemi Arrighetti ◽  
...  
Keyword(s):  
Synovial Sarcoma ◽  
Cell Response ◽  
Histone Deacetylases ◽  
Molecular Mechanisms ◽  
Combined Treatment ◽  
Single Agent ◽  
Hdac Inhibitors ◽  
Xenograft Model

Abstract Background Synovial sarcoma (SS) is an aggressive soft tissue tumor with limited therapeutic options in advanced stage. SS18-SSX fusion oncogenes, which are the hallmarks of SS, cause epigenetic rewiring involving histone deacetylases (HDACs). Promising preclinical studies supporting HDAC targeting for SS treatment were not reflected in clinical trials with HDAC inhibitor (HDACi) monotherapies. We investigated pathways implicated in SS cell response to HDACi to identify vulnerabilities exploitable in combination treatments and improve the therapeutic efficacy of HDACi-based regimens. Methods Antiproliferative and proapoptotic effects of the HDACi SAHA and FK228 were examined in SS cell lines in parallel with biochemical and molecular analyses to bring out cytoprotective pathways. Treatments combining HDACi with drugs targeting HDACi-activated prosurvival pathways were tested in functional assays in vitro and in a SS orthotopic xenograft model. Molecular mechanisms underlying synergisms were investigated in SS cells through pharmacological and gene silencing approaches and validated by qRT-PCR and Western blotting. Results SS cell response to HDACi was consistently characterized by activation of a cytoprotective and auto-sustaining axis involving ERKs, EGR1, and the β-endoglycosidase heparanase, a well recognized pleiotropic player in tumorigenesis and disease progression. HDAC inhibition was shown to upregulate heparanase by inducing expression of the positive regulator EGR1 and by hampering negative regulation by p53 through its acetylation. Interception of HDACi-induced ERK-EGR1-heparanase pathway by cell co-treatment with a MEK inhibitor (trametinib) or a heparanase inhibitor (SST0001/roneparstat) enhanced antiproliferative and pro-apoptotic effects. HDAC and heparanase inhibitors had opposite effects on histone acetylation and nuclear heparanase levels. The combination of SAHA with SST0001 prevented the upregulation of ERK-EGR1-heparanase induced by the HDACi and promoted caspase-dependent cell death. In vivo, the combined treatment with SAHA and SST0001 potentiated the antitumor efficacy against the CME-1 orthotopic SS model as compared to single agent administration. Conclusions The present study provides preclinical rationale and mechanistic insights into drug combinatory strategies based on the use of ERK pathway and heparanase inhibitors to improve the efficacy of HDACi-based antitumor therapies in SS. The involvement of classes of agents already clinically available, or under clinical evaluation, indicates the transferability potential of the proposed approaches.

scholarly journals NBM-HD-1: A Novel Histone Deacetylase Inhibitor with Anticancer Activity

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Wei-Jan Huang ◽  
Yu-Chih Liang ◽  
Shuang-En Chuang ◽  
Li-Ling Chi ◽  
Chi-Yun Lee ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
Cancer Cells ◽  
Anticancer Agents ◽  
Xenograft Model ◽  
Cyclin B1 ◽  
Dependent Manner ◽  
Cell Cycle Regulators ◽  
Anticancer Activities ◽  
Gene Expressions

HDAC inhibitors (HDACis) have been developed as promising anticancer agents in recent years. In this study, we synthesized and characterized a novel HDACi, termed NBM-HD-1. This agent was derived from the semisynthesis of propolin G, isolated from Taiwanese green propolis (TGP), and was shown to be a potent suppressor of tumor cell growth in human breast cancer cells (MCF-7 and MDA-MB-231) and rat glioma cells (C6), with an IC50ranging from 8.5 to 10.3 μM. Western blot demonstrated that levels of p21(Waf1/Cip1), gelsolin, Ac-histone 4, and Ac-tubulin markedly increased after treatment of cancer cells with NBM-HD-1. After NBM-HD-1 treatment for 1–4 h, p-PTEN and p-AKT levels were markedly decreased. Furthermore, we also found the anticancer activities of NBM-HD-1 in regulating cell cycle regulators. Treatment with NBM-HD-1,p21(Waf1/Cip1)gene expression had markedly increased whilecyclin B1andD1gene expressions had markedly decreased. On the other hand, we found that NBM-HD-1 increased the expressions of tumor-suppressor genep53in a dose-dependent manner. Finally, we showed that NBM-HD-1 exhibited potent antitumor activity in a xenograft model. In conclusion, this study demonstrated that this compound, NBM-HD-1, is a novel and potent HDACi with anticancer activityin vitroandin vivo.

scholarly journals Inhibition of EZH2 by chidamide exerts antileukemia activity and increases chemosensitivity through Smo/Gli-1 pathway in acute myeloid leukemia

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Xuejie Jiang ◽  
Ling Jiang ◽  
Jiaying Cheng ◽  
Fang Chen ◽  
Jinle Ni ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Histone Deacetylases ◽  
Myeloid Leukemia ◽  
Hdac Inhibitors ◽  
Annexin V ◽  
Fluorescein Isothiocyanate ◽  
Gli 1 ◽  
Acute Myeloid

Abstract Background Epigenetic dysregulation plays important roles in leukemogenesis and the progression of acute myeloid leukemia (AML). Histone acetyltransferases (HATs) and histone deacetylases (HDACs) reciprocally regulate the acetylation and deacetylation of nuclear histones. Aberrant activation of HDACs results in uncontrolled proliferation and blockade of differentiation, and HDAC inhibition has been investigated as epigenetic therapeutic strategy against AML. Methods Cell growth was assessed with CCK-8 assay, and apoptosis was evaluated by flow cytometry in AML cell lines and CD45 + and CD34 + CD38- cells from patient samples after staining with Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI). EZH2 was silenced with short hairpin RNA (shRNA) or overexpressed by lentiviral transfection. Changes in signaling pathways were detected by western blotting. The effect of chidamide or EZH2-specific shRNA (shEZH2) in combination with adriamycin was studied in vivo in leukemia-bearing nude mouse models. Results In this study, we investigated the antileukemia effects of HDAC inhibitor chidamide and its combinatorial activity with cytotoxic agent adriamycin in AML cells. We demonstrated that chidamide suppressed the levels of EZH2, H3K27me3 and DNMT3A, exerted potential antileukemia activity and increased the sensitivity to adriamycin through disruption of Smo/Gli-1 pathway and downstream signaling target p-AKT in AML cells and stem/progenitor cells. In addition to decreasing the levels of H3K27me3 and DNMT3A, inhibition of EZH2 either pharmacologically by chidamide or genetically by shEZH2 suppressed the activity of Smo/Gli-1 pathway and increased the antileukemia activity of adriamycin against AML in vitro and in vivo. Conclusions Inhibition of EZH2 by chidamide has antileukemia activity and increases the chemosensitivity to adriamycin through Smo/Gli-1 pathway in AML cells (Fig. 5). These findings support the rational combination of HDAC inhibitors and chemotherapy for the treatment of AML.

A supramolecular adduct of tegafur and syringic acid: the first tegafur-nutraceutical cocrystal with perfected in vitro and in vivo characteristics as well as synergized anticancer activities

2020 ◽  
Vol 44 (37) ◽  
pp. 15994-16005
Author(s):  
Yue-Ming Yu ◽  
Ming-Chao Yu ◽  
Ling-Yang Wang ◽  
Yan-Tuan Li ◽  
Zhi-Yong Wu ◽  
...  
Keyword(s):  
Syringic Acid ◽  
Anticancer Activities ◽  
Antitumor Activities ◽  
Supramolecular Adduct

The in vitro and in vivo properties as well as synergistic antitumor activities of the first tegafur-nutraceutical cocrystal are reported.

scholarly journals Synthesis and biological evaluation of novel benzo[b]xanthone derivatives as potential antitumor agents

2013 ◽  
Vol 78 (9) ◽  
pp. 1301-1308 ◽  
Author(s):  
Lin Luo ◽  
Jiang-Ke Qin ◽  
Zhi-Kai Dai ◽  
Shi-Hua Gao
Keyword(s):  
Cell Lines ◽  
Antitumor Agents ◽  
Biological Evaluation ◽  
Structural Factors ◽  
Anticancer Activities ◽  
Antitumor Activities ◽  
Mtt Method ◽  
Human Solid Tumor ◽  
Synthesis And Biological Evaluation

Nine novel aminoalkoxy substituted benzoxanthones (3a-3i) were synthesized. Their antitumor activities were evaluated in five human solid tumor cell lines including Hep-G2, BEL-7402, HeLa, MGC-803 and CNE by MTT method. The results showed that most of the compounds displayed moderate to good inhibitory activities on the tested cancer cell lines in vitro, among them compounds 3a and 3h showed higher antitumor activity than other tested compounds against most cell lines. The influence of two kinds of structural factors including the terminal amino group and length of carbon spacers on the anticancer activities were explored to discuss the preliminary structure-activity relationships.

scholarly journals Design, synthesis and biological evaluation of a series of CNS penetrant HDAC inhibitors structurally derived from amyloid-β probes

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Myeong A Choi ◽  
Sun You Park ◽  
Hye Yun Chae ◽  
Yoojin Song ◽  
Chiranjeev Sharma ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Hdac Inhibitors ◽  
Amyloid Β ◽  
Biological Evaluation ◽  
Pharmacokinetic Studies ◽  
Dependent Manner ◽  
Reference Drug ◽  
Novel Scaffold

Abstract To develop novel CNS penetrant HDAC inhibitors, a new series of HDAC inhibitors having benzoheterocycle were designed, synthesized, and biologically evaluated. Among the synthesized compounds, benzothiazole derivative 9b exhibited a remarkable anti-proliferative activity (GI50 = 2.01 μM) against SH-SY5Y cancer cell line in a dose and time-dependent manner, better than the reference drug SAHA (GI50 = 2.90 μM). Moreover, compound 9b effectively promoted the accumulation of acetylated Histone H3 and α-tubulin through inhibition of HDAC1 and HDAC6 enzymes, respectively. HDAC enzyme assay also confirmed that compound 9b efficiently inhibited HDAC1 and HDAC6 isoforms with IC50 values of 84.9 nM and 95.9 nM. Furthermore, compound 9b inhibited colony formation capacity of SH-SY5Y cells, which is considered a hallmark of cell carcinogenesis and metastatic potential. The theoretical prediction, in vitro PAMPA-BBB assay, and in vivo brain pharmacokinetic studies confirmed that compound 9b had much higher BBB permeability than SAHA. In silico docking study demonstrated that compound 9b fitted in the substrate binding pocket of HDAC1 and HDAC6. Taken together, compound 9b provided a novel scaffold for developing CNS penetrant HDAC inhibitors and therapeutic potential for CNS-related diseases.

scholarly journals Synthesis, in vitro and in vivo biological evaluation of substituted 3-(5-imidazo[2,1-b]thiazolylmethylene)-2-indolinones as new potent anticancer agents

2019 ◽  
Vol 166 ◽  
pp. 514-530 ◽  
Author(s):  
Rita Morigi ◽  
Alessandra Locatelli ◽  
Alberto Leoni ◽  
Mirella Rambaldi ◽  
Roberta Bortolozzi ◽  
...  
Keyword(s):  
Anticancer Agents ◽  
Biological Evaluation

scholarly journals Targeting Histone Deacetylases: A Novel Approach in Parkinson’s Disease

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Sorabh Sharma ◽  
Rajeev Taliyan
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Transcriptional Activation ◽  
Histone Deacetylases ◽  
Therapeutic Potential ◽  
Hdac Inhibitors ◽  
Clinical Manifestations ◽  
Future Research

The worldwide prevalence of movement disorders is increasing day by day. Parkinson’s disease (PD) is the most common movement disorder. In general, the clinical manifestations of PD result from dysfunction of the basal ganglia. Although the exact underlying mechanisms leading to neural cell death in this disease remains unknown, the genetic causes are often established. Indeed, it is becoming increasingly evident that chromatin acetylation status can be impaired during the neurological disease conditions. The acetylation and deacetylation of histone proteins are carried out by opposing actions of histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively. In the recent past, studies with HDAC inhibitors result in beneficial effects in bothin vivoandin vitromodels of PD. Various clinical trials have also been initiated to investigate the possible therapeutic potential of HDAC inhibitors in patients suffering from PD. The possible mechanisms assigned for these neuroprotective actions of HDAC inhibitors involve transcriptional activation of neuronal survival genes and maintenance of histone acetylation homeostasis, both of which have been shown to be dysregulated in PD. In this review, the authors have discussed the putative role of HDAC inhibitors in PD and associated abnormalities and suggest new directions for future research in PD.

scholarly journals Structure-based analysis of a natural GOT1-inhibitor Aspulvinone H arrests pancreatic ductal adenocarcinoma cells growth

2021 ◽  
Author(s):  
Zhang Yonghui ◽  
Shan Yan ◽  
Wei Song ◽  
Qianqian Xu ◽  
Changxing Qi ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Anticancer Agents ◽  
Active Sites ◽  
Redox Homeostasis ◽  
Xenograft Model ◽  
Glutamine Metabolism ◽  
Ductal Adenocarcinoma ◽  
Biological Study

Pancreatic ductal adenocarcinoma (PDAC) cells are Gln-metabolism dependence, which can preferentially utilize glutamic oxaloacetate transaminase 1 (GOT1) to maintain the redox homeostasis of cancer cells. Therefore, small molecule inhibitors targeting GOT1 can be used as a new strategy for developing cancer therapies. Here, we identified a cyclobutyrolactone lignan, Aspulvinone H (AH), showing significant GOT1 inhibitory activity in vitro. The complex crystal structure of GOT1-AH elucidated the molecular mechanism, which AH and the cofactor pyrido-aldehyde 5-phosphate (PLP) competitively bound to the active sites of GOT1. Structure-activity relationship (SAR) analysis exhibited that the π-π stacking and isopentenyl side chain of aspulvinone were related to the inhibition of GOT1 activity. Further biological study indicated that AH could suppress glutamine metabolism, which made PDAC cells sensitive to oxidative stress and inhibited cell proliferation. Besides, AH exhibited potent in vivo antitumor activity in the SW1990 cell-induced xenograft model. These findings suggest that AH could be considered as a promising lead molecule for the development of PDAC anticancer agents.

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