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Sample records for inhibitor suberoylanilide hydroxamic

  1. Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, attenuates postoperative cognitive dysfunction in aging mice

    PubMed Central

    Jia, Min; Liu, Wen-Xue; Sun, He-Liang; Chang, Yan-Qing; Yang, Jiao-Jiao; Ji, Mu-Huo; Yang, Jian-Jun; Feng, Chen-Zhuo

    2015-01-01

    Postoperative cognitive dysfunction (POCD) is a recognized clinical entity characterized with cognitive deficits after anesthesia and surgery, especially in aged patients. Previous studies have shown that histone acetylation plays a key role in hippocampal synaptic plasticity and memory formation. However, its role in POCD remains to be determined. Here, we show that suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, attenuates POCD in aging Mice. After exposed to the laparotomy, a surgical procedure involving an incision into abdominal walls to examine the abdominal organs, 16- but not 3-month old male C57BL/6 mice developed obvious cognitive impairments in the test of long-term contextual fear conditioning. Intracerebroventricular (i.c.v.) injection of SAHA at the dose of (20 μg/2 μl) 3 h before and daily after the laparotomy restored the laparotomy-induced reduction of hippocampal acetyl-H3 and acetyl-H4 levels and significantly attenuated the hippocampus-dependent long-term memory (LTM) impairments in 16-month old mice. SAHA also reduced the expression of cleaved caspase-3, inducible nitric oxide synthase (iNOS) and N-methyl-D-aspartate (NMDA) receptor-calcium/calmodulin dependent kinase II (CaMKII) pathway, and increased the expression of brain-derived neurotrophic factor (BDNF), synapsin 1, and postsynaptic density 95 (PSD95). Taken together, our data suggest that the decrease of histone acetylation contributes to POCD and may serve as a target to improve the neurological outcome of POCD. PMID:26441515

  2. The Histone Deacetylase Inhibitor Suberoylanilide Hydroxamic Acid (SAHA) Confers Acute Neuroprotection After Intracerebral Hemorrhage in Mice.

    PubMed

    Sukumari-Ramesh, Sangeetha; Alleyne, Cargill H; Dhandapani, Krishnan M

    2016-04-01

    Spontaneous intracerebral hemorrhage (ICH) is a stroke subtype with no effective treatment. Though ICH is known to induce severe neurological damage, the molecular mechanisms of neurological injury after ICH remain largely unclear. Given the emerging role of epigenetic mechanisms in neurodegeneration, the present study evaluated whether suberoylanilide hydroxamic acid (SAHA: vorinostat), a clinically well-tolerated pan-histone deacetylase inhibitor (HDACi), would attenuate neurological injury and improve functional outcomes in a preclinical model of ICH. Mice were administered with SAHA or vehicle after an induction of ICH and acute neuronal death, glial activation, and neurological outcomes were assessed. SAHA-treated mice exhibited less neurodegeneration with concomitant improvement in neurological outcomes than vehicle-treated mice. Furthermore, SAHA downregulated glial activation and the expression of heme oxygenase-1, a stress-inducible enzyme that plays critical roles in neurological damage after ICH. Altogether, the data strongly suggest the role of epigenetic mechanisms in inducing neurological injury after ICH and raise the possible clinical utility of SAHA for therapeutic intervention after ICH. PMID:26338677

  3. The histone deacetylase inhibitor suberoylanilide hydroxamic acid induces apoptosis, down-regulates the CXCR4 chemokine receptor and impairs migration of chronic lymphocytic leukemia cells

    PubMed Central

    Stamatopoulos, Basile; Meuleman, Nathalie; De Bruyn, Cécile; Delforge, Alain; Bron, Dominique; Lagneaux, Laurence

    2010-01-01

    Background Chronic lymphocytic leukemia is a neoplastic disorder that arises largely as a result of defective apoptosis leading to chemoresistance. Stromal cell-derived factor-1 and its receptor, CXCR4, have been shown to play an important role in chronic lymphocytic leukemia cell trafficking and survival. Design and Methods Since histone acetylation is involved in the modulation of gene expression, we evaluated the effects of suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, on chronic lymphocytic leukemia cells and in particular on cell survival, CXCR4 expression, migration, and drug sensitization. Results Here, we showed that treatment with suberoylanilide hydroxamic acid (20 μM) for 48 hours induced a decrease in chronic lymphocytic leukemia cell viability via apoptosis (n=20, P=0.0032). Using specific caspase inhibitors, we demonstrated the participation of caspases-3, -6 and -8, suggesting an activation of the extrinsic pathway. Additionally, suberoylanilide hydroxamic acid significantly decreased CXCR4 mRNA (n=10, P=0.0010) and protein expression (n=40, P<0.0001). As a result, chronic lymphocytic leukemia cell migration in response to stromal cell-derived factor-1 (n=23, P<0.0001) or through bone marrow stromal cells was dramatically impaired. Consequently, suberoylanilide hydroxamic acid reduced the protective effect of the microenvironment and thus sensitized chronic lymphocytic leukemia cells to chemotherapy such as fludarabine. Conclusions In conclusion, suberoylanilide hydroxamic acid induces apoptosis in chronic lymphocytic leukemia cells via the extrinsic pathway and down-regulates CXCR4 expression leading to decreased cell migration. Suberoylanilide hydroxamic acid in combination with other drugs represents a promising therapeutic approach to inhibiting migration, chronic lymphocytic leukemia cell survival and potentially overcoming drug resistance. PMID:20145270

  4. In silico modification of suberoylanilide hydroxamic acid (SAHA) as potential inhibitor for class II histone deacetylase (HDAC)

    PubMed Central

    2011-01-01

    Background The cervical cancer is the second most prevalent cancer for the woman in the world. It is caused by the oncogenic human papilloma virus (HPV). The inhibition activity of histone deacetylase (HDAC) is a potential strategy for cancer therapy. Suberoylanilide hydroxamic acid (SAHA) is widely known as a low toxicity HDAC inhibitor. This research presents in silico SAHA modification by utilizing triazole, in order to obtain a better inhibitor. We conducted docking of the SAHA inhibitor and 12 modified versions to six class II HDAC enzymes, and then proceeded with drug scanning of each one of them. Results The docking results show that the 12 modified inhibitors have much better binding affinity and inhibition potential than SAHA. Based on drug scan analysis, six of the modified inhibitors have robust pharmacological attributes, as revealed by drug likeness, drug score, oral bioavailability, and toxicity levels. Conclusions The binding affinity, free energy and drug scan screening of the best inhibitors have shown that 1c and 2c modified inhibitors are the best ones to inhibit class II HDAC. PMID:22373132

  5. Suppression of IL-12p40-related regulatory cytokines by suberoylanilide hydroxamic acid an inhibitor of histone deacetylases.

    PubMed

    Dobreva, Zlatka Georgieva; Grigorov, Boncho Grigorov; Stanilova, Spaska Angelova

    2016-08-01

    Small molecule inhibitors of histone deacetylases (HDACs) are a new class drugs used in clinical trials for the treatment of various malignancies. Emerging evidence suggest that HDAC inhibitors may also have anti-inflammatory properties, although the molecular mechanisms remain poorly defined. Our study investigates the effect of the HDACs inhibitor suberoylanilide hydroxamic acid (SAHA) on the expression of IL-12p40-related cytokines. For this purpose, human peripheral blood mononuclear cells (PBMC) were stimulated with LPS and C3bgp with or without SAHA. IL-12p40, IL-12p35 and IL-23p19 mRNA was determined at 6 h by qRT-PCR. Cytokine levels were determined in culture supernatants at 6 and 24 h, by ELISA. SAHA significantly inhibited IL-12p40 and IL-23p19 mRNA synthesis and did not change IL-12p35 mRNA transcription. Early at 6 h, we detected significantly decreased IL-12p40 and IL-23, but not IL-12p70 protein production in cultures treated with SAHA. Results also showed that the suppression of IL-12p40-related cytokines was clearly defined at 24 h. However, this suppression was less pronounced regarding IL-12p70. The present study showed that SAHA suppressed the gene expression of IL-23p19 stronger than the expression of IL-12p35, as well as the synthesis of IL-23 compared to that of IL-12p70. We suggest that this inhibitory effect of SAHA may be beneficial during treatment of inflammatory and autoimmune diseases mediated by Th17 immune response. PMID:27240992

  6. Synthesis, Biological Evaluation, and Computer-Aided Drug Designing of New Derivatives of Hyperactive Suberoylanilide Hydroxamic Acid Histone Deacetylase Inhibitors.

    PubMed

    Zhang, Song; Huang, Weibin; Li, Xiaonan; Yang, Zhicheng; Feng, Binghong

    2015-10-01

    The synthesis and biological evaluation of a novel series of compounds based on suberoylanilide hydroxamic acid (SAHA) had been designed as potential histone deacetylase inhibitors (HDACis). Molecular docking studies indicated that our derivatives had better fitting in the binding sites of HDAC8 than SAHA. Compounds 1-5 were synthesized through the synthetic routes. In biological test, compounds also showed good inhibitory activity in HDAC enzyme assay and more potent growth inhibition in human glioma cell lines (MGR2, U251, and U373). A representative compound, N3F, exhibited better inhibitory effect (HDAC, IC50  = 0.1187 μm; U251, IC50  = 0.8949 μm) and lower toxicity for human normal cells (LO2, IC50  = 172.5 μm and MRC5, IC50  = 213.6 μm) compared with SAHA (HDAC, IC50  = 0.8717 μm; U251, IC50  = 8.938 μm; LO2, IC50  = 86.52 μm and MRC5, IC50  = 81.02 μm). In addition, N3F obviously increased Beclin-1 and Caspase-3 and 9 as well as inhibited Bcl-2 in U251 cells. All of our results indicated that these SAHA cap derivatives could serve as potential lead compounds for further optimization. In addition, N3F and N2E both displayed promising profile as antitumor candidates for the treatment of human glioma. PMID:25763653

  7. Suberoylanilide Hydroxamic Acid, an Inhibitor of Histone Deacetylase, Induces Apoptosis in Rheumatoid Arthritis Fibroblast-Like Synoviocytes.

    PubMed

    Chen, Hui; Pan, Jing; Wang, Jin-dan; Liao, Qiu-mei; Xia, Xiao-ru

    2016-02-01

    Here, we explored the effects of suberoylanilide hydroxamic acid (SAHA) on the viability and apoptosis of rheumatoid arthritis of fibroblast-like synoviocytes (rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS)). FLS obtained from RA patients were treated with SAHA. SAHA significantly inhibited the viability of RA FLS in a concentration-dependent manner up to 5 μM. SAHA-treated FLS showed a significant increase in the percentage of apoptosis and the expression and activity of caspase-3 and higher intracellular ROS levels. N-acetyl-l-cysteine (NAC) pretreatment significantly attenuated SAHA-induced apoptosis, decreasing the percentage of apoptosis by about 60 %. A significant decline in phosphorylated IκBα and nuclear factor kappa B (NF-κB) p65 and concomitant increase in total IκBα were shown in SAHA-treated FLS. Additionally, the levels of anti-apoptotic Bcl-2 proteins (Bcl-xL and Mcl-1) were significantly reduced by SAHA. Collectively, SAHA induces apoptosis of RA FLS, at least partially, through generation of ROS and suppression of NF-κB activation and Bcl-xL and Mcl-1 expression. PMID:26228975

  8. (7-Diethylaminocoumarin-4-yl)methyl ester of suberoylanilide hydroxamic acid as a caged inhibitor for photocontrol of histone deacetylase activity.

    PubMed

    Ieda, Naoya; Yamada, Sota; Kawaguchi, Mitsuyasu; Miyata, Naoki; Nakagawa, Hidehiko

    2016-06-15

    Histone deacetylases (HDACs) are involved in epigenetic control of the expression of various genes by catalyzing deacetylation of ε-acetylated lysine residues. Here, we report the design, synthesis and evaluation of the (7-diethylaminocoumarin-4-yl)methyl ester of suberoylanilide hydroxamic acid (AC-SAHA) as a caged HDAC inhibitor, which releases the known pan-HDAC inhibitor SAHA upon cleavage of the photolabile (7-diethylaminocoumarin-4-yl)methyl protecting group in response to photoirradiation. A key advantage of AC-SAHA is that the caged derivative itself shows essentially no HDAC-inhibitory activity. Upon photoirradiation, AC-SAHA decomposes to SAHA and a 7-diethylaminocoumarin derivative, together with some minor products. We confirmed that AC-SAHA inhibits HDAC in response to photoirradiation in vitro by means of chemiluminescence assay. AC-SAHA also showed photoinduced inhibition of proliferation of human colon cancer cell line HCT116, as determined by MTT assay. Thus, AC-SAHA should be a useful tool for spatiotemporally controlled inhibition of HDAC activity, as well as a candidate chemotherapeutic reagent for human colon cancer. PMID:27143132

  9. Mechanisms of suberoylanilide hydroxamic acid inhibition of mammary cell growth

    PubMed Central

    Said, Thenaa K; Moraes, Ricardo CB; Sinha, Raghu; Medina, Daniel

    2001-01-01

    The mechanism of suberoylanilide hydroxamic acid in cell growth inhibition involved induction of pRb-2/p130 interaction and nuclear translocation with E2F-4, followed by significant repression in E2F-1 and PCNA nuclear levels, which led to inhibition in DNA synthesis in mammary epithelial cell lines. PMID:11250759

  10. Redox-Mediated Suberoylanilide Hydroxamic Acid Sensitivity in Breast Cancer

    PubMed Central

    Chiaradonna, Ferdinando; Barozzi, Iros; Miccolo, Claudia; Bucci, Gabriele; Palorini, Roberta; Fornasari, Lorenzo; Botrugno, Oronza A.; Pruneri, Giancarlo; Masullo, Michele; Passafaro, Alfonso; Galimberti, Viviana E.; Fantin, Valeria R.; Richon, Victoria M.; Pece, Salvatore; Viale, Giuseppe; Di Fiore, Pier Paolo; Draetta, Giulio; Pelicci, Pier Giuseppe

    2015-01-01

    Abstract Aims: Vorinostat (suberoylanilide hydroxamic acid; SAHA) is a histone deacetylase inhibitor (HDACi) approved in the clinics for the treatment of T-cell lymphoma and with the potential to be effective also in breast cancer. We investigated the responsiveness to SAHA in human breast primary tumors and cancer cell lines. Results: We observed a differential response to drug treatment in both human breast primary tumors and cancer cell lines. Gene expression analysis of the breast cancer cell lines revealed that genes involved in cell adhesion and redox pathways, especially glutathione metabolism, were differentially expressed in the cell lines resistant to SAHA compared with the sensitive ones, indicating their possible association with drug resistance mechanisms. Notably, such an association was also observed in breast primary tumors. Indeed, addition of buthionine sulfoximine (BSO), a compound capable of depleting cellular glutathione, significantly enhanced the cytotoxicity of SAHA in both breast cancer cell lines and primary breast tumors. Innovation: We identify and validate transcriptional differences in genes involved in redox pathways, which include potential predictive markers of sensitivity to SAHA. Conclusion: In breast cancer, it could be relevant to evaluate the expression of antioxidant genes that may favor tumor resistance as a factor to consider for potential clinical application and treatment with epigenetic drugs (HDACis). Antioxid. Redox Signal. 23, 15–29. PMID:25897982

  11. Synergistic effects of combined treatment with histone deacetylase inhibitor suberoylanilide hydroxamic acid and TRAIL on human breast cancer cells

    PubMed Central

    Zhou, Weiqiang; Feng, Xiuyan; Han Han; Guo, Shanchun; Wang, Guangdi

    2016-01-01

    Previous studies showed that either histone deacetylase (HDAC) inhibitors or tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can induce apoptosis in tumor cells including breast cancer. However, the underling mechanisms of combining HDAC inhibitors with TRAIL in the treatment of breast cancer are poorly understood. In this study, we determined the ability of SAHA and TRAIL as single agents or in combination to inhibit the growth and survival of MCF-7 and MDA-MB-231 breast cancer cells. Our results demonstrate that the distinct effects of SAHA or TRAIL individually and in combination on the proliferation, cell viability, apoptosis, cell cycle distribution, and morphological changes of MDA-MB-231 and MCF-7 cells. We further determined the different effects of SAHA or TRAIL alone and combining SAHA with TRAIL on the expression of a number of apoptosis-related molecules, cell cycle, growth factors and their receptors in cancer cells. Our results demonstrated that the combinatorial treatment of SAHA and TRAIL may target multiple pathways and serve as an effective therapeutic strategy against breast cancer. An improved understanding of the molecular mechanisms may facilitate either SAHA or TRAIL targeted use and the selection of suitable combinations. PMID:27292433

  12. In silico modification of Zn2+ binding group of suberoylanilide hydroxamic acid (SAHA) by organoselenium compounds as Homo sapiens class II HDAC inhibitor of cervical cancer

    NASA Astrophysics Data System (ADS)

    Sumo Friend Tambunan, Usman; Bakri, Ridla; Aditya Parikesit, Arli; Ariyani, Titin; Dyah Puspitasari, Ratih; Kerami, Djati

    2016-02-01

    Cervical cancer is the most common cancer in women, and ranks seventh of all cancers worldwide, with 529000 cases in 2008 and more than 85% cases occur in developing countries. One way to treat this cancer is through the inhibition of HDAC enzymes which play a strategic role in the regulation of gene expression. Suberoyl Anilide Hydroxamic Acid (SAHA) or Vorinostat is a drug which commercially available to treat the cancer, but still has some side effects. This research present in silico SAHA modification in Zinc Binding Group (ZBG) by organoselenium compound to get ligands which less side effect. From molecular docking simulation, and interaction analysis, there are five best ligands, namely CC27, HA27, HB28, IB25, and KA7. These five ligands have better binding affinity than the standards, and also have interaction with Zn2+ cofactor of inhibited HDAC enzymes. This research is expected to produce more potent HDAC inhibitor as novel drug for cervical cancer treatment.

  13. Proteins implicated in the increase of adhesivity induced by suberoylanilide hydroxamic acid in leukemic cells.

    PubMed

    Grebeňová, D; Röselová, P; Pluskalová, M; Halada, P; Rösel, D; Suttnar, J; Brodská, B; Otevřelová, P; Kuželová, K

    2012-12-21

    We have previously shown that suberoylanilide hydroxamic acid (SAHA) treatment increases the adhesivity of leukemic cells to fibronectin at clinically relevant concentrations. Now, we present the results of the proteomic analysis of SAHA effects on leukemic cell lines using 2-DE and ProteomLab PF2D system. Histone acetylation at all studied acetylation sites reached the maximal level after 5 to 10 h of SAHA treatment. No difference in histone acetylation between subtoxic and toxic SAHA doses was observed. SAHA treatment induced cofilin phosphorylation at Ser3, an increase in vimentin and paxillin expression and a decrease in stathmin expression as confirmed by western-blotting and immunofluorescence microscopy. The interaction of cofilin with 14-3-3 epsilon was documented using both Duolink system and coimmunoprecipitation. However, this interaction was independent of cofilin Ser3 phosphorylation and the amount of 14-3-3-ε-bound cofilin did not rise following SAHA treatment. SAHA-induced increase in the cell adhesivity was associated with an increase in PAK phosphorylation in CML-T1 cells and was abrogated by simultaneous treatment with IPA-3, a PAK inhibitor. The effects of SAHA on JURL-MK1 cells were similar to those of other histone deacetylase inhibitors, tubastatin A and sodium butyrate. The proteome analysis also revealed several potential non-histone targets of histone deacetylases. PMID:23022583

  14. Suberoylanilide hydroxamic acid (SAHA) at subtoxic concentrations increases the adhesivity of human leukemic cells to fibronectin.

    PubMed

    Kuzelová, Katerina; Pluskalová, Michaela; Brodská, Barbora; Otevrelová, Petra; Elknerová, Klára; Grebenová, Dana; Hrkal, Zbynek

    2010-01-01

    Suberoylanilide hydroxamic acid (SAHA) is an inhibitor of histone deacetylases (HDACs) which is being introduced into clinic for the treatment of hematological diseases. We studied the effect of this compound on six human hematopoietic cell lines (JURL-MK1, K562, CML-T1, Karpas-299, HL-60, and ML-2) as well as on normal human lymphocytes and on leukemic primary cells. SAHA induced dose-dependent and cell type-dependent cell death which displayed apoptotic features (caspase-3 activation and apoptotic DNA fragmentation) in most cell types including the normal lymphocytes. At subtoxic concentrations (0.5-1 microM), SAHA increased the cell adhesivity to fibronectin (FN) in all leukemia/lymphoma-derived cell lines but not in normal lymphocytes. This increase was accompanied by an enhanced expression of integrin beta1 and paxillin, an essential constituent of focal adhesion complexes, both at the protein and mRNA level. On the other hand, the inhibition of ROCK protein, an important regulator of cytoskeleton structure, had no consistent effect on SAHA-induced increase in the cell adhesivity. The promotion of cell adhesivity to FN seems to be specific for SAHA as we observed no such effects with other HDAC inhibitors (trichostatin A and sodium butyrate). PMID:19911379

  15. Suberoylanilide hydroxamic acid synergistically enhances the antitumor activity of etoposide in Ewing sarcoma cell lines.

    PubMed

    Unland, Rebekka; Clemens, Dagmar; Heinicke, Ulrike; Potratz, Jenny C; Hotfilder, Marc; Fulda, Simone; Wardelmann, Eva; Frühwald, Michael C; Dirksen, Uta

    2015-09-01

    Ewing sarcomas (ES) are highly malignant tumors arising in bone and soft tissues. Given the poor outcome of affected patients with primary disseminated disease or at relapse, there is a clear need for new targeted therapies. The HDAC inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA, Vorinostat) inhibits ES tumor growth and induces apoptosis in vitro and in vivo. Thus, SAHA may be considered a novel treatment. However, it is most likely that not a single agent but a combination of agents with synergistic mechanisms will help improve the prognosis in high-risk ES patients. Therefore, the aim of the present study was to assess a putative synergistic effect of SAHA in combination with conventional chemotherapeutic agents. The antitumor activity of SAHA in combination with conventional chemotherapeutics (doxorubicin, etoposide, rapamycin, topotecan) was assessed using an MTT cell proliferation assay on five well-characterized ES cell lines (CADO-ES-1, RD-ES, TC-71, SK-ES-1, SK-N-MC) and a newly established ES cell line (DC-ES-15). SAHA antagonistically affected the antiproliferative effect of doxorubicin and topotecan in the majority of the ES cell lines, but synergistically enhanced the antiproliferative activity of etoposide. In functional analyses, pretreatment with SAHA significantly increased the effects of etoposide on apoptosis and clonogenicity. The in-vitro analyses presented in this work show that SAHA synergistically enhances the antitumor activity of etoposide in ES cells. Sequential treatment with etoposide combined with SAHA may represent a new therapeutic approach in ES. PMID:26053276

  16. Single Conformation Spectroscopy of Suberoylanilide Hydroxamic Acid: a Molecule Bites its Tail

    NASA Astrophysics Data System (ADS)

    Zhang, Di; Dean, Jacob; Zwier, Timothy S.

    2012-06-01

    Suberoylanilide hydroxamic acid (C_6H_5NHCO(CH_2)_6CONHOH, SAHA) is a histone deacetylase inhibitor approved by the FDA for the treatment of cutaneous T-cell lymphoma. With one hydrogen bonding group adjacent to ring and the other at the end of a long C_6 hydrocarbon tail, SAHA possesses an interesting potential energy landscape to be probed by single-conformation methods. A large number of extended structures favored by entropy are offset by a few structures in which head-to-tail or tail-to-head H-bonds close a large loop between the two groups separated by the C_6 chain. We use laser desorption to bring SAHA into the gas phase and cool it in a supersonic expansion before interrogation with resonant two-photon ionization. Single-conformation UV spectra in the S_0-S_1 region and infrared spectra in the hydride stretch region were recorded using IR-UV hole-burning and resonant ion-dip infrared (RIDIR) spectroscopies, respectively. Four different conformers were observed and spectroscopically characterized. Comparison of the experimental IR spectra with density functional theory (DFT) calculations leads to assignments for two of the major conformers, which adopt head-to-tail and tail-to-head binding patterns. The implication of the observed structures for the folding landscape and configuration preference of SAHA will be discussed.

  17. Effects of suberoylanilide hydroxamic acid on rat cytochrome P450 enzyme activities

    PubMed Central

    Lin, Kezhi; Zhang, Qingwei; Liu, Zezheng; Yang, Suping; Lin, Yingying; Wen, Congcong; Zheng, Yuancai

    2015-01-01

    Vorinostat (suberoylanilide hydroxamic acid, SAHA) is the first approved histone deacetylase (HDAC) inhibitor for the treatment of cutaneous T-cell lymphoma after progressive disease following two systemic therapies. The rats were randomly divided into SAHA groups (low, medium and high dosage) and control group. The SAHA group rats were given 12.3, 24.5, and 49 mg/kg SAHA, respectively, by continuous intragastric administration for 7 days. The influence of SAHA on the activities of CYP450 isoforms CYP2B6, CYP1A2, CYP2C19, CYP2D6 and CYP2C9 were evaluated by cocktail method, they were responsed by the changes of pharmacokinetic parameters of bupropion, phenacetin, tolbutamide, metroprolol and omeprazole. The five probe drugs were given to rats through intragastric administration, and the plasma concentration were determined by UPLC-MS/MS. The result of SAHA group compared to control group, there were statistical pharmacokinetics difference for bupropion, phenacetin, tolbutamide and metroprolol. Continuous intragastric administration for 7 days may induce the activities of CYP2C19 of rats, inhibit CYP1A2 and slightly inhibit CYP2B6 and CYP2D6 of rats. This may give advising for reasonable drug use after co-used with SAHA. The results indicated that drug co-administrated with SAHA may need dose adjustment. Furthermore, continuous intragastric administration of SAHA for 7 days, liver cell damaged, causing liver cell edema, in liver metabolism process. PMID:26191268

  18. Effects of suberoylanilide hydroxamic acid on rat cytochrome P450 enzyme activities.

    PubMed

    Lin, Kezhi; Zhang, Qingwei; Liu, Zezheng; Yang, Suping; Lin, Yingying; Wen, Congcong; Zheng, Yuancai

    2015-01-01

    Vorinostat (suberoylanilide hydroxamic acid, SAHA) is the first approved histone deacetylase (HDAC) inhibitor for the treatment of cutaneous T-cell lymphoma after progressive disease following two systemic therapies. The rats were randomly divided into SAHA groups (low, medium and high dosage) and control group. The SAHA group rats were given 12.3, 24.5, and 49 mg/kg SAHA, respectively, by continuous intragastric administration for 7 days. The influence of SAHA on the activities of CYP450 isoforms CYP2B6, CYP1A2, CYP2C19, CYP2D6 and CYP2C9 were evaluated by cocktail method, they were responsed by the changes of pharmacokinetic parameters of bupropion, phenacetin, tolbutamide, metroprolol and omeprazole. The five probe drugs were given to rats through intragastric administration, and the plasma concentration were determined by UPLC-MS/MS. The result of SAHA group compared to control group, there were statistical pharmacokinetics difference for bupropion, phenacetin, tolbutamide and metroprolol. Continuous intragastric administration for 7 days may induce the activities of CYP2C19 of rats, inhibit CYP1A2 and slightly inhibit CYP2B6 and CYP2D6 of rats. This may give advising for reasonable drug use after co-used with SAHA. The results indicated that drug co-administrated with SAHA may need dose adjustment. Furthermore, continuous intragastric administration of SAHA for 7 days, liver cell damaged, causing liver cell edema, in liver metabolism process. PMID:26191268

  19. Suberoylanilide Hydroxamic Acid (SAHA) enhances olaparib activity by targeting homologous recombination DNA repair in ovarian cancer

    PubMed Central

    Konstantinopoulos, Panagiotis A.; Wilson, Andrew J.; Saskowski, Jeanette; Wass, Erica; Khabele, Dineo

    2015-01-01

    Objectives Approximately 50% of serous epithelial ovarian cancers (EOC) contain molecular defects in homologous recombination (HR) DNA repair pathways. Poly(ADP-ribose) polymerase inhibitors (PARPi) have efficacy in HR-deficient, but not HR-proficient, EOC tumors as a single agent. Our goal was to determine whether the histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), can sensitize HR-proficient ovarian cancer cells to the PARPi AZD-2281 (olaparib). Methods Ovarian cancer cell lines (SKOV-3, OVCAR-8, NCI/ADR-Res, UWB1.289 BRCA1null and UWB1.289 + BRCA1 wild-type) were treated with saline vehicle, olaparib, SAHA or olaparib/SAHA. Sulforhodamine B (SRB) assessed cytotoxicity and immunofluorescence and Western blot assays assessed markers of apoptosis (cleaved PARP) and DNA damage (pH2AX and RAD51). Drug effects were also tested in SKOV-3 xenografts in Nude mice. Affymetrix microarray experiments were performed in vehicle and SAHA-treated SKOV-3 cells. Results In a microarray analysis, SAHA induced coordinated down-regulation of HR pathway genes, including RAD51 and BRCA1. Nuclear co-expression of RAD51 and pH2AX, a marker of efficient HR repair, was reduced approximately 40% by SAHA treatment alone and combined with olaparib. SAHA combined with olaparib induced apoptosis and pH2AX expression to a greater extent than either drug alone. Olaparib reduced cell viability at increasing concentrations and SAHA enhanced these effects in 4 of 5 cell lines, including BRCA1 null and wild-type cells, in vitro and in SKOV-3 xenografts in vivo. Conclusions These results provide preclinical rationale for targeting DNA damage response pathways by combining small molecule PARPi with HDACi as a mechanism for reducing HR efficiency in ovarian cancer. PMID:24631446

  20. Suberoylanilide Hydroxamic Acid Restores Estrogen Reduced-cTnI Expression in Neonatal Hearts of Mice.

    PubMed

    Peng, Chang; Luo, Xiaomei; Xing, Qianlu; Sun, Huichao; Huang, Xupei

    2016-10-01

    Diastolic cardiac dysfunction can be caused by abnormality in cTnI expression during cardiogenesis. In this study, we investigated the effects of estrogen on the abnormal expression of cTnI in the hearts of neonatal mice and its potential epigenetic mechanisms. We then evaluated suberoylanilide hydroxamic acid (SAHA), a HDAC inhibitor, as a new target treatment of diastolic cardiac dysfunction. Postnatal day 0.5 C57BL/6 mice were injected with estrogen for 1 week, then the hearts of 7-day-old neonatal mice were retrieved for examination. The activities of HDAC and HAT were assayed by colorimetry, and the interaction of cTnI with HDAC5 in mice hearts were examined using chromatin immunoprecipitation assays. The expression of cTnI was tested by quantitative real-time RT-PCR and Western blot. Estrogen treated groups displayed a significantly increased HDAC activity in the hearts of neonatal mice while HAT activity remained unchanged. Additionally, HDAC5 was higher at the cTnI promoter, as compared to the saline treated control groups. The acetylation of histone H3K9ac on cTnI promoter significantly decreased in the hearts of neonatal mice treated with estrogen, and the expression of cTnI at transcriptional and protein levels also decreased. SAHA was shown to increase the acetylation of histone H3K9ac and upregulate the expression of cTnI. The data demonstrated that SAHA can correct cTnI expression abnormality caused by estrogen through inhibiting the binding of HDAC5 to the promoter of cTnI. J. Cell. Biochem. 117: 2377-2384, 2016. © 2016 Wiley Periodicals, Inc. PMID:27379430

  1. Treatment of chronically FIV-infected cats with suberoylanilide hydroxamic acid

    PubMed Central

    McDonnel, Samantha J; Liepnieks, Molly L.; Murphy, Brian G

    2014-01-01

    Feline immunodeficiency virus (FIV) is a naturally-occurring, large animal model of lentiviral-induced immunodeficiency syndrome, and has been used as a model of HIV pathogenesis and therapeutic interventions. HIV reservoirs in the form of latent virus remain the primary roadblock to viral eradication and cure, and FIV has been previously established an animal model of lentiviral latency. The goal of this study was to determine whether administration of the histone deacetylase inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA) to aviremic, chronically FIV-infected cats would induce latent viral reactivation in vivo. A proof-of-concept experiment in a Transwell co-culture system demonstrated the ability of SAHA to reactivate latent virus which was replication competent and able to infect naïve cells. Oral SAHA (250 mg/m2) was administered with food to four asymptomatic, experimentally FIV-infected cats and one uninfected control cat, and a limited pharmacokinetic and pharmacodynamic analysis was performed. A statistically significant increase in cell-associated FIV RNA was detected in the cat with the greatest serum SAHA exposure, and cell-free viral RNA was detected at one time point in the three cats that achieved the highest levels of SAHA in serum. Interestingly, there was a significant decrease in viral DNA burden at 2 hours post drug administration in the same three cats. Though the sample size is small and the drug response was modest, this study provides evidence that in vivo treatment of FIV-infected cats with the HDACi SAHA can induce viral transcriptional reactivation, which may be dependent upon the concentration of SAHA achieved in blood. Importantly, alternative putative antilatency therapy drugs, and multimodal drug combinations, could be studied in this in vivo system. The FIV/cat model provides a unique opportunity to test novel therapeutic interventions aimed at eradicating latent virus in vivo. PMID:24954265

  2. Suberoylanilide hydroxamic acid (SAHA; vorinostat) causes bone loss by inhibiting immature osteoblasts

    PubMed Central

    McGee-Lawrence, Meghan E.; McCleary-Wheeler, Angela L.; Secreto, Frank J.; Razidlo, David F.; Zhang, Minzhi; Stensgard, Bridget A.; Li, Xiaodong; Stein, Gary S.; Lian, Jane B.; Westendorf, Jennifer J.

    2011-01-01

    Histone deacetylase (Hdac) inhibitors are used clinically to treat cancer and epilepsy. Although Hdac inhibition accelerates osteoblast maturation and suppresses osteoclast maturation in vitro, the effects of Hdac inhibitors on the skeleton are not understood. The purpose of this study was to determine how the pan-Hdac inhibitor, suberoylanilide hydroxamic acid (SAHA; a.k.a. vorinostat or Zolinza™) affects bone mass and remodeling in vivo. Male C57BL/6 mice received daily SAHA (100 mg/kg) or vehicle injections for three to four weeks. SAHA decreased trabecular bone volume fraction and trabecular number in the distal femur. Cortical bone at the femoral midshaft was not affected. SAHA reduced serum levels of P1NP, a bone formation marker, and also suppressed tibial mRNA levels of type I collagen, osteocalcin and osteopontin, but did not alter Runx2 or osterix transcripts. SAHA decreased histological measures of osteoblast number but interestingly increased indices of osteoblast activity including mineral apposition rate and bone formation rate. Neither serum (TRAcP 5b) nor histological markers of bone resorption were affected by SAHA. P1NP levels returned to baseline in animals which were allowed to recover for four weeks after four weeks of daily SAHA injections, but bone density remained low. In vitro, SAHA suppressed osteogenic colony formation, decreased osteoblastic gene expression, induced cell cycle arrest, and caused DNA damage in bone marrow-derived adherent cells. Collectively, these data demonstrate that bone loss following treatment with SAHA is primarily due to a reduction in osteoblast number. Moreover, these decreases in osteoblast number can be attributed to the deleterious effects of SAHA on immature osteoblasts, even while mature osteoblasts are resistant to the harmful effects and demonstrate increased activity in vivo, indicating that the response of osteoblasts to SAHA is dependent upon their differentiation state. These studies suggest that

  3. Suberoylanilide hydroxamic acid increases progranulin production in iPSC-derived cortical neurons of frontotemporal dementia patients.

    PubMed

    Almeida, Sandra; Gao, Fuying; Coppola, Giovanni; Gao, Fen-Biao

    2016-06-01

    Mutations in the granulin (GRN) gene cause frontotemporal dementia (FTD) due to progranulin haploinsufficiency. Compounds that can increase progranulin production and secretion may be considered as potential therapeutic drugs; however, very few of them have been directly tested on human cortical neurons. To this end, we differentiated 9 induced pluripotent stem cell lines derived from a control subject, a sporadic FTD case and an FTD patient with progranulin S116X mutation. Treatment with 1 μM suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, increased the production of progranulin in cortical neurons of all subjects at both the mRNA and protein levels without affecting their viability. Microarray analysis revealed that SAHA treatment not only reversed some gene expression changes caused by progranulin haploinsufficiency but also caused massive alterations in the overall transcriptome. Thus, histone deacetylase inhibitors may be considered as therapeutic drugs for GRN mutation carriers. However, this class of drugs also causes drastic changes in overall gene expression in human cortical neurons and their side effects and potential impacts on other pathways should be carefully evaluated. PMID:27143419

  4. Altering histone acetylation status in donor cells with suberoylanilide hydroxamic acid does not affect dog cloning efficiency.

    PubMed

    Kim, Min Jung; Oh, Hyun Ju; Kim, Geon A; Suh, Han Na; Jo, Young Kwang; Choi, Yoo Bin; Kim, Dong Hoon; Han, Ho Jae; Lee, Byeong Chun

    2015-10-15

    Although dog cloning technology has been applied to conservation of endangered canids, propagation of elite dogs, and production of transgenic dogs, the efficiency of cloning is still very low. To help overcome this problem, we evaluated the effect of treating donor cells with suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, on dog cloning efficiency. Relative messenger RNA expressions of the bax1/bcl2 ratio and Dnmt1 in fibroblasts treated with different concentrations (0, 1, 10, 50 μM) of SAHA and durations (0, 20, 44 hours) were compared. Treatment with 1 μM for 20 hours showed significantly lower bax1/bcl2 and Dnmt1 transcript abundance. Acetylation of H3K9 was significantly increased after SAHA treatment, but H4K5, H4K8 and H4K16 were not changed. After SCNT using control or donor cells treated with SAHA, a total of 76 and 64 cloned embryos were transferred to seven and five recipients, respectively. Three fetuses were diagnosed in both control and SAHA-treated groups by ultrasonography 29 days after the embryo transfer, but there was no significant difference in the pregnancy rate (4.2% vs. 4.3%). In conclusion, although SAHA treatment as used in this study significantly decreased bax1/bcl2 and Dnmt1 transcripts of donor nuclei, as well as increased H3 acetylation, it was not enough to increase in vivo developmental competence of cloned dog embryos. PMID:26259535

  5. The levels of HDAC1 and thioredoxin1 are related to the death of mesothelioma cells by suberoylanilide hydroxamic acid.

    PubMed

    You, Bo Ra; Park, Woo Hyun

    2016-05-01

    Mesothelioma is an aggressive tumor which is mainly derived from the pleura of lung. In the present study, we evaluated the anticancer effect of suberoylanilide hydroxamic acid (SAHA), a histone deacetylase (HDAC) inhibitor on human mesothelioma cells in relation to the levels of HDAC1, reactive oxygen species (ROS) and thioredoxin (Trx). While 1 µM SAHA inhibited cell growth in Phi and ROB cells at 24 h, it did not affect the growth in ADA and Mill cells. Notably, the level of HDAC1 was relatively overexpressed among Phi, REN and ROB cells. SAHA induced necrosis and apoptosis, which was accompanied by the cleavages of PARP and caspase-3 in Phi cells. This agent also increased the loss of mitochondrial membrane potential (MMP, ΔΨm) in Phi cells. All the tested caspase inhibitors attenuated apoptosis in SAHA-treated Phi cells whereas HDAC1 siRNA enhanced the apoptotic cell death. SAHA increased intracellular ROS levels including O2•- in Phi cells. N-acetyl cysteine (NAC) and vitamin C (Vit.C) significantly reduced the growth inhibition and death of Phi cells caused by SAHA. This drug decreased the mRNA and protein levels of Trx1 in Phi and ROB cells. Furthermore, Trx1 siRNA increased cell death and O2•- level in SAHA-treated Phi cells. In conclusion, SAHA selectively inhibited the growth of Phi and ROB mesothelioma cells, which showed the higher basal level of HDAC1. SAHA-induced Phi cell death was related to oxidative stress and Trx1 levels. PMID:26936390

  6. Enhanced suppression of tumor growth by concomitant treatment of human lung cancer cells with suberoylanilide hydroxamic acid and arsenic trioxide

    SciTech Connect

    Chien, Chia-Wen; Yao, Ju-Hsien; Chang, Shih-Yu; Lee, Pei-Chih; Lee, Te-Chang

    2011-11-15

    The efficacy of arsenic trioxide (ATO) against acute promyelocytic leukemia (APL) and relapsed APL has been well documented. ATO may cause DNA damage by generating reactive oxygen intermediates. Suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, modulates gene and protein expression via histone-dependent or -independent pathways that may result in chromatin decondensation, cell cycle arrest, differentiation, and apoptosis. We investigated whether ATO and SAHA act synergistically to enhance the death of cancer cells. Our current findings showed that combined treatment with ATO and SAHA resulted in enhanced suppression of non-small-cell lung carcinoma in vitro in H1299 cells and in vivo in a xenograft mouse model. Flow cytometric analysis of annexin V+ cells showed that apoptotic cell death was significantly enhanced after combined treatment with ATO and SAHA. At the doses used, ATO did not interfere with cell cycle progression, but SAHA induced p21 expression and led to G1 arrest. A Comet assay demonstrated that ATO, but not SAHA, induced DNA strand breaks in H1299 cells; however, co-treatment with SAHA significantly increased ATO-induced DNA damage. Moreover, SAHA enhanced acetylation of histone H3 and sensitized genomic DNA to DNase I digestion. Our results suggest that SAHA may cause chromatin relaxation and increase cellular susceptibility to ATO-induced DNA damage. Combined administration of SAHA and ATO may be an effective approach to the treatment of lung cancer. -- Highlights: Black-Right-Pointing-Pointer ATO and SAHA are therapeutic agents with different action modes. Black-Right-Pointing-Pointer Combination of ATO and SAHA synergistically inhibits tumor cell growth. Black-Right-Pointing-Pointer SAHA loosens chromatin structure resulting in increased sensitivity to DNase I. Black-Right-Pointing-Pointer ATO-induced DNA damage and apoptosis are enhanced by co-treatment with SAHA.

  7. Suberoylanilide hydroxamic acid treatment reveals crosstalks among proteome, ubiquitylome and acetylome in non-small cell lung cancer A549 cell line.

    PubMed

    Wu, Quan; Cheng, Zhongyi; Zhu, Jun; Xu, Weiqing; Peng, Xiaojun; Chen, Chuangbin; Li, Wenting; Wang, Fengsong; Cao, Lejie; Yi, Xingling; Wu, Zhiwei; Li, Jing; Fan, Pingsheng

    2015-01-01

    Suberoylanilide hydroxamic acid (SAHA) is a well-known histone deacetylase (HDAC) inhibitor and has been used as practical therapy for breast cancer and non-small cell lung cancer (NSCLC). It is previously demonstrated that SAHA treatment could extensively change the profile of acetylome and proteome in cancer cells. However, little is known about the impact of SAHA on other protein modifications and the crosstalks among different modifications and proteome, hindering the deep understanding of SAHA-mediated cancer therapy. In this work, by using SILAC technique, antibody-based affinity enrichment and high-resolution LC-MS/MS analysis, we investigated quantitative proteome, acetylome and ubiquitylome as well as crosstalks among the three datasets in A549 cells toward SAHA treatment. In total, 2968 proteins, 1099 acetylation sites and 1012 ubiquitination sites were quantified in response to SAHA treatment, respectively. With the aid of intensive bioinformatics, we revealed that the proteome and ubiquitylome were negatively related upon SAHA treatment. Moreover, the impact of SAHA on acetylome resulted in 258 up-regulated and 99 down-regulated acetylation sites at the threshold of 1.5 folds. Finally, we identified 55 common sites with both acetylation and ubiquitination, among which ubiquitination level in 43 sites (78.2%) was positive related to acetylation level. PMID:25825284

  8. Suberoylanilide Hydroxamic Acid Treatment Reveals Crosstalks among Proteome, Ubiquitylome and Acetylome in Non-Small Cell Lung Cancer A549 Cell Line

    PubMed Central

    Wu, Quan; Cheng, Zhongyi; Zhu, Jun; Xu, Weiqing; Peng, Xiaojun; Chen, Chuangbin; Li, Wenting; Wang, Fengsong; Cao, Lejie; Yi, Xingling; Wu, Zhiwei; Li, Jing; Fan, Pingsheng

    2015-01-01

    Suberoylanilide hydroxamic acid (SAHA) is a well-known histone deacetylase (HDAC) inhibitor and has been used as practical therapy for breast cancer and non-small cell lung cancer (NSCLC). It is previously demonstrated that SAHA treatment could extensively change the profile of acetylome and proteome in cancer cells. However, little is known about the impact of SAHA on other protein modifications and the crosstalks among different modifications and proteome, hindering the deep understanding of SAHA-mediated cancer therapy. In this work, by using SILAC technique, antibody-based affinity enrichment and high-resolution LC-MS/MS analysis, we investigated quantitative proteome, acetylome and ubiquitylome as well as crosstalks among the three datasets in A549 cells toward SAHA treatment. In total, 2968 proteins, 1099 acetylation sites and 1012 ubiquitination sites were quantified in response to SAHA treatment, respectively. With the aid of intensive bioinformatics, we revealed that the proteome and ubiquitylome were negatively related upon SAHA treatment. Moreover, the impact of SAHA on acetylome resulted in 258 up-regulated and 99 down-regulated acetylation sites at the threshold of 1.5 folds. Finally, we identified 55 common sites with both acetylation and ubiquitination, among which ubiquitination level in 43 sites (78.2%) was positive related to acetylation level. PMID:25825284

  9. Suberoylanilide hydroxamic acid (SAHA) inhibits EGF-induced cell transformation via reduction of cyclin D1 mRNA stability

    SciTech Connect

    Zhang, Jingjie; Ouyang, Weiming; Li, Jingxia; Zhang, Dongyun; Yu, Yonghui; Wang, York; Li, Xuejun; Huang, Chuanshu

    2012-09-01

    Suberoylanilide hydroxamic acid (SAHA) inhibiting cancer cell growth has been associated with its downregulation of cyclin D1 protein expression at transcription level or translation level. Here, we have demonstrated that SAHA inhibited EGF-induced Cl41 cell transformation via the decrease of cyclin D1 mRNA stability and induction of G0/G1 growth arrest. We found that SAHA treatment resulted in the dramatic inhibition of EGF-induced cell transformation, cyclin D1 protein expression and induction of G0/G1 growth arrest. Further studies showed that SAHA downregulation of cyclin D1 was only observed with endogenous cyclin D1, but not with reconstitutionally expressed cyclin D1 in the same cells, excluding the possibility of SAHA regulating cyclin D1 at level of protein degradation. Moreover, SAHA inhibited EGF-induced cyclin d1 mRNA level, whereas it did not show any inhibitory effect on cyclin D1 promoter-driven luciferase reporter activity under the same experimental conditions, suggesting that SAHA may decrease cyclin D1 mRNA stability. This notion was supported by the results that treatment of cells with SAHA decreased the half-life of cyclin D1 mRNA from 6.95 h to 2.57 h. Consistent with downregulation of cyclin D1 mRNA stability, SAHA treatment also attenuated HuR expression, which has been well-characterized as a positive regulator of cyclin D1 mRNA stability. Thus, our study identifies a novel mechanism responsible for SAHA inhibiting cell transformation via decreasing cyclin D1 mRNA stability and induction of G0/G1 growth arrest in Cl41 cells. -- Highlights: ► SAHA inhibits cell transformation in Cl41 cells. ► SAHA suppresses Cyclin D1 protein expression. ► SAHA decreases cyclin D1 mRNA stability.

  10. Structural Requirements of Histone Deacetylase Inhibitors: SAHA Analogs Modified on the Hydroxamic Acid.

    PubMed

    Bieliauskas, Anton V; Weerasinghe, Sujith V W; Negmeldin, Ahmed T; Pflum, Mary Kay H

    2016-05-01

    Histone deacetylase (HDAC) proteins have emerged as targets for anti-cancer therapeutics, with several inhibitors used in the clinic, including suberoylanilide hydroxamic acid (SAHA, vorinostat). Because SAHA and many other inhibitors target all or most of the 11 human HDAC proteins, the creation of selective inhibitors has been studied intensely. Recently, inhibitors selective for HDAC1 and HDAC2 were reported where selectivity was attributed to interactions between substituents on the metal binding moiety of the inhibitor and residues in the 14-Å internal cavity of the HDAC enzyme structure. Based on this earlier work, we synthesized and tested SAHA analogs with substituents on the hydroxamic acid metal binding moiety. The N-substituted SAHA analogs displayed reduced potency and solubility, but greater selectivity, compared to SAHA. Docking studies suggested that the N-substituent accesses the 14-Å internal cavity to impart preferential inhibition of HDAC1. These studies with N-substituted SAHA analogs are consistent with the strategy exploiting the 14-Å internal cavity of HDAC proteins to create HDAC1/2 selective inhibitors. PMID:27062198

  11. The safety profile of vorinostat (suberoylanilide hydroxamic acid) in hematologic malignancies: A review of clinical studies.

    PubMed

    Duvic, Madeleine; Dimopoulos, Meletios

    2016-02-01

    Histone acetyltransferases and histone deacetylases (HDACs) are multifunctional enzymes that posttranslationally modify both histone and nonhistone acetylation sites, affecting a broad range of cellular processes (e.g., cell cycle, apoptosis, and protein folding) often dysregulated in cancer. HDAC inhibitors are small molecules that directly interact with HDAC catalytic sites preventing the removal of acetyl groups, thereby counteracting the effects of HDACs. Since the first HDAC inhibitor, valproic acid, was investigated as a potential antitumor agent, there have been a number of other HDAC inhibitors developed to improve efficacy and safety. Despite significant progress in the management of patients with hematologic malignancies, overall survival is still poor. The discovery that HDACs may play a role in hematologic malignancies and preclinical studies showing promising activity with HDAC inhibitors in various tumor types, led to clinical evaluation of HDAC inhibitors as potential treatment options for patients with advanced hematologic malignancies. The Food and Drug Administration has approved two HDAC inhibitors, vorinostat (2006) and romidepsin (2009), for the treatment of cutaneous T-cell lymphoma. This review highlights the safety of HDAC inhibitors currently approved or being investigated for the treatment of hematologic malignancies, with a specific focus on the safety experience with vorinostat in cutaneous T-cell lymphoma. PMID:26827693

  12. Pyridoxine hydroxamic acids as novel HIV-integrase inhibitors.

    PubMed

    Stranix, Brent R; Wu, Jinzi J; Milot, Guy; Beaulieu, Françis; Bouchard, Jean-Emanuel; Gouveia, Kristine; Forte, André; Garde, Seema; Wang, Zhigang; Mouscadet, Jean-François; Delelis, Olivier; Xiao, Yong

    2016-02-15

    A series of pyridoxine hydroxamic acid analog bearing a 5-aryl-spacers were synthesized. Evaluation of these novel HIV integrase complex inhibitors revealed compounds with high potency against wild-type HIV virus. PMID:26826732

  13. Combined Effects of Suberoylanilide Hydroxamic Acid and Cisplatin on Radiation Sensitivity and Cancer Cell Invasion in Non-Small Cell Lung Cancer.

    PubMed

    Feng, Jianguo; Zhang, Shirong; Wu, Kan; Wang, Bing; Wong, Jeffrey Y C; Jiang, Hong; Xu, Rujun; Ying, Lisha; Huang, Haixiu; Zheng, Xiaoliang; Chen, Xufeng; Ma, Shenglin

    2016-05-01

    Lung cancer is a leading cause of cancer-related mortality worldwide, and concurrent chemoradiotherapy has been explored as a therapeutic option. However, the chemotherapeutic agents cannot be administered for most patients at full doses safely with radical doses of thoracic radiation, and further optimizations of the chemotherapy regimen to be given with radiation are needed. In this study, we examined the effects of suberoylanilide hydroxamic acid (SAHA) and cisplatin on DNA damage repairs, and determined the combination effects of SAHA and cisplatin on human non-small cell lung cancer (NSCLC) cells in response to treatment of ionizing radiation (IR), and on tumor growth of lung cancer H460 xenografts receiving radiotherapy. We also investigated the potential differentiation effect of SAHA and its consequences on cancer cell invasion. Our results showed that SAHA and cisplatin compromise distinct DNA damage repair pathways, and treatment with SAHA enhanced synergistic radiosensitization effects of cisplatin in established NSCLC cell lines in a p53-independent manner, and decreased the DNA damage repair capability in cisplatin-treated primary NSCLC tumor tissues in response to IR. SAHA combined with cisplatin also significantly increased inhibitory effect of radiotherapy on tumor growth in the mouse xenograft model. In addition, SAHA can induce differentiation in stem cell-like cancer cell population, reduce tumorigenicity, and decrease invasiveness of human lung cancer cells. In conclusion, our data suggest a potential clinical impact for SAHA as a radiosensitizer and as a part of a chemoradiotherapy regimen for NSCLC. Mol Cancer Ther; 15(5); 842-53. ©2016 AACR. PMID:26839308

  14. Effect of Suberoylanilide Hydroxamic Acid (SAHA) Administration on the Residual Virus Pool in a Model of Combination Antiretroviral Therapy-Mediated Suppression in SIVmac239-Infected Indian Rhesus Macaques

    PubMed Central

    Del Prete, Gregory Q.; Shoemaker, Rebecca; Oswald, Kelli; Lara, Abigail; Trubey, Charles M.; Fast, Randy; Schneider, Douglas K.; Kiser, Rebecca; Coalter, Vicky; Wiles, Adam; Wiles, Rodney; Freemire, Brandi; Keele, Brandon F.; Estes, Jacob D.; Quiñones, Octavio A.; Smedley, Jeremy; Macallister, Rhonda; Sanchez, Rosa I.; Wai, John S.; Tan, Christopher M.; Alvord, W. Gregory; Hazuda, Daria J.; Piatak, Michael

    2014-01-01

    Nonhuman primate models are needed for evaluations of proposed strategies targeting residual virus that persists in HIV-1-infected individuals receiving suppressive combination antiretroviral therapy (cART). However, relevant nonhuman primate (NHP) models of cART-mediated suppression have proven challenging to develop. We used a novel three-class, six-drug cART regimen to achieve durable 4.0- to 5.5-log reductions in plasma viremia levels and declines in cell-associated viral RNA and DNA in blood and tissues of simian immunodeficiency virus SIVmac239-infected Indian-origin rhesus macaques, then evaluated the impact of treatment with the histone deacetylase inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA; Vorinostat) on the residual virus pool. Ex vivo SAHA treatment of CD4+ T cells obtained from cART-suppressed animals increased histone acetylation and viral RNA levels in culture supernatants. cART-suppressed animals each received 84 total doses of oral SAHA. We observed SAHA dose-dependent increases in acetylated histones with evidence for sustained modulation as well as refractoriness following prolonged administration. In vivo virologic activity was demonstrated based on the ratio of viral RNA to viral DNA in peripheral blood mononuclear cells, a presumptive measure of viral transcription, which significantly increased in SAHA-treated animals. However, residual virus was readily detected at the end of treatment, suggesting that SAHA alone may be insufficient for viral eradication in the setting of suppressive cART. The effects observed were similar to emerging data for repeat-dose SAHA treatment of HIV-infected individuals on cART, demonstrating the feasibility, utility, and relevance of NHP models of cART-mediated suppression for in vivo assessments of AIDS virus functional cure/eradication approaches. PMID:25182644

  15. Mixed effects of suberoylanilide hydroxamic acid (SAHA) on the host transcriptome and proteome and their implications for HIV reactivation from latency.

    PubMed

    White, Cory H; Johnston, Harvey E; Moesker, Bastiaan; Manousopoulou, Antigoni; Margolis, David M; Richman, Douglas D; Spina, Celsa A; Garbis, Spiros D; Woelk, Christopher H; Beliakova-Bethell, Nadejda

    2015-11-01

    Suberoylanilide hydroxamic acid (SAHA) has been assessed in clinical trials as part of a "shock and kill" strategy to cure HIV-infected patients. While it was effective at inducing expression of HIV RNA ("shock"), treatment with SAHA did not result in a reduction of reservoir size ("kill"). We therefore utilized a combined analysis of effects of SAHA on the host transcriptome and proteome to dissect its mechanisms of action that may explain its limited success in "shock and kill" strategies. CD4+ T cells from HIV seronegative donors were treated with 1μM SAHA or its solvent dimethyl sulfoxide (DMSO) for 24h. Protein expression and post-translational modifications were measured with iTRAQ proteomics using ultra high-precision two-dimensional liquid chromatography-tandem mass spectrometry. Gene expression was assessed by Illumina microarrays. Using limma package in the R computing environment, we identified 185 proteins, 18 phosphorylated forms, 4 acetylated forms and 2982 genes, whose expression was modulated by SAHA. A protein interaction network integrating these 4 data types identified the HIV transcriptional repressor HMGA1 to be upregulated by SAHA at the transcript, protein and acetylated protein levels. Further functional category assessment of proteins and genes modulated by SAHA identified gene ontology terms related to NFκB signaling, protein folding and autophagy, which are all relevant to HIV reactivation. In summary, SAHA modulated numerous host cell transcripts, proteins and post-translational modifications of proteins, which would be expected to have very mixed effects on the induction of HIV-specific transcription and protein function. Proteome profiling highlighted a number of potential counter-regulatory effects of SAHA with respect to viral induction, which transcriptome profiling alone would not have identified. These observations could lead to a more informed selection and design of other HDACi with a more refined targeting profile, and

  16. Pyridone Methylsulfone Hydroxamate LpxC Inhibitors for the Treatment of Serious Gram-Negative Infections

    SciTech Connect

    Montgomery, Justin I.; Brown, Matthew F.; Reilly, Usa; Price, Loren M.; Abramite, Joseph A.; Arcari, Joel; Barham, Rose; Che, Ye; Chen, Jinshan Michael; Chung, Seung Won; Collantes, Elizabeth M.; Desbonnet, Charlene; Doroski, Matthew; Doty, Jonathan; Engtrakul, Juntyma J.; Harris, Thomas M.; Huband, Michael; Knafels, John D.; Leach, Karen L.; Liu, Shenping; Marfat, Anthony; McAllister, Laura; McElroy, Eric; Menard, Carol A.; Mitton-Fry, Mark; Mullins, Lisa; Noe, Mark C.; O’Donnell, John; Oliver, Robert; Penzien, Joseph; Plummer, Mark; Shanmugasundaram, Veerabahu; Thoma, Christy; Tomaras, Andrew P.; Uccello, Daniel P.; Vaz, Alfin; Wishka, Donn G.

    2012-11-09

    The synthesis and biological activity of a new series of LpxC inhibitors represented by pyridone methylsulfone hydroxamate 2a is presented. Members of this series have improved solubility and free fraction when compared to compounds in the previously described biphenyl methylsulfone hydroxamate series, and they maintain superior Gram-negative antibacterial activity to comparator agents.

  17. Suberoylanilide hydroxamic acid (SAHA) promotes the epithelial mesenchymal transition of triple negative breast cancer cells via HDAC8/FOXA1 signals.

    PubMed

    Wu, Shao; Luo, Zhi; Yu, Peng-Jiu; Xie, Hui; He, Yu-Wen

    2016-01-01

    Inhibitor of histone deacetylases (HDACIs) have great therapeutic value for triple negative breast cancer (TNBC) patients. Interestingly, our present study reveals that suberoyl anilide hydroxamic acid (SAHA), one of the most advanced pan-HDAC inhibitor, can obviously promote in vitro motility of MDA-MB-231 and BT-549 cells via induction of epithelial-mesenchymal transition (EMT). SAHA treatment significantly down-regulates the expression of epithelial markers E-cadherin (E-Cad) while up-regulates the mesenchymal markers N-cadherin (N-Cad), vimentin (Vim) and fibronectin (FN). However, SAHA has no effect on the expression and nuclear translocation of EMT related transcription factors including Snail, Slug, Twist and ZEB. While SAHA treatment down-regulates the protein and mRNA expression of FOXA1 and then decreases its nuclear translocation. Over-expression of FOXA1 markedly attenuates SAHA induced EMT of TNBC cells. Further, silence of HDAC8, while not HDAC6, alleviates the down-regulation of FOXA1 and up-regulation of N-Cad and Vim in MDA-MB-231 cells treated with SAHA. Collectively, our present study reveals that SAHA can promote EMT of TNBC cells via HDAC8/FOXA1 signals, which suggests that more attention should be paid when SAHA is used as anti-cancer agent for cancer treatment. PMID:26431101

  18. Structure of 'linkerless' hydroxamic acid inhibitor-HDAC8 complex confirms the formation of an isoform-specific subpocket.

    PubMed

    Tabackman, Alexa A; Frankson, Rochelle; Marsan, Eric S; Perry, Kay; Cole, Kathryn E

    2016-09-01

    Histone deacetylases (HDACs) catalyze the hydrolysis of acetylated lysine side chains in histone and non-histone proteins, and play a critical role in the regulation of many biological processes, including cell differentiation, proliferation, senescence, and apoptosis. Aberrant HDAC activity is associated with cancer, making these enzymes important targets for drug design. In general, HDAC inhibitors (HDACi) block the proliferation of tumor cells by inducing cell differentiation, cell cycle arrest, and/or apoptosis, and comprise some of the leading therapies in cancer treatments. To date, four HDACi have been FDA approved for the treatment of cancers: suberoylanilide hydroxamic acid (SAHA, Vorinostat, Zolinza®), romidepsin (FK228, Istodax®), belinostat (Beleodaq®), and panobinostat (Farydak®). Most current inhibitors are pan-HDACi, and non-selectively target a number of HDAC isoforms. Six previously reported HDACi were rationally designed, however, to target a unique sub-pocket found only in HDAC8. While these inhibitors were indeed potent against HDAC8, and even demonstrated specificity for HDAC8 over HDACs 1 and 6, there were no structural data to confirm the mode of binding. Here we report the X-ray crystal structure of Compound 6 complexed with HDAC8 to 1.98Å resolution. We also describe the use of molecular docking studies to explore the binding interactions of the other 5 related HDACi. Our studies confirm that the HDACi induce the formation of and bind in the HDAC8-specific subpocket, offering insights into isoform-specific inhibition. PMID:27374062

  19. Cytotoxic effects of Jay Amin hydroxamic acid (JAHA), a ferrocene-based class I histone deacetylase inhibitor, on triple-negative MDA-MB231 breast cancer cells.

    PubMed

    Librizzi, Mariangela; Longo, Alessandra; Chiarelli, Roberto; Amin, Jahanghir; Spencer, John; Luparello, Claudio

    2012-11-19

    The histone deacetylase inhibitors (HDACis) are a class of chemically heterogeneous anticancer agents of which suberoylanilide hydroxamic acid (SAHA) is a prototypical member. SAHA derivatives may be obtained by three-dimensional manipulation of SAHA aryl cap, such as the incorporation of a ferrocene unit like that present in Jay Amin hydroxamic acid (JAHA) and homo-JAHA [ Spencer , et al. ( 2011 ) ACS Med. Chem. Lett. 2 , 358 - 362 ]. These metal-based SAHA analogues have been tested for their cytotoxic activity toward triple-negative MDA-MB231 breast cancer cells. The results obtained indicate that of the two compounds tested, only JAHA was prominently active on breast cancer cells with an IC(50) of 8.45 μM at 72 h of treatment. Biological assays showed that exposure of MDA-MB231 cells to the HDACi resulted in cell cycle perturbation with an alteration of S phase entry and a delay at G(2)/M transition and in an early reactive oxygen species production followed by mitochondrial membrane potential (MMP) dissipation and autophagy inhibition. No annexin binding was observed after short- (5 h) and longer (24 and 48 h) term incubation with JAHA, thereby excluding the promotion of apoptosis by the HDACi. Although caution must be exercised in extrapolation of in vitro results to the in vivo situation for which research on animals and human trials are needed, nevertheless JAHA treatment possesses the potential for its development as an agent for prevention and/or therapy of "aggressive" breast carcinoma, thus prompting us to get more insight into the molecular basis of its antibreast cancer activity. PMID:23094795

  20. A Rational Approach for the Identification of Non-Hydroxamate HDAC6-Selective Inhibitors.

    PubMed

    Goracci, Laura; Deschamps, Nathalie; Randazzo, Giuseppe Marco; Petit, Charlotte; Dos Santos Passos, Carolina; Carrupt, Pierre-Alain; Simões-Pires, Claudia; Nurisso, Alessandra

    2016-01-01

    The human histone deacetylase isoform 6 (HDAC6) has been demonstrated to play a major role in cell motility and aggresome formation, being interesting for the treatment of multiple tumour types and neurodegenerative conditions. Currently, most HDAC inhibitors in preclinical or clinical evaluations are non-selective inhibitors, characterised by a hydroxamate zinc-binding group (ZBG) showing off-target effects and mutagenicity. The identification of selective HDAC6 inhibitors with novel chemical properties has not been successful yet, also because of the absence of crystallographic information that makes the rational design of HDAC6 selective inhibitors difficult. Using HDAC inhibitory data retrieved from the ChEMBL database and ligand-based computational strategies, we identified 8 original new non-hydroxamate HDAC6 inhibitors from the SPECS database, with activity in the low μM range. The most potent and selective compound, bearing a hydrazide ZBG, was shown to increase tubulin acetylation in human cells. No effects on histone H4 acetylation were observed. To the best of our knowledge, this is the first report of an HDAC6 selective inhibitor bearing a hydrazide ZBG. Its capability to passively cross the blood-brain barrier (BBB), as observed through PAMPA assays, and its low cytotoxicity in vitro, suggested its potential for drug development. PMID:27404291

  1. A Rational Approach for the Identification of Non-Hydroxamate HDAC6-Selective Inhibitors

    NASA Astrophysics Data System (ADS)

    Goracci, Laura; Deschamps, Nathalie; Randazzo, Giuseppe Marco; Petit, Charlotte; Dos Santos Passos, Carolina; Carrupt, Pierre-Alain; Simões-Pires, Claudia; Nurisso, Alessandra

    2016-07-01

    The human histone deacetylase isoform 6 (HDAC6) has been demonstrated to play a major role in cell motility and aggresome formation, being interesting for the treatment of multiple tumour types and neurodegenerative conditions. Currently, most HDAC inhibitors in preclinical or clinical evaluations are non-selective inhibitors, characterised by a hydroxamate zinc-binding group (ZBG) showing off-target effects and mutagenicity. The identification of selective HDAC6 inhibitors with novel chemical properties has not been successful yet, also because of the absence of crystallographic information that makes the rational design of HDAC6 selective inhibitors difficult. Using HDAC inhibitory data retrieved from the ChEMBL database and ligand-based computational strategies, we identified 8 original new non-hydroxamate HDAC6 inhibitors from the SPECS database, with activity in the low μM range. The most potent and selective compound, bearing a hydrazide ZBG, was shown to increase tubulin acetylation in human cells. No effects on histone H4 acetylation were observed. To the best of our knowledge, this is the first report of an HDAC6 selective inhibitor bearing a hydrazide ZBG. Its capability to passively cross the blood-brain barrier (BBB), as observed through PAMPA assays, and its low cytotoxicity in vitro, suggested its potential for drug development.

  2. A Rational Approach for the Identification of Non-Hydroxamate HDAC6-Selective Inhibitors

    PubMed Central

    Goracci, Laura; Deschamps, Nathalie; Randazzo, Giuseppe Marco; Petit, Charlotte; Dos Santos Passos, Carolina; Carrupt, Pierre-Alain; Simões-Pires, Claudia; Nurisso, Alessandra

    2016-01-01

    The human histone deacetylase isoform 6 (HDAC6) has been demonstrated to play a major role in cell motility and aggresome formation, being interesting for the treatment of multiple tumour types and neurodegenerative conditions. Currently, most HDAC inhibitors in preclinical or clinical evaluations are non-selective inhibitors, characterised by a hydroxamate zinc-binding group (ZBG) showing off-target effects and mutagenicity. The identification of selective HDAC6 inhibitors with novel chemical properties has not been successful yet, also because of the absence of crystallographic information that makes the rational design of HDAC6 selective inhibitors difficult. Using HDAC inhibitory data retrieved from the ChEMBL database and ligand-based computational strategies, we identified 8 original new non-hydroxamate HDAC6 inhibitors from the SPECS database, with activity in the low μM range. The most potent and selective compound, bearing a hydrazide ZBG, was shown to increase tubulin acetylation in human cells. No effects on histone H4 acetylation were observed. To the best of our knowledge, this is the first report of an HDAC6 selective inhibitor bearing a hydrazide ZBG. Its capability to passively cross the blood-brain barrier (BBB), as observed through PAMPA assays, and its low cytotoxicity in vitro, suggested its potential for drug development. PMID:27404291

  3. HDACi Valproic Acid (VPA) and Suberoylanilide Hydroxamic Acid (SAHA) Delay but Fail to Protect against Warm Hepatic Ischemia-Reperfusion Injury

    PubMed Central

    Ruess, Dietrich A.; Probst, Moriz; Marjanovic, Goran; Wittel, Uwe A.; Hopt, Ulrich T.; Keck, Tobias; Bausch, Dirk

    2016-01-01

    Background Histone deacetylases (HDAC) catalyze N-terminal deacetylation of lysine-residues on histones and multiple nuclear and cytoplasmic proteins. In various animal models, such as trauma/hemorrhagic shock, ischemic stroke or myocardial infarction, HDAC inhibitor (HDACi) application is cyto- and organoprotective and promotes survival. HDACi reduce stress signaling, cell death and inflammation. Hepatic ischemia-reperfusion (I/R) injury during major liver resection or transplantation increases morbidity and mortality. Assuming protective properties, the aim of this study was to investigate the effect of the HDACi VPA and SAHA on warm hepatic I/R. Material and Methods Male Wistar-Kyoto rats (age: 6–8 weeks) were randomized to VPA, SAHA, vehicle control (pre-) treatment or sham-groups and underwent partial no-flow liver ischemia for 90 minutes with subsequent reperfusion for 6, 12, 24 and 60 hours. Injury and regeneration was quantified by serum AST and ALT levels, by macroscopic aspect and (immuno-) histology. HDACi treatment efficiency, impact on MAPK/SAPK-activation and Hippo-YAP signaling was determined by Western blot. Results Treatment with HDACi significantly enhanced hyperacetylation of Histone H3-K9 during I/R, indicative of adequate treatment efficiency. Liver injury, as measured by macroscopic aspect, serum transaminases and histology, was delayed, but not alleviated in VPA and SAHA treated animals. Importantly, tissue destruction was significantly more pronounced with VPA. SAPK-activation (p38 and JNK) was reduced by VPA and SAHA in the early (6h) reperfusion phase, but augmented later on (JNK, 24h). Regeneration appeared enhanced in SAHA and VPA treated animals and was dependent on Hippo-YAP signaling. Conclusions VPA and SAHA delay warm hepatic I/R injury at least in part through modulation of SAPK-activation. However, these HDACi fail to exert organoprotective effects, in this setting. For VPA, belated damage is even aggravated. PMID:27513861

  4. Molecular design and structural optimization of potent peptide hydroxamate inhibitors to selectively target human ADAM metallopeptidase domain 17.

    PubMed

    Wang, Zhengting; Wang, Lei; Fan, Rong; Zhou, Jie; Zhong, Jie

    2016-04-01

    Human ADAMs (a disintegrin and metalloproteinases) have been established as an attractive therapeutic target of inflammatory disorders such as inflammatory bowel disease (IBD). The ADAM metallopeptidase domain 17 (ADAM17 or TACE) and its close relative ADAM10 are two of the most important ADAM members that share high conservation in sequence, structure and function, but exhibit subtle difference in regulation of downstream cell signaling events. Here, we described a systematic protocol that combined computational modeling and experimental assay to discover novel peptide hydroxamate derivatives as potent and selective inhibitors for ADAM17 over ADAM10. In the procedure, a virtual combinatorial library of peptide hydroxamate compounds was generated by exploiting intermolecular interactions involved in crystal and modeled structures. The library was examined in detail to identify few promising candidates with both high affinity to ADAM17 and low affinity to ADAM10, which were then tested in vitro with enzyme inhibition assay. Consequently, two peptide hydroxamates Hxm-Phe-Ser-Asn and Hxm-Phe-Arg-Gln were found to exhibit potent inhibition against ADAM17 (Ki=92 and 47nM, respectively) and strong selectivity for ADAM17 over ADAM10 (∼7-fold and ∼5-fold, S=0.86 and 0.71, respectively). The structural basis and energetic property of ADAM17 and ADAM10 interactions with the designed inhibitors were also investigated systematically. It is found that the exquisite network of nonbonded interactions involving the side chains of peptide hydroxamates is primarily responsible for inhibitor selectivity, while the coordination interactions and hydrogen bonds formed by the hydroxamate moiety and backbone of peptide hydroxamates confer high affinity to inhibitor binding. PMID:26709988

  5. Effects of hydroxamate metalloendoprotease inhibitors on botulinum neurotoxin A poisoned mouse neuromuscular junctions

    PubMed Central

    Thyagarajan, Baskaran; Potian, Joseph G.; Garcia, Carmen C.; Hognason, Kormakur; Čapková, Kateřina; Moe, Scott T.; Jacobson, Alan R.; Janda, Kim D.; McArdle, Joseph J.

    2010-01-01

    Summary Currently the only therapy for botulinum neurotoxin A (BoNT/A) poisoning is antitoxin. Antidotes that are effective after BoNT/A has entered the motor nerve terminals would dramatically benefit BoNT/A therapy. Inhibition of proteolytic activity of BoNT/A light chain by metalloendoprotease inhibitors (MEIs) is under development. We tested the effects of MEIs on in vitro as well as in vivo BoNT/A poisoned mouse nerve muscle preparations (NMPs). The Ki for inhibition of BoNT/A metalloendoprotease was 0.40 and 0.36 μM, respectively, for 2, 4 – dichlorocinnamic acid hydroxamate (DCH) and its methyl derivative, ABS 130. Acute treatment of nerve muscle preparations with 10 pM BoNT/A inhibited nerve evoked muscle twitches, reduced mean quantal content, and induced failures of endplate currents (EPCs). Bath application of 10 μM DCH or 5 μM ABS 130 reduced failures, increased the quantal content of EPCs, and partially restored muscle twitches after a delay of 40 to 90 min. The restorative effects of DCH and ABS 130, as well as 3,4 diaminopyridine (DAP) on twitch tension were greater at 22 °C compared to 37 °C. Unlike DAP, neither DCH nor ABS 130 increased Ca2+ levels in cholinergic Neuro 2a cells. Injection of MEIs into mouse hind limbs before or after BoNT/A injection neither prevented the toe spread reflex inhibition nor improved muscle functions. We suggest that hydroxamate MEIs partially restore neurotransmission of acutely BoNT/A poisoned nerve muscle preparations in vitro in a temperature dependent manner without increasing the Ca2+ levels within motor nerve endings. PMID:20211192

  6. Structure-based rational design of peptide hydroxamic acid inhibitors to target tumor necrosis factor-α converting enzyme as potential therapeutics for hepatitis.

    PubMed

    Wu, Dan; Gu, Qiuhong; Zhao, Ning; Xia, Fei; Li, Zhiwei

    2015-12-01

    The human tumor necrosis factor-α converting enzyme (TACE) has recently been raised as a new and promising therapeutic target of hepatitis and other inflammatory diseases. Here, we reported a successful application of the solved crystal structure of TACE complex with a peptide-like ligand INN for rational design of novel peptide hydroxamic acid inhibitors with high potency and selectivity to target and inhibit TACE. First, the intermolecular interactions between TACE catalytic domain and INN were characterized through an integrated bioinformatics approach, with which the key substructures of INN that dominate ligand binding were identified. Subsequently, the INN molecular structure was simplified to a chemical sketch of peptide hydroxamic acid compound, which can be regarded as a linear tripeptide capped by a N-terminal carboxybenzyl group (chemically protective group) and a C-terminal hydroxamate moiety (coordinated to the Zn(2+) at TACE active site). Based on the sketch, a virtual combinatorial library containing 180 peptide hydroxamic acids was generated, from which seven samples were identified as promising candidates by using a knowledge-based protein-peptide affinity predictor and were then tested in vitro with a standard TACE activity assay protocol. Consequently, three designed peptide hydroxamic acids, i.e. Cbz-Pro-Ile-Gln-hydroxamic acid, Cbz-Leu-Ile-Val-hydroxamic acid and Cbz-Phe-Val-Met-hydroxamic acid, exhibited moderate or high inhibitory activity against TACE, with inhibition constants Ki of 36 ± 5, 510 ± 46 and 320 ± 26 nM, respectively. We also examined the structural basis and non-bonded profile of TACE interaction with a designed peptide hydroxamic acid inhibitor, and found that the inhibitor ligand is tightly buried in the active pocket of TACE, forming a number of hydrogen bonds, hydrophobic forces and van der Waals contacts at the interaction interface, conferring both stability and specificity for TACE-inhibitor complex

  7. Hydroxamic acid derivatives of mycophenolic acid inhibit histone deacetylase at the cellular level.

    PubMed

    Batovska, Daniela I; Kim, Dong Hoon; Mitsuhashi, Shinya; Cho, Yoon Sun; Kwon, Ho Jeong; Ubukata, Makoto

    2008-10-01

    Mycophenolic acid (MPA, 1), an inhibitor of IMP-dehydrogenase (IMPDH) and a latent PPARgamma agonist, is used as an effective immunosuppressant for clinical transplantation and recently entered clinical trials in advanced multiple myeloma patients. On the other hand, suberoylanilide hydroxamic acid (SAHA), a non-specific histone deacetylase (HDAC) inhibitor, has been approved for treating cutaneous T-cell lymphoma. MPA seemed to bear a cap, a linker, and a weak metal-binding site as a latent inhibitor of HDAC. Therefore, the hydroxamic acid derivatives of mycophenolic acid having an effective metal-binding site, mycophenolic hydroxamic acid (MPHA, 2), 7-O-acetyl mycophenolic acid (7-O-Ac MPHA, 3), and 7-O-lauroyl mycophenolic hydroxamic acid (7-O-L MPHA, 4) were designed and synthesized. All these compounds inhibited histone deacetylase with IC50 values of 1, 0.9 and 0.5 microM, and cell proliferation at concentrations of 2, 1.5 and 1 microM, respectively. PMID:18838793

  8. A Scalable Synthesis of the Difluoromethyl-allo-threonyl Hydroxamate-Based LpxC Inhibitor LPC-058.

    PubMed

    Liang, Xiaofei; Gopalaswamy, Ramesh; Navas, Frank; Toone, Eric J; Zhou, Pei

    2016-05-20

    The difluoromethyl-allo-threonyl hydroxamate-based compound LPC-058 is a potent inhibitor of UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) in Gram-negative bacteria. A scalable synthesis of this compound is described. The key step in the synthetic sequence is a transition metal/base-catalyzed aldol reaction of methyl isocyanoacetate and difluoroacetone, giving rise to 4-(methoxycarbonyl)-5,5-disubstituted 2-oxazoline. A simple NMR-based determination of enantiomeric purity is also described. PMID:27128325

  9. Fragment based G-QSAR and molecular dynamics based mechanistic simulations into hydroxamic-based HDAC inhibitors against spinocerebellar ataxia.

    PubMed

    Sinha, Siddharth; Tyagi, Chetna; Goyal, Sukriti; Jamal, Salma; Somvanshi, Pallavi; Grover, Abhinav

    2016-10-01

    Expansion of polyglutamine (CAG) triplets within the coding gene ataxin 2 results in transcriptional repression, forming the molecular basis of the neurodegenerative disorder named spinocerebellar ataxia type-2 (SCA2). HDAC inhibitors (HDACi) have been elements of great interest in polyglutamine disorders such as Huntington's and Ataxia's. In this study, we have selected hydroxamic acid derivatives as HDACi and performed fragment-based G-QSAR, molecular docking studies and molecular dynamics simulations for elucidating the dynamic mode of action of HDACi with His-Asp catalytic dyad of HDAC4. The model was statistically validated to establish its predictive robustness. The model was statistically significant with r(2) value of .6297, cross-validated co-relation coefficient q(2) value of .5905 and pred_r(2) (predicted square co-relation coefficient) value of .85. An F-test value of 56.11 confirms absolute robustness of the model. Two combinatorial libraries comprising of 3180 compounds were created with hydroxamate moiety as the template and their pIC50 activities were predicted based on the G-QSAR model. The combinatorial library created was screened on the basis of predicted activity (pIC50), with two resultant top scoring compounds, HIC and DHC. The interaction of the compounds with His-Asp dyad in terms of H-bond interactions with His802, Asp840, Pro942, and Gly975 residues of HDAC4 was evaluated by docking and 20 ns long molecular dynamics simulations. This study provides valuable leads for structural substitutions required for hydroxamate moiety to exhibit enhanced inhibitory activity against HDAC4. The reported compounds demonstrated good binding and thus can be considered as potent therapeutic leads against ataxia. PMID:26510381

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

    PubMed

    Peng, Fan-Wei; Wu, Ting-Ting; Ren, Zi-Wei; Xue, Jia-Yu; Shi, Lei

    2015-11-15

    A series of hybrids derived from 4-anilinoquinazoline and hydroxamic acid were designed, synthesized, and evaluated as dual inhibitors of vascular endothelia growth factor receptor-2 (VEGFR-2) tyrosine kinase and histone deacetylase (HDAC). Most of these compounds exhibited potent HDAC inhibition and moderate VEGFR-2 inhibition. Among them, compound 6l exhibited the most potent inhibitory activities against VEGFR-2 (IC50=84 nM) and HDAC (IC50=2.8 nM). It also showed the most potent antiproliferative ability against MCF-7, a human breast cancer line, with IC50 of 1.2 μM. Docking simulation supported the initial pharmacophoric hypothesis and suggested a common mode of interaction of compound 6l at the active binding sites of VEGFR-2 and HDAC. PMID:26475519

  11. Molecular and cellular effects of a novel hydroxamate-based HDAC inhibitor - belinostat - in glioblastoma cell lines: a preliminary report.

    PubMed

    Kusaczuk, Magdalena; Krętowski, Rafał; Stypułkowska, Anna; Cechowska-Pasko, Marzanna

    2016-10-01

    Histone deacetylase (HDAC) inhibitors are now intensively investigated as potential cytostatic agents in many malignancies. Here, we provide novel information concerning the influence of belinostat (Bel), a hydroxamate-based pan-HDAC inhibitor, on glioblastoma LN-229 and LN-18 cells. We found that LN-229 cells stimulated with 2 μmol/L of Bel for 48 h resulted in 70 % apoptosis, while equivalent treatment of LN-18 cells resulted in only 28 % apoptosis. In LN-229 cells this effect was followed by up-regulation of pro-apoptotic genes including Puma, Bim, Chop and p21. In treated LN-18 cells only p21 was markedly overexpressed. Simultaneously, LN-229 cells treated with 2 μmol/L of Bel for 48 h exhibited down-regulation of molecular chaperones GRP78 and GRP94 at the protein level. In contrast, in LN-18 cells Western blot analysis did not show any marked changes in GRP78 nor GRP94 expression. Despite noticeable overexpression of p21, there were no signs of evident G1 nor G2/M cell cycle arrest, however, the reduction in number of the S phase cells was observed in both cell lines. These results collectively suggest that Bel can be considered as potential anti-glioblastoma agent. To our knowledge this is the first report presenting the effects of belinostat treatment in glioblastoma cell lines. PMID:27468826

  12. [Prevention of infected urinary stones by urease inhibitor. IV. Treatment of infection stones in rats by a new hydroxamic acid and cefalexin].

    PubMed

    Takeuchi, H; Tomoyoshi, T; Okada, Y; Yoshida, O; Kobashi, K

    1983-03-01

    We investigated the combined effectiveness of a new urease inhibitor, N-( pivaroyl ) glycinohydroxamic acid, with Cefalexin in the treatment of infection stones in rats. Combination therapy with the hydroxamic acid and Cefalexin inhibited bladder stone formation, and dissolved the stone dose dependently, while separate therapy was not significantly effective against stone formation or bacterial growth. This compound may become a useful medicine for the treatment of infection stones. PMID:6375315

  13. Substitution of the phosphonic acid and hydroxamic acid functionalities of the DXR inhibitor FR900098: an attempt to improve the activity against Mycobacterium tuberculosis.

    PubMed

    Andaloussi, Mounir; Lindh, Martin; Björkelid, Christofer; Suresh, Surisetti; Wieckowska, Anna; Iyer, Harini; Karlén, Anders; Larhed, Mats

    2011-09-15

    Two series of FR900098/fosmidomycin analogs were synthesized and evaluated for MtDXR inhibition and Mycobacterium tuberculosis whole-cell activity. The design rationale of these compounds involved the exchange of either the phosphonic acid or the hydroxamic acid part for alternative acidic and metal-coordinating functionalities. The best inhibitors provided IC(50) values in the micromolar range, with a best value of 41 μM. PMID:21824775

  14. Dual-Mode HDAC Prodrug for Covalent Modification and Subsequent Inhibitor Release

    PubMed Central

    2016-01-01

    Histone deacetylase inhibitors (HDACi) target abnormal epigenetic states associated with a variety of pathologies, including cancer. Here, the development of a prodrug of the canonical broad-spectrum HDACi suberoylanilide hydroxamic acid (SAHA) is described. Although hydroxamic acids are utilized universally in the development of metalloenzyme inhibitors, they are considered to be poor pharmacophores with reduced activity in vivo. We developed a prodrug of SAHA by appending a promoiety, sensitive to thiols, to the hydroxamic acid warhead (termed SAHA-TAP). After incubation of SAHA-TAP with an HDAC, the thiol of a conserved HDAC cysteine residue becomes covalently tagged with the promoiety, initiating a cascade reaction that leads to the release of SAHA. Mass spectrometry and enzyme kinetics experiments validate that the cysteine residue is covalently appended with the TAP promoiety. SAHA-TAP demonstrates cytotoxicity activity against various cancer cell lines. This strategy represents an original prodrug design with a dual mode of action for HDAC inhibition. PMID:25974739

  15. Synthesis/biological evaluation of hydroxamic acids and their prodrugs as inhibitors for Botulinum neurotoxin A light chain

    PubMed Central

    Seki, Hajime; Pellett, Sabine; Šilhár, Peter; Stowe, G. Neil; Blanco, Beatriz; Lardy, Matthew; Johnson, Eric A.; Janda, Kim D.

    2014-01-01

    Botulinum neurotoxin A (BoNT/A) is the most potent toxin known. Unfortunately, it is also a potential bioweapon in terrorism, which is without an approved therapeutic treatment once cellular intoxication takes place. Previously, we reported how hydroxamic acid prodrug carbamates increased cellular uptake, which translated to successful inhibition of this neurotoxin. Building upon this research, we detail BoNT/A protease molecular modeling studies accompanied by the construction of small library of hydroxamic acids based on 2,4-dichlorocinnamic hydroxamic acid scaffold and their carbamate prodrug derivatization along with the evaluation of these molecules in both enzymatic and cellular models. PMID:24360826

  16. Design, synthesis, and evaluation of hydroxamic acid-based molecular probes for in vivo imaging of histone deacetylase (HDAC) in brain

    PubMed Central

    Wang, Changning; Eessalu, Thomas E; Barth, Vanessa N; Mitch, Charles H; Wagner, Florence F; Hong, Yijia; Neelamegam, Ramesh; Schroeder, Frederick A; Holson, Edward B; Haggarty, Stephen J; Hooker, Jacob M

    2014-01-01

    Hydroxamic acid-based histone deacetylase inhibitors (HDACis) are a class of molecules with therapeutic potential currently reflected in the use of suberoylanilide hydroxamic acid (SAHA; Vorinostat) to treat cutaneous T-cell lymphomas (CTCL). HDACis may have utility beyond cancer therapy, as preclinical studies have ascribed HDAC inhibition as beneficial in areas such as heart disease, diabetes, depression, neurodegeneration, and other disorders of the central nervous system (CNS). However, little is known about the pharmacokinetics (PK) of hydroxamates, particularly with respect to CNS-penetration, distribution, and retention. To explore the rodent and non-human primate (NHP) brain permeability of hydroxamic acid-based HDAC inhibitors using positron emission tomography (PET), we modified the structures of belinostat (PXD101) and panobinostat (LBH-589) to incorporate carbon-11. We also labeled PCI 34051 through carbon isotope substitution. After characterizing the in vitro affinity and efficacy of these compounds across nine recombinant HDAC isoforms spanning Class I and Class II family members, we determined the brain uptake of each inhibitor. Each labeled compound has low uptake in brain tissue when administered intravenously to rodents and NHPs. In rodent studies, we observed that brain accumulation of the radiotracers were unaffected by the pre-administration of unlabeled inhibitors. Knowing that CNS-penetration may be desirable for both imaging applications and therapy, we explored whether a liquid chromatography, tandem mass spectrometry (LC-MS-MS) method to predict brain penetrance would be an appropriate method to pre-screen compounds (hydroxamic acid-based HDACi) prior to PET radiolabeling. LC-MS-MS data were indeed useful in identifying additional lead molecules to explore as PET imaging agents to visualize HDAC enzymes in vivo. However, HDACi brain penetrance predicted by LC-MS-MS did not strongly correlate with PET imaging results. This underscores the

  17. Design, synthesis, and evaluation of hydroxamic acid-based molecular probes for in vivo imaging of histone deacetylase (HDAC) in brain.

    PubMed

    Wang, Changning; Eessalu, Thomas E; Barth, Vanessa N; Mitch, Charles H; Wagner, Florence F; Hong, Yijia; Neelamegam, Ramesh; Schroeder, Frederick A; Holson, Edward B; Haggarty, Stephen J; Hooker, Jacob M

    2013-01-01

    Hydroxamic acid-based histone deacetylase inhibitors (HDACis) are a class of molecules with therapeutic potential currently reflected in the use of suberoylanilide hydroxamic acid (SAHA; Vorinostat) to treat cutaneous T-cell lymphomas (CTCL). HDACis may have utility beyond cancer therapy, as preclinical studies have ascribed HDAC inhibition as beneficial in areas such as heart disease, diabetes, depression, neurodegeneration, and other disorders of the central nervous system (CNS). However, little is known about the pharmacokinetics (PK) of hydroxamates, particularly with respect to CNS-penetration, distribution, and retention. To explore the rodent and non-human primate (NHP) brain permeability of hydroxamic acid-based HDAC inhibitors using positron emission tomography (PET), we modified the structures of belinostat (PXD101) and panobinostat (LBH-589) to incorporate carbon-11. We also labeled PCI 34051 through carbon isotope substitution. After characterizing the in vitro affinity and efficacy of these compounds across nine recombinant HDAC isoforms spanning Class I and Class II family members, we determined the brain uptake of each inhibitor. Each labeled compound has low uptake in brain tissue when administered intravenously to rodents and NHPs. In rodent studies, we observed that brain accumulation of the radiotracers were unaffected by the pre-administration of unlabeled inhibitors. Knowing that CNS-penetration may be desirable for both imaging applications and therapy, we explored whether a liquid chromatography, tandem mass spectrometry (LC-MS-MS) method to predict brain penetrance would be an appropriate method to pre-screen compounds (hydroxamic acid-based HDACi) prior to PET radiolabeling. LC-MS-MS data were indeed useful in identifying additional lead molecules to explore as PET imaging agents to visualize HDAC enzymes in vivo. However, HDACi brain penetrance predicted by LC-MS-MS did not strongly correlate with PET imaging results. This underscores the

  18. Succinyl hydroxamates as potent and selective non-peptidic inhibitors of procollagen C-proteinase: design, synthesis, and evaluation as topically applied, dermal anti-scarring agents.

    PubMed

    Bailey, Simon; Fish, Paul V; Billotte, Stephane; Bordner, Jon; Greiling, Doris; James, Kim; McElroy, Andrew; Mills, James E; Reed, Charlotte; Webster, Robert

    2008-12-15

    Succinyl hydroxamates 1 and 2 are disclosed as novel series of potent and selective inhibitors of procollagen C-proteinase (PCP) which may have potential as anti-fibrotic agents. Carboxamide 7 demonstrated good PCP inhibition and had excellent selectivity over MMPs involved in wound healing. In addition, 7 was effective in a cell-based model of collagen deposition (fibroplasia model) and was very effective at penetrating human skin in vitro. Compound 7 (UK-383,367) was selected as a candidate for evaluation in clinical studies as a topically applied, dermal anti-scarring agent. PMID:18945617

  19. Hydroxamic Acid and Benzoic Acid-Based STAT3 Inhibitors Suppress Human Glioma and Breast Cancer Phenotypes In Vitro and In Vivo.

    PubMed

    Yue, Peibin; Lopez-Tapia, Francisco; Paladino, David; Li, Yifei; Chen, Chih-Hong; Namanja, Andrew T; Hilliard, Tyvette; Chen, Yuan; Tius, Marcus A; Turkson, James

    2016-02-01

    STAT3 offers an attractive target for cancer therapy, but small-molecule inhibitors with appealing pharmacologic properties have been elusive. Here, we report hydroxamic acid-based and benzoic acid-based inhibitors (SH5-07 and SH4-54, respectively) with robust bioactivity. Both inhibitors blocked STAT3 DNA-binding activity in vitro and in human glioma, breast, and prostate cancer cells and in v-Src-transformed murine fibroblasts. STAT3-dependent gene transcription was blocked along with Bcl-2, Bcl-xL, Mcl-1, cyclin D1, c-Myc, and survivin expression. Nuclear magnetic resonance analysis of STAT3-inhibitor complexes defined interactions with the SH2 and DNA-binding domains of STAT3. Ectopic expression of the SH2 domain in cells was sufficient to counter the STAT3-inhibitory effects of SH4-54. Neither compound appreciably affected STAT1 or STAT5 DNA-binding activities, STAT3-independent gene transcription, or activation of a panel of oncogenic kinases in malignant cells. Each compound decreased the proliferation and viability of glioma, breast, and prostate cancer cells and v-Src-transformed murine fibroblasts harboring constitutively active STAT3. Further, in mouse xenograft models of glioma and breast cancer, administration of SH5-07 or SH4-54 effectively inhibited tumor growth. Our results offer preclinical proof of concept for SH5-07 and SH4-54 as candidates for further development as cancer therapeutics. PMID:26088127

  20. Complex structure of a bacterial class 2 histone deacetylase homologue with a trifluoromethylketone inhibitor

    SciTech Connect

    Nielsen, Tine Kragh; Hildmann, Christian; Riester, Daniel; Wegener, Dennis; Schwienhorst, Andreas; Ficner, Ralf

    2007-04-01

    The crystal structure of HDAH FB188 in complex with a trifluoromethylketone at 2.2 Å resolution is reported and compared to a previously determined inhibitor complex. Histone deacetylases (HDACs) have emerged as attractive targets in anticancer drug development. To date, a number of HDAC inhibitors have been developed and most of them are hydroxamic acid derivatives, typified by suberoylanilide hydroxamic acid (SAHA). Not surprisingly, structural information that can greatly enhance the design of novel HDAC inhibitors is so far only available for hydroxamic acids in complex with HDAC or HDAC-like enzymes. Here, the first structure of an enzyme complex with a nonhydroxamate HDAC inhibitor is presented. The structure of the trifluoromethyl ketone inhibitor 9,9,9-trifluoro-8-oxo-N-phenylnonanamide in complex with bacterial FB188 HDAH (histone deacetylase-like amidohydrolase from Bordetella/Alcaligenes strain FB188) has been determined. HDAH reveals high sequential and functional homology to human class 2 HDACs and a high structural homology to human class 1 HDACs. Comparison with the structure of HDAH in complex with SAHA reveals that the two inhibitors superimpose well. However, significant differences in binding to the active site of HDAH were observed. In the presented structure the O atom of the trifluoromethyl ketone moiety is within binding distance of the Zn atom of the enzyme and the F atoms participate in interactions with the enzyme, thereby involving more amino acids in enzyme–inhibitor binding.

  1. Utilization of Boron Compounds for the Modification of Suberoyl Anilide Hydroxamic Acid as Inhibitor of Histone Deacetylase Class II Homo sapiens

    PubMed Central

    Bakri, Ridla; Parikesit, Arli Aditya; Satriyanto, Cipta Prio; Kerami, Djati; Tambunan, Usman Sumo Friend

    2014-01-01

    Histone deacetylase (HDAC) has a critical function in regulating gene expression. The inhibition of HDAC has developed as an interesting anticancer research area that targets biological processes such as cell cycle, apoptosis, and cell differentiation. In this study, an HDAC inhibitor that is available commercially, suberoyl anilide hydroxamic acid (SAHA), has been modified to improve its efficacy and reduce the side effects of the compound. Hydrophobic cap and zinc-binding group of these compounds were substituted with boron-based compounds, whereas the linker region was substituted with p-aminobenzoic acid. The molecular docking analysis resulted in 8 ligands with ΔGbinding value more negative than the standards, SAHA and trichostatin A (TSA). That ligands were analyzed based on the nature of QSAR, pharmacological properties, and ADME-Tox. It is conducted to obtain a potent inhibitor of HDAC class II Homo sapiens. The screening process result gave one best ligand, Nova2 (513246-99-6), which was then further studied by molecular dynamics simulations. PMID:25214833

  2. Metal complexes of salicylhydroxamic acid (H2Sha), anthranilic hydroxamic acid and benzohydroxamic acid. Crystal and molecular structure of [Cu(phen)2(Cl)]Cl x H2Sha, a model for a peroxidase-inhibitor complex.

    PubMed

    O'Brien, E C; Farkas, E; Gil, M J; Fitzgerald, D; Castineras, A; Nolan, K B

    2000-04-01

    Stability constants of iron(III), copper(II), nickel(II) and zinc(II) complexes of salicylhydroxamic acid (H2Sha), anthranilic hydroxamic acid (HAha) and benzohydroxamic acid (HBha) have been determined at 25.0 degrees C, I=0.2 mol dm(-3) KCl in aqueous solution. The complex stability order, iron(III) > copper(II) > nickel(II) approximately = zinc(II) was observed whilst complexes of H2Sha were found to be more stable than those of the other two ligands. In the preparation of ternary metal ion complexes of these ligands and 1,10-phenanthroline (phen) the crystalline complex [Cu(phen)2(Cl)]Cl x H2Sha was obtained and its crystal structure determined. This complex is a model for hydroxamate-peroxidase inhibitor interactions. PMID:10830846

  3. Hydroxamate-induced spectral perturbations of cobalt Aeromonas aminopeptidase.

    PubMed

    Wilkes, S H; Prescott, J M

    1987-06-25

    The absorption spectrum of cobalt(II)-substituted Aeromonas aminopeptidase is markedly perturbed by the presence of equimolar concentrations of D-amino acid hydroxamates and acyl hydroxamates that have previously been shown to be powerful inhibitors of this enzyme (Wilkes, S. H., and Prescott, J. M. (1983) J. Biol. Chem. 258, 13517-13521). D-Valine hydroxamate produces the most distinctive perturbation, splitting the characteristic 527 nm absorption peak of the cobalt enzyme to form peaks at 564, 520, and 487 nm with molar extinction values of 126, 98, and 67 M-1 cm-1, respectively. A qualitatively similar perturbation, albeit with lower extinction values, results from the addition of D-leucine hydroxamate, whereas D-alanine hydroxamate perturbs the spectrum, but does not evoke the peak at 564 nm. In contrast, hydroxamates of L-valine and L-leucine in concentrations equi-molar to that of the enzyme produce only faint indications of change in the spectrum, but the hydroxamates of several other L-amino acids perturb the spectrum essentially independently of the identity of the side chain and in a qualitatively different manner from that of D-valine hydroxamate and D-leucine hydroxamate. At the high enzyme:substrate ratios used in the spectral experiments, L-leucine hydroxamate and L-valine hydroxamate proved to be rapidly hydrolyzed, hence their inability to perturb the spectrum of the cobalt-substituted enzyme during the time course of a spectral experiment. Values of kcat for L-amino acid hydroxamates, all of which are good reversible inhibitors of the hydrolysis of L-leucine-p-nitroanilide by Aeromonas aminopeptidase, were found to range from 0.01 min-1 to 5.6 min-1 for the native enzyme and from 0.27 min-1 to 108 min-1 for the cobalt-substituted enzyme; their km values toward the cobalt aminopeptidase range from 1.2 X 10(-7) M to 1.9 X 10(-5) M. The mutual exclusivity of binding for hydroxamate inhibitors and 1-butaneboronic acid, previously shown by kinetics

  4. A hybrid of thiazolidinone with the hydroxamate scaffold for developing novel histone deacetylase inhibitors with antitumor activities.

    PubMed

    Yang, Feifei; Peng, Shihong; Li, Yunqi; Su, Liqiang; Peng, Yangrui; Wu, Jing; Chen, Huang; Liu, Mingyao; Yi, Zhengfang; Chen, Yihua

    2016-02-01

    A series of novel histone deacetylase (HDAC) inhibitors were designed, synthesized and evaluated based on the strategies of a hybrid of the classic pharmacophore of HDAC inhibitors with the thiazolidinone scaffold. Some of the compounds 12i showed potent HDAC1 inhibition with nM IC50 values, more importantly, compound displayed much better anti-metastatic effects than vorinostat (SAHA) against migration of the A549 cell line. Further mechanism exploration implied that compound 12i may inhibit tumor metastasis via modulating the epithelial-mesenchymal transition (EMT) and upregulating the acetylation of α-tubulin. PMID:26732459

  5. Synthesis of N-hydroxycinnamides capped with a naturally occurring moiety as inhibitors of histone deacetylase.

    PubMed

    Huang, Wei-Jan; Chen, Ching-Chow; Chao, Shi-Wei; Lee, Shoei-Sheng; Hsu, Fen-Lin; Lu, Yeh-Lin; Hung, Ming-Fang; Chang, Chung-I

    2010-04-01

    Histone deacetylase (HDAC) inhibitors are regarded as promising therapeutics for the treatment of cancer. All reported HDAC inhibitors contain three pharmacophoric features: a zinc-chelating group, a hydrophobic linker, and a hydrophobic cap for surface recognition. In this study we investigated the effectiveness of osthole, a hydrophobic Chinese herbal compound, as the surface recognition cap in hydroxamate-based compounds as inhibitors of HDAC. Nine novel osthole-based N-hydroxycinnamides were synthesized and screened for enzyme inhibition activity. Compounds 9 d, 9 e, 9 g exhibited inhibitory activities (IC(50)=24.5, 20.0, 19.6 nM) against nuclear HDACs in HeLa cells comparable to that of suberoylanilide hydroxamic acid (SAHA; IC(50)=24.5 nM), a potent inhibitor clinically used for the treatment of cutaneous T-cell lymphoma (CTCL). While compounds 9 d and 9 e showed SAHA-like activity towards HDAC1 and HDAC6, compound 9 g was more selective for HDAC1. Compound 9 d exhibited the best cellular effect, which was comparable to that of SAHA, of enhancing acetylation of either alpha-tubulin or histone H3. Molecular docking analysis showed that the osthole moiety of compound 9 d may interact with the same hydrophobic surface pocket exploited by SAHA and it may be modified to provide class-specific selectivity. These results suggest that osthole is an effective hydrophobic cap when incorporated into N-hydroxycinnamide-derived HDAC inhibitors. PMID:20209563

  6. Antimalarial Activity of the Anticancer Histone Deacetylase Inhibitor SB939

    PubMed Central

    Sumanadasa, Subathdrage D. M.; Goodman, Christopher D.; Lucke, Andrew J.; Skinner-Adams, Tina; Sahama, Ishani; Haque, Ashraful; Do, Tram Anh; McFadden, Geoffrey I.; Fairlie, David P.

    2012-01-01

    Histone deacetylase (HDAC) enzymes posttranslationally modify lysines on histone and nonhistone proteins and play crucial roles in epigenetic regulation and other important cellular processes. HDAC inhibitors (e.g., suberoylanilide hydroxamic acid [SAHA; also known as vorinostat]) are used clinically to treat some cancers and are under investigation for use against many other diseases. Development of new HDAC inhibitors for noncancer indications has the potential to be accelerated by piggybacking onto cancer studies, as several HDAC inhibitors have undergone or are undergoing clinical trials. One such compound, SB939, is a new orally active hydroxamate-based HDAC inhibitor with an improved pharmacokinetic profile compared to that of SAHA. In this study, the in vitro and in vivo antiplasmodial activities of SB939 were investigated. SB939 was found to be a potent inhibitor of the growth of Plasmodium falciparum asexual-stage parasites in vitro (50% inhibitory concentration [IC50], 100 to 200 nM), causing hyperacetylation of parasite histone and nonhistone proteins. In combination with the aspartic protease inhibitor lopinavir, SB939 displayed additive activity. SB939 also potently inhibited the in vitro growth of exoerythrocytic-stage Plasmodium parasites in liver cells (IC50, ∼150 nM), suggesting that inhibitor targeting to multiple malaria parasite life cycle stages may be possible. In an experimental in vivo murine model of cerebral malaria, orally administered SB939 significantly inhibited P. berghei ANKA parasite growth, preventing development of cerebral malaria-like symptoms. These results identify SB939 as a potent new antimalarial HDAC inhibitor and underscore the potential of investigating next-generation anticancer HDAC inhibitors as prospective new drug leads for treatment of malaria. PMID:22508312

  7. Stereospecificity of amino acid hydroxamate inhibition of aminopeptidases.

    PubMed

    Wilkes, S H; Prescott, J M

    1983-11-25

    Hydroxamates of amino acids and aliphatic acids are effective inhibitors of Aeromonas proteolytica amino-peptidase (EC 3.4.11.10) and of both the cytosolic (EC 3.4.11.1) and microsomal (EC 3.4.11.2) aminopeptidases of swine kidney. Cytosolic leucine aminopeptidase and the Aeromonas enzyme were inhibited to a greater extent by D isomers than by the L enantiomorphs, manganese-activated kidney cytosolic leucine aminopeptidase being inhibited 10 times more effectively by D-leucine and D-valine hydroxamic acids than by the L isomers. The D isomers of these two compounds inhibited Aeromonas aminopeptidase to an even greater extent with Ki values of 2 X 10(-9) and 5 X 10(-9), respectively, whereas the corresponding L isomers were bound 150 times less tightly. With the Aeromonas enzyme, a comparison of inhibition by racemic mixtures with that of the corresponding L isomers indicated that in all cases the contribution of the D isomer was predominant. Isocaproic hydroxamic acid inhibited this enzyme equally well as L-leucine hydroxamic acid, indicating that the amino group orientation in the D isomer contributes to the binding efficacy. Swine kidney microsomal aminopeptidase was also inhibited by D isomers of leucine and valine hydroxamic acids but in contrast to the other two enzymes, the inhibition was 10-fold less than that observed for the corresponding L isomers. Cytosolic leucine aminopeptidase with either 6 g atoms of zinc per mol or 12 g atoms of zinc per mol was inhibited only slightly by any of the hydroxamic acid compounds; evidently enzyme-bound manganese (or magnesium) is specific for hydroxamate binding to this aminopeptidase. PMID:6643439

  8. An appraisal of cinnamyl sulfonamide hydroxamate derivatives (HDAC inhibitors) for anti-cancer, anti-angiogenic and anti-metastatic activities in human cancer cells.

    PubMed

    Reddy, Neetinkumar D; Shoja, M H; Biswas, Subhankar; Nayak, Pawan G; Kumar, Nitesh; Rao, C Mallikarjuna

    2016-06-25

    Multiple genetic mutations along with unusual epigenetic modifications play a major role in cancer development. Histone deacetylase (HDAC) enzyme overexpression observed in the majority of cancers is responsible for tumor suppressor gene silencing and activation of proto-oncogenes to oncogenes. Cinnamic acid derivatives exhibit anti-cancer potential through HDAC enzyme inhibition. We have synthesized a few cinnamyl sulfonamide hydroxamate derivatives (NMJ-1, -2 and -3) by already published in-house procedures and their purity, and chemical characterization were performed by NMR, mass spectrometry and elemental analysis. The anti-cancer activities were also evaluated against colon cancer. The rationale for synthesis was based on bioisosterism concept. To take the work forward, these compounds were considered for in vitro anti-angiogenic and anti-metastatic activities in cancer cells. The effectiveness of these compounds was determined by SRB assay. The compounds showed cancer cell cytotoxicity (IC50 range of 5.7 ± 0.43 to 20.5 ± 1.9 μM). The mechanism of compound-induced cell death involves an intrinsic apoptosis pathway which was supported by the following: increase in apoptotic index, arrest in cell cycle at G2/M phase, increase in annexin V binding and induction of p21(Waf1/Cip1) expression in the treated cells. Further, their target modulating effect, measured as the expression of acetyl-H3 histone and acetyl α-tubulin was determined by Western blots. Hyper acetylation of H3 histone and α-tubulin were observed. Furthermore, increased expression of cleaved caspase-3, cleaved PARP, total Bad was estimated by ELISA. The anti-angiogenic effect was examined through cobalt (II) chloride (CoCl2)-induced HIF-1α expression, where the compounds reduced the expression of induced HIF-1α. In addition, their anti-metastatic ability was determined through phorbol-12-myristate-13-acetate (PMA)-induced expression of MMP-2 and -9 by Western blotting and gelatin

  9. Hydroxamic Acids in Asymmetric Synthesis

    PubMed Central

    Li, Zhi; Yamamoto, Hisashi

    2012-01-01

    Metal-catalyzed stereoselective reactions are a central theme in organic chemistry research. In these reactions, the stereoselection is achieved predominantly by introducing chiral ligands at the metal catalyst’s center. For decades, researchers have sought better chiral ligands for asymmetric catalysis and have made great progress. Nevertheless, to achieve optimal stereoselectivity and to catalyze new reactions, new chiral ligands are needed. Due to their high metal affinity, hydroxamic acids play major roles across a broad spectrum of fields from biochemistry to metal extraction. Dr. K. Barry Sharpless first revealed their potential as chiral ligands for asymmetric synthesis in 1977: He published the chiral vanadium-hydroxamic-acid-catalyzed, enantioselective epoxidation of allylic alcohols before his discovery of Sharpless Asymmetric Epoxidation, which uses titanium-tartrate complex as the chiral reagent. However, researchers have reported few highly enantioselective reactions using metal-hydroxamic acid as catalysts since then. This Account summarizes our research on metal-catalyzed asymmetric epoxidation using hydroxamic acids as chiral ligands. We designed and synthesized a series of new hydroxamic acids, most notably the C2-symmetric bis-hydroxamic acid (BHA) family. V-BHA-catalyzed epoxidation of allylic and homoallylic alcohols achieved higher activity and stereoselectivity than Sharpless Asymmetric Epoxidation in many cases. Changing the metal species led to a series of unprecedented asymmetric epoxidation reactions, such as (i) single olefins and sulfides with Mo-BHA, (ii) homoallylic and bishomoallylic alcohols with Zr- and Hf-BHA, and (iii) N-alkenyl sulfonamides and N-sulfonyl imines with Hf-BHA. These reactions produce uniquely functionalized chiral epoxides with good yields and enantioselectivities. PMID:23157425

  10. Hydroxamic acids in asymmetric synthesis.

    PubMed

    Li, Zhi; Yamamoto, Hisashi

    2013-02-19

    Metal-catalyzed stereoselective reactions are a central theme in organic chemistry research. In these reactions, the stereoselection is achieved predominantly by introducing chiral ligands at the metal catalyst's center. For decades, researchers have sought better chiral ligands for asymmetric catalysis and have made great progress. Nevertheless, to achieve optimal stereoselectivity and to catalyze new reactions, new chiral ligands are needed. Because of their high metal affinity, hydroxamic acids play major roles across a broad spectrum of fields from biochemistry to metal extraction. Dr. K. Barry Sharpless first revealed their potential as chiral ligands for asymmetric synthesis in 1977: He published the chiral vanadium-hydroxamic-acid-catalyzed, enantioselective epoxidation of allylic alcohols before his discovery of Sharpless asymmetric epoxidation, which uses the titanium-tartrate complex as the chiral reagent. However, researchers have reported few highly enantioselective reactions using metal-hydroxamic acid as catalysts since then. This Account summarizes our research on metal-catalyzed asymmetric epoxidation using hydroxamic acids as chiral ligands. We designed and synthesized a series of new hydroxamic acids, most notably the C2-symmetric bis-hydroxamic acid (BHA) family. V-BHA-catalyzed epoxidation of allylic and homoallylic alcohols achieved higher activity and stereoselectivity than Sharpless asymmetric epoxidation in many cases. Changing the metal species led to a series of unprecedented asymmetric epoxidation reactions, such as (i) single olefins and sulfides with Mo-BHA, (ii) homoallylic and bishomoallylic alcohols with Zr- and Hf-BHA, and (iii) N-alkenyl sulfonamides and N-sulfonyl imines with Hf-BHA. These reactions produce uniquely functionalized chiral epoxides with good yields and enantioselectivities. PMID:23157425

  11. Development of Purine-Based Hydroxamic Acid Derivatives: Potent Histone Deacetylase Inhibitors with Marked in Vitro and in Vivo Antitumor Activities.

    PubMed

    Chen, Yong; Wang, Xiaoyan; Xiang, Wei; He, Lin; Tang, Minghai; Wang, Fang; Wang, Taijin; Yang, Zhuang; Yi, Yuyao; Wang, Hairong; Niu, Ting; Zheng, Li; Lei, Lei; Li, Xiaobin; Song, Hang; Chen, Lijuan

    2016-06-01

    In the present study, a series of novel histone deacetylase (HDAC) inhibitors using the morpholinopurine as the capping group were designed and synthesized. Several compounds demonstrated significant HDAC inhibitory activities and antiproliferative effects against diverse human tumor cell lines. Among them, compound 10o was identified as a potent class I and class IIb HDAC inhibitor with good pharmaceutical profile and druglike properties. Western blot analysis further confirmed that 10o more effectively increased acetylated histone H3 than panobinostat (LBH-589) and vorinostat (SAHA) at the same concentration in vitro. In in vivo efficacy evaluations of HCT116, MV4-11, Ramos, and MM1S xenograft models, 10o showed higher efficacy than SAHA or LBH-589 without causing significant loss of body weight and toxicity. All the results indicated that 10o could be a suitable candidate for treatment of both solid and hematological cancer. PMID:27186676

  12. Blocking TH17-polarizing cytokines by histone deacetylase inhibitors in vitro and in vivo

    PubMed Central

    Bosisio, Daniela; Vulcano, Marisa; Del Prete, Annalisa; Sironi, Marina; Salvi, Valentina; Salogni, Laura; Riboldi, Elena; Leoni, Flavio; Dinarello, Charles A.; Girolomoni, Giampiero; Sozzani, Silvano

    2008-01-01

    Histone deacetylase (HDAC) inhibitors are small molecules inducing cell-cycle arrest, differentiation, and apoptosis, currently undergoing clinical trials as anticancer drugs. In addition, emerging evidence suggests HDAC inhibitors may have anti-inflammatory and immunomodulatory properties as well, although the molecular mechanisms remain poorly defined. Given the central role of dendritic cells (DC) in the induction and maintenance of the inflammatory and immune response, we investigated the effects of HDAC inhibitors on the maturation and activation of human monocyte-derived DC in the presence of LPS and IFN-γ. Our results show that the production of TH1- and TH17-inducing cytokines, namely IL-12 and IL-23, was inhibited by trichostatin A (72% and 52%, respectively) and suberoylanilide hydroxamic acid (86% and 83%). Strikingly, HDAC inhibitors were effective if added simultaneously as well as after the proinflammatory challenge, and their effect was not associated to a reduction of expression or function of LPS/IFN-γ receptors. These findings were confirmed in two different murine models. In addition, HDAC inhibitors selectively blocked the production of TH1-attracting chemokines CXCL9, CXCL10, and CXCL11. The reduction of TH1- and TH17-inducing cytokines as well as TH1-attracting chemokines may represent relevant mechanisms through which HDAC inhibitors at nonproapoptotic doses exert their immunomodulatory properties. PMID:18780875

  13. Amidation inhibitors 4-phenyl-3-butenoic acid and 5-(acetylamino)-4-oxo-6-phenyl-2-hexenoic acid methyl ester are novel HDAC inhibitors with anti-tumorigenic properties.

    PubMed

    Ali, Amna; Burns, Timothy J; Lucrezi, Jacob D; May, Sheldon W; Green, George R; Matesic, Diane F

    2015-08-01

    4-Phenyl-3-butenoic acid (PBA) is an inhibitor of peptidylglycine alpha-amidating monooxygenase with anti-inflammatory properties that has been shown to inhibit the growth of ras-mutated epithelial and human lung carcinoma cells. In this report, we show that PBA also increases the acetylation levels of selected histone subtypes in a dose and time dependent manner, an effect that is attributable to the inhibition of histone deacetylase (HDAC) enzymes. Comparison studies with the known HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) using high resolution two-dimensional polyacrylamide gels and Western analysis provide evidence that PBA acts as an HDAC inhibitor within cells. PBA and a more potent amidation inhibitor, 5-(acetylamino)-4-oxo-6-phenyl-2-hexenoic acid methyl ester (AOPHA-Me), inhibit HDAC enzymes in vitro at micromolar concentrations, with IC50 values approximately 30 fold lower for AOPHA-Me than PBA for selected HDAC isoforms. Overall, these results indicate that PBA and AOPHA-Me are novel anti-tumorigenic HDAC inhibitors. PMID:26065689

  14. The heat shock protein 90 inhibitor SNX5422 has a synergistic activity with histone deacetylase inhibitors in induction of death of anaplastic thyroid carcinoma cells.

    PubMed

    Kim, Si Hyoung; Kang, Jun Goo; Kim, Chul Sik; Ihm, Sung-Hee; Choi, Moon Gi; Yoo, Hyung Joon; Lee, Seong Jin

    2016-02-01

    The influence of the heat shock protein 90 (hsp90) inhibitor SNX5422 alone or in combination with the histone deacetylase (HDAC) inhibitors PXD101, suberoylanilide hydroxamic acid (SAHA), and trichostatin A (TSA) on survival of anaplastic thyroid carcinoma (ATC) cells was investigated. In 8505C and CAL62 cells, SNX5422 caused cell death with concomitant changes in the expression of hsp90 client proteins. After treatment of both SNX5422 and PXD101, SAHA and TSA, compared with treatment of SNX5422 alone, cell viability was diminished, whereas inhibition rate and cytotoxic activity were enhanced. All of the combination index values were lower than 1.0, suggesting the synergism between SNX5422 and PXD101, SAHA and TSA in induction of cell death. In cells treated with both SNX5422 and PXD101, SAHA and TSA, compared with cells treated with SNX5422 alone, the protein levels of Akt, phospho-4EBP1, phospho-S6 K, and survivin were diminished, while those of γH2AX, acetyl. histone H3, acetyl. histone H4, cleaved PARP, and cleaved caspase-3 were enhanced. In conclusion, these results demonstrate that SNX5422 has a cytotoxic activity in conjunction with alterations in the expression of hsp90 client proteins in ATC cells. Moreover, SNX5422 synergizes with HDAC inhibitors in induction of cytotoxicity accompanied by the suppression of PI3K/Akt/mTOR signaling and survivin, and the overexpression of DNA damage-related proteins in ATC cells. PMID:26219406

  15. Histone Deacetylase Inhibitors Antagonize Distinct Pathways to Suppress Tumorigenesis of Embryonal Rhabdomyosarcoma

    PubMed Central

    Vleeshouwer-Neumann, Terra; Phelps, Michael; Bammler, Theo K.; MacDonald, James W.; Jenkins, Isaac; Chen, Eleanor Y.

    2015-01-01

    Embryonal rhabdomyosarcoma (ERMS) is the most common soft tissue cancer in children. The prognosis of patients with relapsed or metastatic disease remains poor. ERMS genomes show few recurrent mutations, suggesting that other molecular mechanisms such as epigenetic regulation might play a major role in driving ERMS tumor biology. In this study, we have demonstrated the diverse roles of histone deacetylases (HDACs) in the pathogenesis of ERMS by characterizing effects of HDAC inhibitors, trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA; also known as vorinostat) in vitro and in vivo. TSA and SAHA suppress ERMS tumor growth and progression by inducing myogenic differentiation as well as reducing the self-renewal and migratory capacity of ERMS cells. Differential expression profiling and pathway analysis revealed downregulation of key oncogenic pathways upon HDAC inhibitor treatment. By gain-of-function, loss-of-function, and chromatin immunoprecipitation (ChIP) studies, we show that Notch1- and EphrinB1-mediated pathways are regulated by HDACs to inhibit differentiation and enhance migratory capacity of ERMS cells, respectively. Our study demonstrates that aberrant HDAC activity plays a major role in ERMS pathogenesis. Druggable targets in the molecular pathways affected by HDAC inhibitors represent novel therapeutic options for ERMS patients. PMID:26636678

  16. Long-Term Culture of Porcine Induced Pluripotent Stem-Like Cells Under Feeder-Free Conditions in the Presence of Histone Deacetylase Inhibitors.

    PubMed

    Petkov, Stoyan; Glage, Silke; Nowak-Imialek, Monika; Niemann, Heiner

    2016-03-01

    The reprogramming of somatic cells to induced pluripotent stem cells (iPSCs) is a complex process that involves significant epigenetic alterations in the reprogrammed cells. Epigenetic modifiers such as histone deacetylase (HDAC) inhibitors have been shown to increase the efficiency of derivation of iPSCs in humans and mice. In this study, we used three HDAC inhibitors, valproic acid, sodium butyrate, and suberoylanilide hydroxamic acid, together with ascorbic acid, for derivation and long-term feeder-free culture of porcine iPS-like cells. In the absence of exogenous growth factors and/or small molecules, these inhibitors were able to maintain the expression of key pluripotency markers, including genes known to be specific for naive pluripotent state in mouse stem cells, for over 60 passages under feeder-free conditions. Surprisingly, the cells became dependent on HDAC inhibitors for the maintenance of proliferation. Moreover, despite showing successful integration into blastocysts upon injection, the cells were unable to undergo normal differentiation in vitro and in vivo in the form of teratomas. Our results suggest that HDAC inhibitors maintain pluripotency gene expression of porcine iPSC-like cells in long-term culture, but prevent lineage specification, requiring further optimization of culture conditions for porcine iPSC derivation. PMID:26691930

  17. Suberoylanilide Hydroxamic Acid in Treating Patients With Metastatic and/or Locally Advanced or Locally Recurrent Thyroid Cancer

    ClinicalTrials.gov

    2014-07-23

    Insular Thyroid Cancer; Recurrent Thyroid Cancer; Stage II Follicular Thyroid Cancer; Stage II Papillary Thyroid Cancer; Stage IV Follicular Thyroid Cancer; Stage IV Papillary Thyroid Cancer; Thyroid Gland Medullary Carcinoma

  18. Designing Hydroxamates and Reversed Hydroxamates to Inhibit Zinc-containing Proteases but not Cytochrome P450s: Insights from Quantum Mechanics and Protein-ligand Crystal Structures.

    PubMed

    Barker, Charlotte; Lukac, Iva; Leach, Andrew G

    2015-09-01

    The Hydroxamate is a useful functional group that binds to metals in a range of enzymes, notably zinc in matrix metalloproteases and histone deacetylases. The group is also able to form interactions with iron leading to inhibition of the cytochromes P450, particularly the 3A4 isoform. We have studied the available crystal structures of zinc-containing proteins bound to hydroxamates and compared the observed geometries with those found by quantum mechanical calculations. This has revealed the likely binding mode preferences for neutral and anionic protonation states and highlighted the importance of electrostatic complementarity. Calculations were also performed for the interaction of the hydroxamate with iron in a heme environment, as found in the cytochromes P450. These reveal that the preferred binding mode of hydroxamates in this environment involves the s-trans conformation. These calculations provide design guidelines for those interested in designing inhibitors of metalloenzymes that do not block metabolism of other drugs. The ability to predict the geometries and energies of binding modes that cannot be studied experimentally is an advantage offered by this kind of study. PMID:27490712

  19. A novel small molecule inhibitor of deubiquitylating enzyme USP14 and UCHL5 induces apoptosis in multiple myeloma and overcomes bortezomib resistance

    PubMed Central

    Tian, Ze; D’Arcy, Padraig; Wang, Xin; Ray, Arghya; Tai, Yu-Tzu; Hu, Yiguo; Carrasco, Ruben D.; Richardson, Paul; Linder, Stig; Anderson, Kenneth C.

    2014-01-01

    Proteasome inhibitors have demonstrated that targeting protein degradation is effective therapy in multiple myeloma (MM). Here we show that deubiquitylating enzymes (DUBs) USP14 and UCHL5 are more highly expressed in MM cells than in normal plasma cells. USP14 and UCHL5 short interfering RNA knockdown decreases MM cell viability. A novel 19S regulatory particle inhibitor b-AP15 selectively blocks deubiquitylating activity of USP14 and UCHL5 without inhibiting proteasome activity. b-AP15 decreases viability in MM cell lines and patient MM cells, inhibits proliferation of MM cells even in the presence of bone marrow stroma cells, and overcomes bortezomib resistance. Anti-MM activity of b-AP15 is associated with growth arrest via downregulation of CDC25C, CDC2, and cyclin B1 as well as induction of caspase-dependent apoptosis and activation of unfolded protein response. In vivo studies using distinct human MM xenograft models show that b-AP15 is well tolerated, inhibits tumor growth, and prolongs survival. Combining b-AP15 with suberoylanilide hydroxamic acid, lenalidomide, or dexamethasone induces synergistic anti-MM activity. Our preclinical data showing efficacy of b-AP15 in MM disease models validates targeting DUBs in the ubiquitin proteasomal cascade to overcome proteasome inhibitor resistance and provides the framework for clinical evaluation of USP14/UCHL5 inhibitors to improve patient outcome in MM. PMID:24319254

  20. A novel small molecule inhibitor of deubiquitylating enzyme USP14 and UCHL5 induces apoptosis in multiple myeloma and overcomes bortezomib resistance.

    PubMed

    Tian, Ze; D'Arcy, Padraig; Wang, Xin; Ray, Arghya; Tai, Yu-Tzu; Hu, Yiguo; Carrasco, Ruben D; Richardson, Paul; Linder, Stig; Chauhan, Dharminder; Anderson, Kenneth C

    2014-01-30

    Proteasome inhibitors have demonstrated that targeting protein degradation is effective therapy in multiple myeloma (MM). Here we show that deubiquitylating enzymes (DUBs) USP14 and UCHL5 are more highly expressed in MM cells than in normal plasma cells. USP14 and UCHL5 short interfering RNA knockdown decreases MM cell viability. A novel 19S regulatory particle inhibitor b-AP15 selectively blocks deubiquitylating activity of USP14 and UCHL5 without inhibiting proteasome activity. b-AP15 decreases viability in MM cell lines and patient MM cells, inhibits proliferation of MM cells even in the presence of bone marrow stroma cells, and overcomes bortezomib resistance. Anti-MM activity of b-AP15 is associated with growth arrest via downregulation of CDC25C, CDC2, and cyclin B1 as well as induction of caspase-dependent apoptosis and activation of unfolded protein response. In vivo studies using distinct human MM xenograft models show that b-AP15 is well tolerated, inhibits tumor growth, and prolongs survival. Combining b-AP15 with suberoylanilide hydroxamic acid, lenalidomide, or dexamethasone induces synergistic anti-MM activity. Our preclinical data showing efficacy of b-AP15 in MM disease models validates targeting DUBs in the ubiquitin proteasomal cascade to overcome proteasome inhibitor resistance and provides the framework for clinical evaluation of USP14/UCHL5 inhibitors to improve patient outcome in MM. PMID:24319254

  1. Antileukemic activity of the HSP70 inhibitor pifithrin-μ in acute leukemia.

    PubMed

    Kaiser, M; Kühnl, A; Reins, J; Fischer, S; Ortiz-Tanchez, J; Schlee, C; Mochmann, L H; Heesch, S; Benlasfer, O; Hofmann, W-K; Thiel, E; Baldus, C D

    2011-07-01

    Heat shock protein (HSP) 70 is aberrantly expressed in different malignancies and has emerged as a promising new target for anticancer therapy. Here, we analyzed the in vitro antileukemic effects of pifithrin-μ (PFT-μ), an inhibitor of inducible HSP70, in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) cell lines, as well as in primary AML blasts. PFT-μ significantly inhibited cell viability at low micromolar concentrations in all cell lines tested, with IC50 values ranging from 2.5 to 12.7 μ, and was highly active in primary AML blasts with a median IC50 of 8.9 μ (range 5.7-37.2). Importantly, higher IC50 values were seen in normal hematopoietic cells. In AML and ALL, PFT-μ induced apoptosis and cell cycle arrest in a dose-dependent fashion. PFT-μ also led to an increase of the active form of caspase-3 and reduced the intracellular concentrations of AKT and ERK1/2 in NALM-6 cells. Moreover, PFT-μ enhanced cytotoxicity of cytarabine, 17-(allylamino)-17-desmethoxygeldanamycin, suberoylanilide hydroxamic acid, and sorafenib in NALM-6, TOM-1 and KG-1a cells. This is the first study demonstrating significant antileukemic effects of the HSP70 inhibitor PFT-μ, alone and in combination with different antineoplastic drugs in both AML and ALL. Our results suggest a potential therapeutic role for PFT-μ in acute leukemias. PMID:22829184

  2. Antileukemic activity of the HSP70 inhibitor pifithrin-μ in acute leukemia

    PubMed Central

    Kaiser, M; Kühnl, A; Reins, J; Fischer, S; Ortiz-Tanchez, J; Schlee, C; Mochmann, L H; Heesch, S; Benlasfer, O; Hofmann, W-K; Thiel, E; Baldus, C D

    2011-01-01

    Heat shock protein (HSP) 70 is aberrantly expressed in different malignancies and has emerged as a promising new target for anticancer therapy. Here, we analyzed the in vitro antileukemic effects of pifithrin-μ (PFT-μ), an inhibitor of inducible HSP70, in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) cell lines, as well as in primary AML blasts. PFT-μ significantly inhibited cell viability at low micromolar concentrations in all cell lines tested, with IC50 values ranging from 2.5 to 12.7 μ, and was highly active in primary AML blasts with a median IC50 of 8.9 μ (range 5.7–37.2). Importantly, higher IC50 values were seen in normal hematopoietic cells. In AML and ALL, PFT-μ induced apoptosis and cell cycle arrest in a dose-dependent fashion. PFT-μ also led to an increase of the active form of caspase-3 and reduced the intracellular concentrations of AKT and ERK1/2 in NALM-6 cells. Moreover, PFT-μ enhanced cytotoxicity of cytarabine, 17-(allylamino)-17-desmethoxygeldanamycin, suberoylanilide hydroxamic acid, and sorafenib in NALM-6, TOM-1 and KG-1a cells. This is the first study demonstrating significant antileukemic effects of the HSP70 inhibitor PFT-μ, alone and in combination with different antineoplastic drugs in both AML and ALL. Our results suggest a potential therapeutic role for PFT-μ in acute leukemias. PMID:22829184

  3. Histone deacetylase inhibitors induce growth arrest and differentiation in uveal melanoma

    PubMed Central

    Landreville, Solange; Agapova, Olga A.; Matatall, Katie A.; Kneass, Zachary T.; Onken, Michael D.; Lee, Ryan S.; Bowcock, Anne M.; Harbour, J. William

    2011-01-01

    Purpose Metastasis is responsible for the death of most cancer patients, yet few therapeutic agents are available which specifically target the molecular events that lead to metastasis. We recently showed that inactivating mutations in the tumor suppressor gene BAP1 are closely associated with loss of melanocytic differentiation in uveal melanoma and metastasis (UM). The purpose of this study was to identify therapeutic agents that reverse the phenotypic effects of BAP1 loss in UM. Experimental Design In silico screens were performed to identify therapeutic compounds predicted to differentiate UM cells using Gene Set Enrichment Analysis and Connectivity Map databases. Valproic acid, trichostatin A, LBH-589 and suberoylanilide hydroxamic acid were evaluated for their effects on UM cells using morphologic evaluation, MTS viability assays, BrdU incorporation, flow cytometry, clonogenic assays, gene expression profiling, histone acetylation and ubiquitination assays, and a murine xenograft tumorigenicity model. Results HDAC inhibitors induced morphologic differentiation, cell cycle exit, and a shift to a differentiated, melanocytic gene expression profile in cultured UM cells. Valproic acid inhibited the growth of UM tumors in vivo. Conclusions These findings suggest that HDAC inhibitors may have therapeutic potential for inducing differentiation and prolonged dormancy of micrometastatic disease in UM. PMID:22038994

  4. Antitumor Action of a Novel Histone Deacetylase Inhibitor, YF479, in Breast Cancer1

    PubMed Central

    Zhang, Tao; Chen, Yihua; Li, Jingjie; Yang, Feifei; Wu, Haigang; Dai, Fujun; Hu, Meichun; Lu, Xiaoling; Peng, Yi; Liu, Mingyao; Zhao, Yongxiang; Yi, Zhengfang

    2014-01-01

    Accumulating evidence demonstrates important roles for histone deacetylase in tumorigenesis (HDACs), highlighting them as attractive targets for antitumor drug development. Histone deactylase inhibitors (HDACIs), which have shown favorable anti-tumor activity with low toxicity in clinical investigations, are a promising class of anticancer therapeutics. Here, we screened our compound library to explore small molecules that possess anti-HDAC activity and identified a novel HDACI, YF479. Suberoylanilide hydroxamic acid (SAHA), which was the first approved HDAC inhibitor for clinical treatment by the FDA, was as positive control in our experiments. We further demonstrated YF479 abated cell viability, suppressed colony formation and tumor cell motility in vitro. To investigate YF479 with superior pharmacodynamic properties, we developed spontaneous and experimental breast cancer animal models. Our results showed YF479 significantly inhibited breast tumor growth and metastasis in vivo. Further study indicated YF479 suppressed both early and end stages of metastatic progression. Subsequent adjuvant chemotherapy animal experiment revealed the elimination of local-regional recurrence (LRR) and distant metastasis by YF479. More important, YF479 remarkably prolonged the survival of tumor-bearing mice. Intriguingly, YF479 displayed more potent anti-tumor activity in vitro and in vivo compared with SAHA. Together, our results suggest that YF479, a novel HDACI, inhibits breast tumor growth, metastasis and recurrence. In light of these results, YF479 may be an effective therapeutic option in clinical trials for patients burdened by breast cancer. PMID:25220594

  5. Targeting autophagy augments the anticancer activity of the histone deacetylase inhibitor SAHA to overcome Bcr-Abl–mediated drug resistance

    PubMed Central

    Carew, Jennifer S.; Nawrocki, Steffan T.; Kahue, Charissa N.; Zhang, Hui; Yang, Chunying; Chung, Linda; Houghton, Janet A.; Huang, Peng; Giles, Francis J.

    2007-01-01

    Novel therapeutic strategies are needed to address the emerging problem of imatinib resistance. The histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) is being evaluated for imatinib-resistant chronic myelogenous leukemia (CML) and has multiple cellular effects, including the induction of autophagy and apoptosis. Considering that autophagy may promote cancer cell survival, we hypothesized that disrupting autophagy would augment the anticancer activity of SAHA. Here we report that drugs that disrupt the autophagy pathway dramatically augment the antineoplastic effects of SAHA in CML cell lines and primary CML cells expressing wild-type and imatinib-resistant mutant forms of Bcr-Abl, including T315I. This regimen has selectivity for malignant cells and its efficacy was not diminished by impairing p53 function, another contributing factor in imatinib resistance. Disrupting autophagy by chloroquine treatment enhances SAHA-induced superoxide generation, triggers relocalization and marked increases in the lysosomal protease cathepsin D, and reduces the expression of the cathepsin-D substrate thioredoxin. Finally, knockdown of cathepsin D diminishes the potency of this combination, demonstrating its role as a mediator of this therapeutic response. Our data suggest that, when combined with HDAC inhibitors, agents that disrupt autophagy are a promising new strategy to treat imatinib-refractory patients who fail conventional therapy. PMID:17363733

  6. Design, synthesis, and antitumor evaluation of histone deacetylase inhibitors with l-phenylglycine scaffold

    PubMed Central

    Zhang, Yingjie; Li, Xiaoguang; Hou, Jinning; Huang, Yongxue; Xu, Wenfang

    2015-01-01

    In our previous research, a novel series of histone deacetylase (HDAC) inhibitors with l-phenylglycine scaffold were designed and synthesized, among which amides D3 and D7 and ureido D18 were far superior to the positive control (suberoylanilide hydroxamic acid [SAHA]) in HDAC inhibition, but were only comparable to SAHA in antiproliferation on tumor cell lines. Herein, further structural derivation of lead compounds D3, D7, and D18 was carried out to improve their cellular activities. Most of our newly synthesized compounds exhibited more potent HDAC inhibitory activities than the positive control SAHA, and several derivatives were even better than their parent compounds. However, compared with SAHA and our lead compounds, only secondary amine series compounds exhibited improved antiproliferative activities, likely due to their appropriate topological polar surface area values and cell permeabilities. In a human histiocytic lymphoma (U937) xenograft model, the most potent secondary amine 9d exhibited similar in vivo antitumor activity to that of SAHA. PMID:26504374

  7. SB939, a novel potent and orally active histone deacetylase inhibitor with high tumor exposure and efficacy in mouse models of colorectal cancer.

    PubMed

    Novotny-Diermayr, Veronica; Sangthongpitag, Kanda; Hu, Chang Yong; Wu, Xiaofeng; Sausgruber, Nina; Yeo, Pauline; Greicius, Gediminas; Pettersson, Sven; Liang, Ai Leng; Loh, Yung Kiang; Bonday, Zahid; Goh, Kee Chuan; Hentze, Hannes; Hart, Stefan; Wang, Haishan; Ethirajulu, Kantharaj; Wood, Jeanette Marjorie

    2010-03-01

    Although clinical responses in liquid tumors and certain lymphomas have been reported, the clinical efficacy of histone deacetylase inhibitors in solid tumors has been limited. This may be in part due to the poor pharmacokinetic of these drugs, resulting in inadequate tumor concentrations of the drug. SB939 is a new hydroxamic acid based histone deacetylase inhibitor with improved physicochemical, pharmaceutical, and pharmacokinetic properties. In vitro, SB939 inhibits class I, II, and IV HDACs, with no effects on other zinc binding enzymes, and shows significant antiproliferative activity against a wide variety of tumor cell lines. It has very favorable pharmacokinetic properties after oral dosing in mice, with >4-fold increased bioavailability and 3.3-fold increased half-life over suberoylanilide hydroxamic acid (SAHA). In contrast to SAHA, SB939 accumulates in tumor tissue and induces a sustained inhibition of histone acetylation in tumor tissue. These excellent pharmacokinetic properties translated into a dose-dependent antitumor efficacy in a xenograft model of human colorectal cancer (HCT-116), with a tumor growth inhibition of 94% versus 48% for SAHA (both at maximum tolerated dose), and was also effective when given in different intermittent schedules. Furthermore, in APC(min) mice, a genetic mouse model of early-stage colon cancer, SB939 inhibited adenoma formation, hemocult scores, and increased hematocrit values more effectively than 5-fluorouracil. Emerging clinical data from phase I trials in cancer patients indicate that the pharmacokinetic and pharmacologic advantages of SB939 are translated to the clinic. The efficacy of SB939 reported here in two very different models of colorectal cancer warrants further investigation in patients. PMID:20197387

  8. HDAC inhibitors as cognitive enhancers in fear, anxiety and trauma therapy: where do we stand?

    PubMed

    Whittle, Nigel; Singewald, Nicolas

    2014-04-01

    A novel strategy to treat anxiety and fear-related disorders such as phobias, panic and PTSD (post-traumatic stress disorder) is combining CBT (cognitive behavioural therapy), including extinction-based exposure therapy, with cognitive enhancers. By targeting and boosting mechanisms underlying learning, drug development in this field aims at designing CBT-augmenting compounds that help to overcome extinction learning deficits, promote long-term fear inhibition and thus support relapse prevention. Progress in revealing the role of epigenetic regulation of specific genes associated with extinction memory generation has opened new avenues in this direction. The present review examines recent evidence from pre-clinical studies showing that increasing histone acetylation, either via genetic or pharmacological inhibition of HDACs (histone deacetylases) by e.g. vorinostat/SAHA (suberoylanilide hydroxamic acid), entinostat/MS-275, sodium butyrate, TSA (trichostatin A) or VPA (valproic acid), or by targeting HATs (histone acetyltransferases), augments fear extinction and, importantly, generates a long-term extinction memory that can protect from return of fear phenomena. The molecular mechanisms and pathways involved including BDNF (brain-derived neurotrophic factor) and NMDA (N-methyl-D-aspartate) receptor signalling are just beginning to be revealed. First studies in healthy humans are in support of extinction-facilitating effects of HDAC inhibitors. Very recent evidence that HDAC inhibitors can rescue deficits in extinction-memory-impaired rodents indicates a potential clinical utility of this approach also for exposure therapy-resistant patients. Important future work includes investigation of the long-term safety aspects of HDAC inhibitor treatment, as well as design of isotype(s)-specific inhibitors. Taken together, HDAC inhibitors display promising potential as pharmacological adjuncts to augment the efficacy of exposure-based approaches in anxiety and trauma therapy

  9. Biological Effect of a Hybrid Anticancer Agent Based on Kinase and Histone Deacetylase Inhibitors on Triple-Negative (MDA-MB231) Breast Cancer Cells.

    PubMed

    Librizzi, Mariangela; Spencer, John; Luparello, Claudio

    2016-01-01

    We examined the effects of the histone deacetylase inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA) combined with the vascular endothelial growth factor receptor-1/2 inhibitor (3Z)-5-hydroxy-3-(1H-pyrrol-2-ylmethylidene)-2,3-dihydro-1H-indol-2-one on MDA-MB-231 breast cancer cells (triple-negative) in the form of both a cocktail of the separate compounds and a chemically synthesized hybrid (N-hydroxy-N'-[(3Z)-2-oxo-3-(1H-pyrrol-2-ylmethylidene)-2,3-dihydro-1H-indol-5-yl]octanediamide). Comparative flow cytometric and Western blot analyses were performed on cocktail- and hybrid-treated cells to evaluate cell cycle distribution, autophagy/apoptosis modulation, and mitochondrial metabolic state in order to understand the cellular basis of the cytotoxic effect. Cell cycle analysis showed a perturbation of the rate of progression through the cycle, with aspects of redistribution of cells over different cycle phases for the two treatments. In addition, the results suggest that the two distinct classes of compounds under investigation could induce cell death by different preferential pathways, i.e., autophagy inhibition (the cocktail) or apoptosis promotion (the hybrid), thus confirming the enhanced potential of the hybrid approach vs. the combination approach in finely tuning the biological activities of target cells and also showing the hybrid compound as an additional promising drug-like molecule for the prevention or therapy of "aggressive" breast carcinoma. PMID:27483253

  10. PLGA-PEG Nanoparticles Coated with Anti-CD45RO and Loaded with HDAC Plus Protease Inhibitors Activate Latent HIV and Inhibit Viral Spread

    NASA Astrophysics Data System (ADS)

    Tang, Xiaolong; Liang, Yong; Liu, Xinkuang; Zhou, Shuping; Liu, Liang; Zhang, Fujina; Xie, Chunmei; Cai, Shuyu; Wei, Jia; Zhu, Yongqiang; Hou, Wei

    2015-10-01

    Activating HIV-1 proviruses in latent reservoirs combined with inhibiting viral spread might be an effective anti-HIV therapeutic strategy. Active specific delivery of therapeutic drugs into cells harboring latent HIV, without the use of viral vectors, is a critical challenge to this objective. In this study, nanoparticles of poly(lactic-co-glycolic acid)-polyethylene glycol diblock copolymers conjugated with anti-CD45RO antibody and loaded with the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) and/or protease inhibitor nelfinavir (Nel) were tested for activity against latent virus in vitro. Nanoparticles loaded with SAHA, Nel, and SAHA + Nel were characterized in terms of size, surface morphology, zeta potential, entrapment efficiency, drug release, and toxicity to ACH-2 cells. We show that SAHA- and SAHA + Nel-loaded nanoparticles can target latently infected CD4+ T-cells and stimulate virus production. Moreover, nanoparticles loaded with SAHA + NEL were capable of both activating latent virus and inhibiting viral spread. Taken together, these data demonstrate the potential of this novel reagent for targeting and eliminating latent HIV reservoirs.

  11. CD1d induction in solid tumor cells by histone deacetylase inhibitors through inhibition of HDAC1/2 and activation of Sp1.

    PubMed

    Yang, Pei-Ming; Lin, Pei-Jie; Chen, Ching-Chow

    2012-04-01

    CD1d is a MHC class-like molecule that presents glycolipids to natural killer T (NKT) cells, then regulates innate and adaptive immunity. The regulation of CD1d gene expression in solid tumors is still largely unknown. Gene expression can be epigenetically regulated by DNA methylation and histone acetylation. We found that histone deacetylase inhibitors, trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA), induced CD1d gene expression in human (A549 and NCI-H292) and mouse (TC-1 and B16/F0) cancer cells. Simultaneous knockdown of HDAC1 and 2 induced CD1d gene expression. Sp1 inhibitor mitramycin A (MTM) blocked TSA- and SAHA-induced CD1d mRNA expression and Sp1 luciferase activity. Co-transfection of GAL4-Sp1 and Fc-luciferase reporters demonstrated that TSA and SAHA induced Sp1 luciferase reporter activity by enhancing Sp1 transactivation activity. The binding of Sp1 to CD1d promoter and histone H3 acetylation on Sp1 sites were increased by TSA and SAHA. These results indicate that TSA and SAHA could up-regulate CD1d expression in tumor cells through inhibition of HDAC1/2 and activation of Sp1. PMID:22419072

  12. Biological Effect of a Hybrid Anticancer Agent Based on Kinase and Histone Deacetylase Inhibitors on Triple-Negative (MDA-MB231) Breast Cancer Cells

    PubMed Central

    Librizzi, Mariangela; Spencer, John; Luparello, Claudio

    2016-01-01

    We examined the effects of the histone deacetylase inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA) combined with the vascular endothelial growth factor receptor-1/2 inhibitor (3Z)-5-hydroxy-3-(1H-pyrrol-2-ylmethylidene)-2,3-dihydro-1H-indol-2-one on MDA-MB-231 breast cancer cells (triple-negative) in the form of both a cocktail of the separate compounds and a chemically synthesized hybrid (N-hydroxy-N'-[(3Z)-2-oxo-3-(1H-pyrrol-2-ylmethylidene)-2,3-dihydro-1H-indol-5-yl]octanediamide). Comparative flow cytometric and Western blot analyses were performed on cocktail- and hybrid-treated cells to evaluate cell cycle distribution, autophagy/apoptosis modulation, and mitochondrial metabolic state in order to understand the cellular basis of the cytotoxic effect. Cell cycle analysis showed a perturbation of the rate of progression through the cycle, with aspects of redistribution of cells over different cycle phases for the two treatments. In addition, the results suggest that the two distinct classes of compounds under investigation could induce cell death by different preferential pathways, i.e., autophagy inhibition (the cocktail) or apoptosis promotion (the hybrid), thus confirming the enhanced potential of the hybrid approach vs. the combination approach in finely tuning the biological activities of target cells and also showing the hybrid compound as an additional promising drug-like molecule for the prevention or therapy of “aggressive” breast carcinoma. PMID:27483253

  13. 45Ti extraction using hydroxamate resin

    NASA Astrophysics Data System (ADS)

    Gagnon, K.; Severin, G. W.; Barnhart, T. E.; Engle, J. W.; Valdovinos, H. F.; Nickles, R. J.

    2012-12-01

    As an attractive radionuclide for positron emission tomography, this study explores the extraction and reactivity of 45Ti produced via the 45Sc(p,n)45Ti reaction on a GE PETtrace. Using a small hydroxamate column, we have demonstrated an overall recovery of >50% of 45Ti in ˜1 mL of 1M oxalic acid. Conditions for reacting with desferal were also explored, with effective specific activities up to 38 GBq/μmol obtained.

  14. Profiling the anti-protozoal activity of anti-cancer HDAC inhibitors against Plasmodium and Trypanosoma parasites.

    PubMed

    Engel, Jessica A; Jones, Amy J; Avery, Vicky M; Sumanadasa, Subathdrage D M; Ng, Susanna S; Fairlie, David P; Adams, Tina S; Andrews, Katherine T

    2015-12-01

    Histone deacetylase (HDAC) enzymes work together with histone acetyltransferases (HATs) to reversibly acetylate both histone and non-histone proteins. As a result, these enzymes are involved in regulating chromatin structure and gene expression as well as other important cellular processes. HDACs are validated drug targets for some types of cancer, with four HDAC inhibitors clinically approved. However, they are also showing promise as novel drug targets for other indications, including malaria and other parasitic diseases. In this study the in vitro activity of four anti-cancer HDAC inhibitors was examined against parasites that cause malaria and trypanosomiasis. Three of these inhibitors, suberoylanilide hydroxamic acid (SAHA; vorinostat(®)), romidepsin (Istodax(®)) and belinostat (Beleodaq(®)), are clinically approved for the treatment of T-cell lymphoma, while the fourth, panobinostat, has recently been approved for combination therapy use in certain patients with multiple myeloma. All HDAC inhibitors were found to inhibit the growth of asexual-stage Plasmodium falciparum malaria parasites in the nanomolar range (IC50 10-200 nM), while only romidepsin was active at sub-μM concentrations against bloodstream form Trypanosoma brucei brucei parasites (IC50 35 nM). The compounds were found to have some selectivity for malaria parasites compared with mammalian cells, but were not selective for trypanosome parasites versus mammalian cells. All compounds caused hyperacetylation of histone and non-histone proteins in P. falciparum asexual stage parasites and inhibited deacetylase activity in P. falciparum nuclear extracts in addition to recombinant PfHDAC1 activity. P. falciparum histone hyperacetylation data indicate that HDAC inhibitors may differentially affect the acetylation profiles of histone H3 and H4. PMID:26199860

  15. Proteasome inhibitor MG-132 enhances histone deacetylase inhibitor SAHA-induced cell death of chronic myeloid leukemia cells by an ROS-mediated mechanism and downregulation of the Bcr-Abl fusion protein

    PubMed Central

    ZHOU, WENJING; ZHU, WEIWEI; MA, LIYA; XIAO, FENG; QIAN, WENBIN

    2015-01-01

    Recently, there has been progress in the treatment of chronic myeloid leukemia (CML). However, novel therapeutic strategies are required in order to address the emerging problem of imatinib resistance. Histone deacetylase inhibitors (HDACi) and proteasome inhibitors are promising alternatives, and may be amenable to integration with current therapeutic approaches. However, the mechanisms underlying the interaction between these two agents remain unclear. The present study assessed the cytotoxic effect of the HDACi, suberoylanilide hydroxamic acid (SAHA), in combination with the proteasome inhibitor, MG-132, in imatinib-sensitive K562 and imatinib-resistant K562G cells, and investigated the mechanism underlying this effect. Cell viability was measured using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method and protein expression levels were determined by western blotting. Reactive oxygen species (ROS) generation levels were observed under a fluorescence microscope The results indicated that SAHA and MG-132 act in a synergistic manner to induce cell death in K562 and K562G cells. This effect was associated with Bcr-Abl downregulation and the production of ROS. Notably, the ROS scavenger, N-acetyl-L-cysteine, almost fully reversed the cell death and Bcr-Abl downregulation that was induced by the combination of SAHA and MG-132. By contrast, the pan-caspase inhibitor, z-VAD-fmk, only partially reversed the cell death induced by these two drugs in CML cells. These results indicated that increased intracellular ROS levels are important in the induction of cell death and the downregulation of Bcr-Abl. In conclusion, the present results suggested that combined SAHA and MG-132 may be a promising treatment for CML. PMID:26722260

  16. NBM-T-L-BMX-OS01, Semisynthesized from Osthole, Is a Novel Inhibitor of Histone Deacetylase and Enhances Learning and Memory in Rats

    PubMed Central

    Yang, Ying-Chen; Chen, Chia-Nan; Wu, Carol-Imei; Huang, Wei-Jan; Kuo, Tsun-Yung; Kuan, Ming-Chung; Tsai, Tung-Hu; Huang, Jing-Shi; Huang, Chung-Yang

    2013-01-01

    NBM-T-L-BMX-OS01 (BMX) was derived from the semisynthesis of osthole, isolated from Cnidium monnieri (L.) Cuss., and was identified to be a potent inhibitor of HDAC8. This study shows that HDAC8 is highly expressed in the pancreas and the brain. The function of HDAC8 in the brain has not been adequately studied. Because BMX enhances neurite outgrowth and cAMP response element-binding protein (CREB) activation, the effect of BMX on neural plasticity such as learning and memory is examined. To examine declarative and nondeclarative memory, a water maze, a passive one-way avoidance task, and a novel object recognition task were performed. Results from the water maze revealed that BMX and suberoylanilide-hydroxamic-acid-(SAHA-) treated rats showed shorter escape latency in finding the hidden platform. The BMX-treated animals spent more time in the target quadrant in the probe trial performance. An analysis of the passive one-way avoidance results showed that the BMX-treated animals stayed longer in the illuminated chamber by 1 day and 7 days after footshock. The novel object recognition task revealed that the BMX-treated animals showed a marked increase in the time spent exploring novel objects. Furthermore, BMX ameliorates scopolamine-(Sco-) induced learning and memory impairment in animals, indicating a novel role of BMX in learning and memory. PMID:23606881

  17. NBM-T-L-BMX-OS01, Semisynthesized from Osthole, Is a Novel Inhibitor of Histone Deacetylase and Enhances Learning and Memory in Rats.

    PubMed

    Yang, Ying-Chen; Chen, Chia-Nan; Wu, Carol-Imei; Huang, Wei-Jan; Kuo, Tsun-Yung; Kuan, Ming-Chung; Tsai, Tung-Hu; Huang, Jing-Shi; Huang, Chung-Yang

    2013-01-01

    NBM-T-L-BMX-OS01 (BMX) was derived from the semisynthesis of osthole, isolated from Cnidium monnieri (L.) Cuss., and was identified to be a potent inhibitor of HDAC8. This study shows that HDAC8 is highly expressed in the pancreas and the brain. The function of HDAC8 in the brain has not been adequately studied. Because BMX enhances neurite outgrowth and cAMP response element-binding protein (CREB) activation, the effect of BMX on neural plasticity such as learning and memory is examined. To examine declarative and nondeclarative memory, a water maze, a passive one-way avoidance task, and a novel object recognition task were performed. Results from the water maze revealed that BMX and suberoylanilide-hydroxamic-acid-(SAHA-) treated rats showed shorter escape latency in finding the hidden platform. The BMX-treated animals spent more time in the target quadrant in the probe trial performance. An analysis of the passive one-way avoidance results showed that the BMX-treated animals stayed longer in the illuminated chamber by 1 day and 7 days after footshock. The novel object recognition task revealed that the BMX-treated animals showed a marked increase in the time spent exploring novel objects. Furthermore, BMX ameliorates scopolamine-(Sco-) induced learning and memory impairment in animals, indicating a novel role of BMX in learning and memory. PMID:23606881

  18. Inhibitors of Histone Deacetylases Attenuate Noise-Induced Hearing Loss.

    PubMed

    Chen, Jun; Hill, Kayla; Sha, Su-Hua

    2016-08-01

    Loss of auditory sensory hair cells is the major pathological feature of noise-induced hearing loss (NIHL). Currently, no established clinical therapies for prevention or amelioration of NIHL are available. The absence of treatments is due to our lack of a comprehensive understanding of the molecular mechanisms underlying noise-induced damage. Our previous study indicates that epigenetic modification of histones alters hair cell survival. In this study, we investigated the effect of noise exposure on histone H3 lysine 9 acetylation (H3K9ac) in the inner ear of adult CBA/J mice and determined if inhibition of histone deacetylases by systemic administration of suberoylanilide hydroxamic acid (SAHA) could attenuate NIHL. Our results showed that H3K9ac was decreased in the nuclei of outer hair cells (OHCs) and marginal cells of the stria vascularis in the basal region after exposure to a traumatic noise paradigm known to induce permanent threshold shifts (PTS). Consistent with these results, levels of histone deacetylases 1, 2, and 3 (HDAC1, HDAC2 and HDAC3) were increased predominately in the nuclei of cochlear cells. Silencing of HDAC1, HDAC2, or HDAC3 with siRNA reduced the expression of the target HDAC in OHCs, but did not attenuate noise-induced PTS, whereas treatment with the pan-HDAC inhibitor SAHA, also named vorinostat, reduced OHC loss, and attenuated PTS. These findings suggest that histone acetylation is involved in the pathogenesis of noise-induced OHC death and hearing loss. Pharmacological targeting of histone deacetylases may afford a strategy for protection against NIHL. PMID:27095478

  19. Histone deacetylase inhibitors and aspirin interact synergistically to induce cell death in ovarian cancer cells.

    PubMed

    Sonnemann, Jürgen; Hüls, Isabel; Sigler, Michael; Palani, Chithra D; Hong, Le Thi Thu; Völker, Uwe; Kroemer, Heyo K; Beck, James F

    2008-07-01

    Histone deacetylase inhibitors (HDIs) as well as non-steroidal anti-inflammatory drugs including aspirin show promise as antineoplastic agents. The treatment with both HDIs and aspirin can result in hyperacetylation of proteins. In this study, we investigated whether HDIs and aspirin interacted in inducing anticancer activity and histone acetylation. We found that the HDIs, suberoylanilide hydroxamic acid and sodium butyrate, and aspirin cooperated to induce cell death in the ovarian cancer cell line, A2780. The effect was synergistic, as evidenced by CI-isobologram analysis. However, aspirin had no effect on histone acetylation, neither in the absence nor presence of HDIs. To gain insight into the mechanism underlying the synergistic action of HDIs and aspirin, we employed the deacetylated metabolite of aspirin, salicylic acid, and the cyclooxygenase-1- and -2-selective inhibitors, SC-560 and NS-398, respectively. We found that HDIs and salicylic acid interacted synergistically, albeit less efficiently than HDIs and aspirin, to induce cancer cell death, suggesting that the acetyl and the salicyl moiety contributed to the cooperative interaction of aspirin with HDIs. SC-560 and NS-398 had little effect both when applied alone or in conjunction with HDIs, indicating that the combinatorial effect of HDIs and aspirin was not the result of cyclo-oxygenase inhibition. In conclusion, our study demonstrates that HDIs and aspirin synergize to induce cancer cell death and, thus, provides a rationale for a more in-depth exploration into the potential of combining HDIs and aspirin as a strategy for anticancer therapy. PMID:18575740

  20. Photoorganocatalytic One-Pot Synthesis of Hydroxamic Acids from Aldehydes.

    PubMed

    Papadopoulos, Giorgos N; Kokotos, Christoforos G

    2016-05-10

    An efficient one-pot synthesis of hydroxamic acids from aldehydes and hydroxylamine is described. A fast, visible-light-mediated metal-free hydroacylation of dialkyl azodicarboxylates was used to develop the subsequent addition of hydroxylamine hydrochloride. A range of aliphatic and aromatic aldehydes were employed in this reaction to give hydroxamic acids in high to excellent yields. Application of the current methodology was demonstrated in the synthesis of the anticancer medicine vorinostat. PMID:27038037

  1. Identification of the hydroxamate siderophore ferricrocin in Cladosporium cladosporioides.

    PubMed

    Pourhassan, Nina; Gagnon, René; Wichard, Thomas; Bellenger, Jean-Philippe

    2014-04-01

    The hydroxamate siderophore ferricrocin was identified in Cladosporium cladosporioides growth medium by solid phase extraction and ultra high pressure liquid chromatography coupled to a time of flight mass spectrometer (UHPLC/QTOF-MS). Both desferricrocin and ferricrocin were detected in the extracellular medium assisted by high resolution mass spectrometry. This is the first identification of a hydroxamate siderophore in Cladosporium cladosporioides. This finding emphasizes the common meaning of ferricrocin in fungi. PMID:24868878

  2. Hyaluronic acid based hydroxamate and conjugates with biologically active amines: In vitro effect on matrix metalloproteinase-2.

    PubMed

    Ponedel'kina, Irina Yu; Gaskarova, Aigul R; Khaybrakhmanova, Elvira A; Lukina, Elena S; Odinokov, Victor N

    2016-06-25

    In this study, water soluble hyaluronic acid (HA) based hydroxamate and conjugates with biologically active amines and hydrazides such as p- and o-aminophenols, anthranilic, 4- and 5-aminosalicylic acids, nicotinic, N-benzylnicotinic and isonicotinic hydrazides, p-aminobenzenesulfonamide (Streptocide), p-aminobenzoic acid diethylaminoethyl ester (Procaine), and 4-amino-2,3-dimethyl-1-phenyl-3-pyrazolin-5-one (4-aminoantipyrene) were examined as matrix metalloproteinase-2 inhibitors (MMPIs). In a dose of 0.27-270μM, the most efficient MMPIs were HA conjugates with o-aminophenol=4-aminoantipyrine>4-aminosalicylic acid>5-aminosalicylic acid. Conjugates with Streptocide, Procaine and HA hydroxamate showed 40-50% inhibitory effect at all used concentrations. Conjugates with anthranilic acid and isonicotinic hydrazide (Isoniazid) in a dose of 0.27μM inhibited enzyme activity by ∼70%, but with the concentration increase their inhibitory effect was decreased. PMID:27083788

  3. Dose-dependent effects of the caspase inhibitor Q-VD-OPh on different apoptosis-related processes.

    PubMed

    Kuželová, Kateřina; Grebeňová, Dana; Brodská, Barbora

    2011-11-01

    The effects of the pan-caspase inhibitor Q-VD-OPh on caspase activity, DNA fragmentation, PARP cleavage, 7A6 exposition, and cellular adhesivity to fibronectin were analyzed in detail in three different apoptotic systems involving two cell lines (JURL-MK1 and HL60) and two apoptosis inducers (imatinib mesylate and suberoylanilide hydroxamic acid). Q-VD-OPh fully inhibited caspase-3 and -7 activity at 0.05  µM concentration as indicated both by the measurement of the rate of Ac-DEVD-AFC cleavage and anti-caspase immunoblots. Caspase-8 was also inhibited at low Q-VD-OPh concentrations. On the other hand, significantly higher Q-VD-OPh dose (10 µM) was required to fully prevent the cleavage of PARP-1. DNA fragmentation and disruption of the cell membrane functionality (Trypan blue exclusion test) were both prevented at 2 µM Q-VD-OPh while 10 µM inhibitor was needed to inhibit the drug-induced loss of cellular adhesivity to fibronectin which was observed in JURL-MK1 cells. The exposition of the mitochondrial antigen 7A6 occurred independently of Q-VD-OPh addition and may serve to the detection of cumulative incidence of the cells which have initiated the apoptosis. Our results show that Q-VD-OPh efficiency in the inhibition of caspase-3 activity and DNA fragmentation in the whole-cell environment is about two orders of magnitude higher than that of z-VAD-fmk. This difference is not due to a slow permeability of the latter through the cytoplasmic membrane. PMID:21751237

  4. Anticolon Cancer Activity of Largazole, a Marine-Derived Tunable Histone Deacetylase InhibitorS⃞

    PubMed Central

    Liu, Yanxia; Salvador, Lilibeth A.; Byeon, Seongrim; Ying, Yongcheng; Kwan, Jason C.; Law, Brian K.; Hong, Jiyong

    2010-01-01

    Histone deacetylases (HDACs) are validated targets for anticancer therapy as attested by the approval of suberoylanilide hydroxamic acid (SAHA) and romidepsin (FK228) for treating cutaneous T cell lymphoma. We recently described the bioassay-guided isolation, structure determination, synthesis, and target identification of largazole, a marine-derived antiproliferative natural product that is a prodrug that releases a potent HDAC inhibitor, largazole thiol. Here, we characterize the anticancer activity of largazole by using in vitro and in vivo cancer models. Screening against the National Cancer Institute's 60 cell lines revealed that largazole is particularly active against several colon cancer cell types. Consequently, we tested largazole, along with several synthetic analogs, for HDAC inhibition in human HCT116 colon cancer cells. Enzyme inhibition strongly correlated with the growth inhibitory effects, and differential activity of largazole analogs was rationalized by molecular docking to an HDAC1 homology model. Comparative genomewide transcript profiling revealed a close overlap of genes that are regulated by largazole, FK228, and SAHA. Several of these genes can be related to largazole's ability to induce cell cycle arrest and apoptosis. Stability studies suggested reasonable bioavailability of the active species, largazole thiol. We established that largazole inhibits HDACs in tumor tissue in vivo by using a human HCT116 xenograft mouse model. Largazole strongly stimulated histone hyperacetylation in the tumor, showed efficacy in inhibiting tumor growth, and induced apoptosis in the tumor. This effect probably is mediated by the modulation of levels of cell cycle regulators, antagonism of the AKT pathway through insulin receptor substrate 1 down-regulation, and reduction of epidermal growth factor receptor levels. PMID:20739454

  5. Inhibition of urease activity by dipeptidyl hydroxamic acids.

    PubMed

    Odake, S; Nakahashi, K; Morikawa, T; Takebe, S; Kobashi, K

    1992-10-01

    A series of dipeptidyl hydroxamic acids (H-X-Gly-NHOH: X = amino acid residues) was synthesized, and the inhibitory activity against Jack bean and Proteus mirabilis ureases [EC 3.5.1.5] was examined. A number of H-X-Gly-NHOH inhibited Jack bean urease with an I50 of the order of 10(-6) M and inhibited Proteus mirabilis urease with an I50 of the order of 10(-5) M. The inhibition against Jack bean urease was more potent than that with the corresponding aminoacyl hydroxamic acids (H-X-NHOH). PMID:1464106

  6. Hydrolysis of aceto-hydroxamic acid under UREX+ conditions

    SciTech Connect

    Alyapyshev, M.; Paulenova, A.; Tkac, P.; Cleveland, M.A.; Bruso, J.E.

    2007-07-01

    Aceto-hydroxamic acid (AHA) is used as a stripping agent In the UREX process. While extraction yields of uranium remain high upon addition of AHA, hexavalent plutonium and neptunium are rapidly reduced to the pentavalent state while the tetravalent species and removed from the product stream. However, under acidic conditions, aceto-hydroxamic acid undergoes hydrolytic degradation. In this study, the kinetics of the hydrolysis of aceto-hydroxamic acid in nitric and perchloric acid media was investigated at several temperatures. The decrease of the concentration of AHA was determined via its ferric complex using UV-Vis spectroscopy. The data obtained were analyzed using the method of initial rates. The data follow the pseudo-first order reaction model. Gamma irradiation of AHA/HNO{sub 3} solutions with 33 kGy/s caused two-fold faster degradation of AHA. The rate equation and thermodynamic data will be presented for the hydrolysis reaction with respect to the concentrations of aceto-hydroxamic acid, nitrate and hydronium ions, and radiation dose. (authors)

  7. Ionic liquid containing hydroxamate and N-alkyl sulfamate ions

    DOEpatents

    Friesen, Cody A.; Wolfe, Derek; Johnson, Paul Bryan

    2016-03-15

    Embodiments of the invention are related to ionic liquids and more specifically to ionic liquids used in electrochemical metal-air cells in which the ionic liquid includes a cation and an anion selected from hydroxamate and/or N-alkyl sulfamate anions.

  8. Real-time monitoring of hematopoietic cell interaction with fibronectin fragment: the effect of histone deacetylase inhibitors.

    PubMed

    Obr, Adam; Röselová, Pavla; Grebeňová, Dana; Kuželová, Kateřina

    2013-01-01

    Real-time cell analysis (RTCA) system based on measurement of electrical microimpedance has been introduced to monitor adherent cell cultures. We describe its use for real-time analysis of hematopoietic cell adhesion to bone marrow stroma proteins. Cells growing in suspension do not generate any significant change in the microimpedance signal until the surface with embedded microelectrodes is coated with a cell-binding protein. We show that in this case, the microimpedance signal specifically reflects cell binding to the coated surface. The optimized method was used to monitor the effect of two histone deacetylase inhibitors, suberoylanilide hydroxamic acid (SAHA) and tubastatin A, on JURL-MK1 cell adhesion to cell-binding fragment of fibronectin (FNF). Both compounds were used in non-toxic concentrations and induced an increase in the cell adhesivity. The kinetics of this increase was markedly slower for SAHA although tubulin hyperacetylation occurred rapidly for any of the two drugs. The strengthening of cell binding to FNF was paralleled with a decrease of Lyn kinase activity monitored using an anti-phospho-Src family antibody. The inhibition of Src kinase activity with PP2 accordingly enhanced JURL-MK1 cell interaction with FNF. Actin filaments were present at the proximity of the plasma membrane and in numerous membrane protrusions. In some cells, F-actin formed clusters at membrane regions interacting with the coated surface and these clusters colocalized with active Lyn kinase. Our results indicate that the role of Src kinases in the regulation of hematopoetic cell adhesion signaling is similar to that of c-Src in adherent cells. PMID:23567296

  9. Design and synthesis of an activity-based protein profiling probe derived from cinnamic hydroxamic acid.

    PubMed

    Ai, Teng; Qiu, Li; Xie, Jiashu; Geraghty, Robert J; Chen, Liqiang

    2016-02-15

    In our continued effort to discover new anti-hepatitis C virus (HCV) agents, we validated the anti-replicon activity of compound 1, a potent and selective anti-HCV hydroxamic acid recently reported by us. Generally favorable physicochemical and in vitro absorption, distribution, metabolism, and excretion (ADME) properties exhibited by 1 made it an ideal parent compound from which activity-based protein profiling (ABPP) probe 3 was designed and synthesized. Evaluation of probe 3 revealed that it possessed necessary anti-HCV activity and selectivity. Therefore, we have successfully obtained compound 3 as a suitable ABPP probe to identify potential molecular targets of compound 1. Probe 3 and its improved analogs are expected to join a growing list of ABPP probes that have made important contributions to not only the studies of biochemical and cellular functions but also discovery of selective inhibitors of protein targets. PMID:26753813

  10. The Therapeutic Potential of AN-7, a Novel Histone Deacetylase Inhibitor, for Treatment of Mycosis Fungoides/Sezary Syndrome Alone or with Doxorubicin

    PubMed Central

    Goldfeiz, Neta; Rephaeli, Ada; Nudelman, Abraham; Weitman, Michal; Tarasenko, Nataly; Gorovitz, Batia; Maron, Leah; Yehezkel, Shiran; Amitay-Laish, Iris; Lubin, Ido; Hodak, Emmilia

    2016-01-01

    The 2 histone deacetylase inhibitors (HDACIs) approved for the treatment of cutaneous T-cell lymphoma (CTCL) including mycosis fungoides/sezary syndrome (MF/SS), suberoylanilide hydroxamic acid (SAHA) and romidepsin, are associated with low rates of overall response and high rates of adverse effects. Data regarding combination treatments with HDACIs is sparse. Butyroyloxymethyl diethylphosphate (AN-7) is a novel HDACI, which was found to have selective anticancer activity in several cell lines and animal models. The aim of this study was to compare the anticancer effects of AN-7 and SAHA, either alone or combined with doxorubicin, on MF/SS cell lines and peripheral blood lymphocytes (PBL) from patients with Sezary syndrome (SPBL). MyLa cells, Hut78 cells, SPBL, and PBL from healthy normal individuals (NPBL) were exposed to the test drugs, and the findings were analyzed by a viability assay, an apoptosis assay, and Western blot. AN-7 was more selectively toxic to MyLa cells, Hut78 cells, and SPBL (relative to NPBL) than SAHA and also acted more rapidly. Both drugs induced apoptosis in MF/SS cell lines, SAHA had a greater effect on MyLa cell line, while AN-7 induced greater apoptosis in SPBL; both caused an accumulation of acetylated histone H3, but AN-7 was associated with earlier kinetics; and both caused a downregulation of the HDAC1 protein in MF/SS cell lines. AN-7 acted synergistically with doxorubicin in both MF/SS cell lines and SPBL, and antagonistically with doxorubicin in NPBL. By contrast, SAHA acted antagonistically with doxorubicin on MF/SS cell lines, SPBL, and NPBL, leaving <50% viable cells. In conclusion, AN-7 holds promise as a therapeutic agent in MF/SS and has several advantages over SAHA. Our data provide a rationale for combining AN-7, but not SAHA, with doxorubicin to induce the cell death in MF/SS. PMID:26752418

  11. Assessment of Interactions between Cisplatin and Two Histone Deacetylase Inhibitors in MCF7, T47D and MDA-MB-231 Human Breast Cancer Cell Lines – An Isobolographic Analysis

    PubMed Central

    Wawruszak, Anna; Luszczki, Jarogniew J.; Grabarska, Aneta; Gumbarewicz, Ewelina; Dmoszynska-Graniczka, Magdalena; Polberg, Krzysztof; Stepulak, Andrzej

    2015-01-01

    Histone deacetylase inhibitors (HDIs) are promising anticancer drugs, which inhibit proliferation of a wide variety of cancer cells including breast carcinoma cells. In the present study, we investigated the influence of valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA, vorinostat), alone or in combination with cisplatin (CDDP) on proliferation, induction of apoptosis and cell cycle progression in MCF7, T47D and MDA-MB-231 human breast carcinoma cell lines. The type of interaction between HDIs and CDDP was determined by an isobolographic analysis. The isobolographic analysis is a very precise and rigorous pharmacodynamic method, to determine the presence of synergism, addition or antagonism between different drugs with using variety of fixed dose ratios. Our experiments show that the combinations of CDDP with SAHA or VPA at a fixed-ratio of 1:1 exerted additive interaction in the viability of MCF7 cells, while in T47D cells there was a tendency to synergy. In contrast, sub-additive (antagonistic) interaction was observed for the combination of CDDP with VPA in MDA-MB-231 “triple-negative” (i.e. estrogen receptor negative, progesterone receptor negative, and HER-2 negative) human breast cancer cells, whereas combination of CDDP with SAHA in the same MDA-MB-231 cell line yielded additive interaction. Additionally, combined HDIs/CDDP treatment resulted in increase in apoptosis and cell cycle arrest in all tested breast cancer cell lines in comparison with a single therapy. In conclusion, the additive interaction of CDDP with SAHA or VPA suggests that HDIs could be combined with CDDP in order to optimize treatment regimen in some human breast cancers. PMID:26580554

  12. Inhibitors

    MedlinePlus

    ... Community Counts Blood Safety Inhibitors Articles & Key Findings Free Materials Videos Starting the Conversation Playing it Safe A Look at Hemophilia Joint Range of Motion My Story Links to Other Websites ...

  13. Behavioral responses of western corn rootworm larvae to naturally occurring and synthetic hydroxamic acids.

    PubMed

    Xie, Y; Arnason, J T; Philogéne, B J; Atkinson, J; Morand, P

    1992-07-01

    Hydroxamic acids have been shown to be toxic to many pest insects and pathogens. In this study, the behavioral responses of western corn rootworm larvae to naturally occurring and synthetic hydroxamic acids were investigated. In a choice test between corn roots treated with hydroxamic acids and roots treated with distilled water (control), western corn rootworm larvae chose to burrow into the control roots significantly more often than compoundtreated roots. In addition, when corn roots were treated with different hydroxamic acids in a designed searching-behavior test, neonate larvae of western corn rootworm responded by significantly reducing the number of turns, while the area searched and locomotor rate significantly increased. The responses were dependent on the concentrations of the test compounds. These results suggested that hydroxamic acids were acting as behavior-modifying and possibly feeding-deterrent chemicals. PMID:24254140

  14. Characterization of iron uptake from hydroxamate siderophores by Chlorella vulgaris

    SciTech Connect

    Allnutt, F.C.T.

    1985-01-01

    Iron uptake by Chlorella vulgaris from ferric-hydroxamate siderophores and the possible production of siderophores by these algae was investigated. No production of siderophores or organic acids was observed. Iron from the two hydroxamate siderophores tested, ferrioximine B (Fe/sup 3 +/-DFOB) and ferric-rhodotorulate (Fe/sup 3 +/-RA), was taken up at the same rate as iron chelated by citrate or caffeate. Two synthetic chelates, Fe/sup 3 +/-EDTA and Fe/sup 3 +/-EDDHA, provided iron at a slower rate. Iron uptake was inhibited by 50 ..mu..M CCCP or 1 mM vanadate. Cyanide (100 ..mu..M KCN) or 25 ..mu..M antimycin A failed to demonstrate a link between uptake and respiration. Labeled iron (/sup 55/Fe) was taken up while labeled ligands ((/sup 14/C) citrate or RA) were not accumulated. Cation competition from Ni/sup 2 +/ and Co/sup 2 +/ observed using Fe/sup 3 +/-DFOB and Fe/sup 3 +/-RA while iron uptake from Fe/sup 3 +/-citrate was stimulated. Iron-stress induced iron uptake from the hydroxamate siderophores. Ferric reduction from the ferric-siderophores was investigated with electron paramagnetic resonance (EPR) and bathophenathroline disulfonate (BPDS). Ferric reduction was induced by iron-stress and inhibited by CCCP. A close correlation between iron uptake and ferric reduction was measured by the EPR method. Ferric reduction measured by the BPDS method was greater than that measure by EPR. BPDS reduction was interpreted to indicate a potential for reduction while EPR measures the physiological rate of reduction. BPDS inhibition of iron uptake and ferricyanide interference with reduction indicate that reduction and uptake occur exposed to the external medium. Presumptive evidence using a binding dose response curve for Fe/sup 3 +/-DFOB indicated that a receptor may be involved in this mechanism.

  15. Zinc cross-linked hydroxamated alginates for pulsed drug release

    PubMed Central

    Raut, Neha S; Deshmukh, Prasad R; Umekar, Milind J; Kotagale, Nandkishor R

    2013-01-01

    Introduction: Alginates can be tailored chemically to improve solubility, physicochemical, and biological properties and its complexation with metal ion is useful for controlling the drug release. Materials And Methods: Synthesized N,O-dimethyl, N-methyl, or N-Benzyl hydroxylamine derivatives of sodium alginate were subsequently complexed with zinc to form beads. Hydroxamation of sodium alginate was confirmed by Fourier transform infra-red spectroscopy (FTIR) and differential scanning calorimetry (DSC). Results: The synthesized polymeric material exhibited reduced aqueous, HCl and NaOH solubility. The hydroxamated derivatives demonstrated pulsed release where change in pH of the dissolution medium stimulated the atenolol release. Conclusion: Atenolol loaded Zn cross-linked polymeric beads demonstrated the sustained the plasma drug levels with increased half-life. Although the synthesized derivatives greatly altered the aqueous solubility of sodium alginate, no significant differences in in vitro and in vivo atenolol release behavior amongst the N,O-dimethyl, N-methyl, or N-Benzyl hydroxylamine derivatives of sodium alginate were observed. PMID:24350039

  16. Histone deacetylase inhibitors suppress RSV infection and alleviate virus-induced airway inflammation.

    PubMed

    Feng, Qiuqin; Su, Zhonglan; Song, Shiyu; Χu, Hui; Zhang, Bin; Yi, Long; Tian, Man; Wang, Hongwei

    2016-09-01

    Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections in infants and young children. However, the majority of RSV-infected patients only show mild symptoms. Different severities of infection and responses among the RSV-infected population indicate that epigenetic regulation as well as personal genetic background may affect RSV infectivity. Histone deacetylase (HDAC) is an important epigenetic regulator in lung diseases. The present study aimed to explore the possible connection between HDAC expression and RSV-induced lung inflammation. To address this question, RSV-infected airway epithelial cells (BEAS‑2B) were prepared and a mouse model of RSV infection was established, and then treated with various concentrations of HDAC inhibitors (HDACis), namely trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA). Viral replication and markers of virus-induced airway inflammation or oxidative stress were assessed. The activation of the nuclear factor-κB (NF-κB), cyclo-oxygenase-2 (COX-2), mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3) signaling pathways was evaluated by western blot analysis. Our results showed that RSV infection in airway epithelial cells (AECs) significantly decreased histone acetylation levels by altering HDAC2 expression. The treatment of RSV-infected AECs with HDACis significantly restricted RSV replication by upregulating the interferon-α (IFN-α) related signaling pathways. The treatment of RSV-infected AECs with HDACis also significantly inhibited RSV-induced pro-inflammatory cytokine release [interleukin (IL)-6 and IL-8] and oxidative stress-related molecule production [malondialdehyde (MDA), and nitrogen monoxide (NO)]. The activation of NF-κB, COX-2, MAPK and Stat3, which orchestrate pro‑inflammatory gene expression and oxidative stress injury, was also significantly inhibited. Our in vivo study using a mouse model of

  17. Histone deacetylase inhibitors suppress RSV infection and alleviate virus-induced airway inflammation

    PubMed Central

    Feng, Qiuqin; Su, Zhonglan; Song, Shiyu; Xu, Hui; Zhang, Bin; Yi, Long; Tian, Man; Wang, Hongwei

    2016-01-01

    Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections in infants and young children. However, the majority of RSV-infected patients only show mild symptoms. Different severities of infection and responses among the RSV-infected population indicate that epigenetic regulation as well as personal genetic background may affect RSV infectivity. Histone deacetylase (HDAC) is an important epigenetic regulator in lung diseases. The present study aimed to explore the possible connection between HDAC expression and RSV-induced lung inflammation. To address this question, RSV-infected airway epithelial cells (BEAS-2B) were prepared and a mouse model of RSV infection was established, and then treated with various concentrations of HDAC inhibitors (HDACis), namely trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA). Viral replication and markers of virus-induced airway inflammation or oxidative stress were assessed. The activation of the nuclear factor-κB (NF-κB), cyclo-oxygenase-2 (COX-2), mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3) signaling pathways was evaluated by western blot analysis. Our results showed that RSV infection in airway epithelial cells (AECs) significantly decreased histone acetylation levels by altering HDAC2 expression. The treatment of RSV-infected AECs with HDACis significantly restricted RSV replication by upregulating the interferon-α (IFN-α) related signaling pathways. The treatment of RSV-infected AECs with HDACis also significantly inhibited RSV-induced pro-inflammatory cytokine release [interleukin (IL)-6 and IL-8] and oxidative stress-related molecule production [malondialdehyde (MDA), and nitrogen monoxide (NO)]. The activation of NF-κB, COX-2, MAPK and Stat3, which orchestrate pro-inflammatory gene expression and oxidative stress injury, was also significantly inhibited. Our in vivo study using a mouse model of RSV infection

  18. Selective flotation of phosphate minerals with hydroxamate collectors

    DOEpatents

    Miller, Jan D.; Wang, Xuming; Li, Minhua

    2002-01-01

    A method is disclosed for separating phosphate minerals from a mineral mixture, particularly from high-dolomite containing phosphate ores. The method involves conditioning the mineral mixture by contacting in an aqueous in environment with a collector in an amount sufficient for promoting flotation of phosphate minerals. The collector is a hydroxamate compound of the formula; ##STR1## wherein R is generally hydrophobic and chosen such that the collector has solubility or dispersion properties it can be distributed in the mineral mixture, typically an alkyl, aryl, or alkylaryl group having 6 to 18 carbon atoms. M is a cation, typically hydrogen, an alkali metal or an alkaline earth metal. Preferably, the collector also comprises an alcohol of the formula, R'--OH wherein R' is generally hydrophobic and chosen such that the collector has solubility or dispersion properties so that it can be distributed in the mineral mixture, typically an alkyl, aryl, or alkylaryl group having 6 to 18 carbon atoms.

  19. Suberoylanilide Hydroxyamic Acid Modification of Chromatin Architecture Affects DNA Break Formation and Repair

    SciTech Connect

    Singh, Sheetal; Le Hongan; Shih, S.-J.; Ho, Bay; Vaughan, Andrew T.

    2010-02-01

    Purpose: Chromatin-modifying compounds that inhibit the activity of histone deacetylases have shown potency as radiosensitizers, but the action of these drugs at a molecular level is not clear. Here we investigated the effect of suberoylanilide hydroxyamic acid (SAHA) on DNA breaks and their repair and induction of rearrangements. Methods and Materials: The effect of SAHA on both clonogenic survival and repair was assessed using cell lines SCC-25, MCF7, and TK6. In order to study unique DNA double-strand breaks, anti-CD95 antibody was employed to introduce a DNA double-strand break at a known location within the 11q23 region. The effects of SAHA on DNA cleavage and rearrangements were analyzed by ligation-mediated PCR and inverse PCR, respectively. Results: SAHA acts as radiosensitizer at 1 {mu}M, with dose enhancement factors (DEFs) at 10% survival of: SCC-25 - 1.24 +- 0.05; MCF7 - 1.16 +- 0.09 and TK6 - 1.17 +- 0.05, and it reduced the capacity of SCC-25 cells to repair radiation induced lesions. Additionally, SAHA treatment diffused site-specific fragmentation over at least 1 kbp in TK6 cells. Chromosomal rearrangements produced in TK6 cells exposed to SAHA showed a reduction in microhomology at the breakpoint between 11q23 and partner chromosomes. Conclusions: SAHA shows efficacy as a radiosensitizer at clinically obtainable levels. In its presence, targeted DNA strand breaks occur over an expanded region, indicating increased chromatin access. The rejoining of such breaks is degraded by SAHA when measured as rearrangements at the molecular level and rejoining that contributes to cell survival.

  20. EXPRESS: Histone hyperacetylation modulates spinal type II metabotropic glutamate receptor alleviating stress-induced visceral hypersensitivity in female rats.

    PubMed

    Cao, Dong-Yuan; Bai, Guang; Ji, Yaping; Karpowicz, Jane M; Traub, Richard J

    2016-01-01

    Stress is often a trigger to exacerbate chronic pain including visceral hypersensitivity associated with irritable bowel syndrome, a female predominant functional bowel disorder. Epigenetic mechanisms that mediate stress responses are a potential target to interfere with visceral pain. The purpose of this study was to examine the effect of a histone deacetylase inhibitor, suberoylanilide hydroxamic acid, on visceral hypersensitivity induced by a subchronic stressor in female rats and to investigate the involvement of spinal glutamate receptors. Three daily sessions of forced swim induced visceral hypersensitivity. Intrathecal suberoylanilide hydroxamic acid prevented or reversed the stress-induced visceral hypersensitivity, increased spinal histone 3 acetylation and increased mGluR2 and mGluR3 expression. Chromatin immunoprecipitation (ChIP) analysis revealed enrichment of H3K9Ac and H3K18Ac at several promoter Grm2 and Grm3 regions. The mGluR2/3 antagonist LY341495 reversed the inhibitory effect of suberoylanilide hydroxamic acid on the stress-induced visceral hypersensitivity. In surprising contrast, stress and/or suberoylanilide hydroxamic acid had no effect on spinal NMDA receptor expression or function. These data reveal histone modification modulates mGluR2/3 expression in the spinal cord to attenuate stressinduced visceral hypersensitivity. HDAC inhibitors may provide a potential approach to relieve visceral hypersensitivity associated with irritable bowel syndrome. PMID:27385724

  1. Histone hyperacetylation modulates spinal type II metabotropic glutamate receptor alleviating stress-induced visceral hypersensitivity in female rats

    PubMed Central

    Cao, Dong-Yuan; Bai, Guang; Ji, Yaping; Karpowicz, Jane

    2016-01-01

    Stress is often a trigger to exacerbate chronic pain including visceral hypersensitivity associated with irritable bowel syndrome, a female predominant functional bowel disorder. Epigenetic mechanisms that mediate stress responses are a potential target to interfere with visceral pain. The purpose of this study was to examine the effect of a histone deacetylase inhibitor, suberoylanilide hydroxamic acid, on visceral hypersensitivity induced by a subchronic stressor in female rats and to investigate the involvement of spinal glutamate receptors. Three daily sessions of forced swim induced visceral hypersensitivity. Intrathecal suberoylanilide hydroxamic acid prevented or reversed the stress-induced visceral hypersensitivity, increased spinal histone 3 acetylation and increased mGluR2 and mGluR3 expression. Chromatin immunoprecipitation (ChIP) analysis revealed enrichment of H3K9Ac and H3K18Ac at several promoter Grm2 and Grm3 regions. The mGluR2/3 antagonist LY341495 reversed the inhibitory effect of suberoylanilide hydroxamic acid on the stress-induced visceral hypersensitivity. In surprising contrast, stress and/or suberoylanilide hydroxamic acid had no effect on spinal NMDA receptor expression or function. These data reveal histone modification modulates mGluR2/3 expression in the spinal cord to attenuate stress-induced visceral hypersensitivity. HDAC inhibitors may provide a potential approach to relieve visceral hypersensitivity associated with irritable bowel syndrome. PMID:27385724

  2. Iron Complexation to Histone Deacetylase Inhibitors SAHA and LAQ824 in PEGylated Liposomes Can Considerably Improve Pharmacokinetics in Rats

    PubMed Central

    Wang, Yan; Tu, Sheng; Steffen, Dana; Xiong, May P.

    2015-01-01

    PURPOSE The formulation of histone deacetylase inhibitors (HDACi) is challenging due to poor water solubility and rapid elimination of drugs in vivo. This study investigated the effects of complexing iron (Fe3+) to the HDACi suberoylanilide hydroxamic acid (SAHA) and LAQ824 (LAQ) prior to their encapsulation into PEGylated liposomes, and investigated whether this technique could improve drug solubility, in vitro release and in vivo pharmacokinetic (PK) properties. METHODS The reaction stoichiometry, binding constants and solubility were measured for Fe complexes of SAHA and LAQ. The complexes were passively encapsulated into PEGylated liposomes and characterized by size distribution, zeta-potential, encapsulation efficiency (EE), and in vitro drug release studies. PC-3 cells were used to verify the in vitro anticancer activity of the formulations. In vivo pharmacokinetic properties of liposomal LAQ-Fe (L-LAQ-Fe) was evaluated in rats. RESULTS SAHA and LAQ form complexes with Fe at 1:1 stoichiometric ratio, with a binding constant on the order of 104 M−1. Fe complexation improved the aqueous solubility and the liposomal encapsulation efficiency of SAHA and LAQ (29–35% EE, final drug concentration > 1 mM). Liposomal encapsulated complexes (L-HDACi-Fe) exhibited sustained in vitro release properties compared to L-HDACi but cytotoxicity on PC-3 cells was comparable to free drugs. The PK of L-LAQ-Fe revealed 15-fold improvement in the plasma t1/2 (12.11 h) and 211-fold improvement in the AUC∞ (105.7 μg·h/ml) compared to free LAQ (0.79 h, 0.5 μg·h/ml). Similarly, the plasma t1/2 of Fe was determined to be 11.83 h in a separate experiment using radioactive Fe-59. The majority of Fe-59 activity was found in liver and spleen of rats and correlates with liposomal uptake by the mononuclear phagocyte system. CONCLUSIONS We have demonstrated that encapsulation of Fe complexes of HDACi into PEGylated liposomes can improve overall drug aqueous solubility, in vitro

  3. Treatment with Histone Deacetylase Inhibitor Attenuates MAP Kinase Mediated Liver Injury in a Lethal Model of Septic Shock1

    PubMed Central

    Finkelstein, Robert A.; Li, Yongqing; Liu, Baoling; Shuja, Fahad; Fukudome, Eugene; Velmahos, George C.; deMoya, Marc; Alam, Hasan B.

    2016-01-01

    Background Despite global efforts to improve the treatment of sepsis, it remains a leading cause of morbidity and mortality in intensive care units. We have previously shown that suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, markedly improves survival in a murine model of lipopolysaccharide (LPS)-induced shock. SAHA has anti-inflammatory properties that have not been fully characterized. The liver plays an important role in the production of acute phase reactants involved in the inflammatory cascade and is also one of the major organs that can become dysfunctional in septic shock. The purpose of this study was to assess the effect of SAHA treatment on MAP kinases and associated inflammatory markers in murine liver after LPS-induced injury. Methods C57B1/6J mice were randomly divided into three groups: (A) experimental-given intraperitoneal (i.p.) SAHA (50 mg/kg) in dimethyl sulfoxide (DMSO) vehicle solution (n =12); (B) control-given vehicle only (n = 12), and; (C) sham-given no treatment (n = 7). Two hours later, experimental and control mice were injected with LPS (20 mg/kg, i.p.) and experimental mice received a second dose of SAHA. Livers were harvested at 3, 24, and 48 h for analysis of inflammatory markers using Western Blot, Polymerase Chain Reaction (PCR), and Enzyme-Linked Immunosorbent Assay (ELISA) techniques. Results After 3 h, the livers of animals treated with SAHA showed significantly (P < 0.05) decreased expression of the pro-inflammatory MAP kinases phosphorylated p38, phosphorylated ERK, myeloperoxidase and interleukin-6, and increased levels of the anti-inflammatory interleukin-10 compared with controls. Phospho-p38 expression remained low in the SAHA treated groups at 24 and 48 h. Conclusion Administration of SAHA is associated with attenuation of MAPK activation and alteration of inflammatory and anti-inflammatory markers in murine liver after a lethal LPS insult. The suppression of MAPK activity is rapid (within 3 h

  4. Structures of Clostridium Botulinum Neurotoxin Serotype A Light Chain Complexed with Small-Molecule Inhibitors Highlight Active-Site Flexibility

    SciTech Connect

    Silvaggi,N.; Boldt, G.; Hixon, M.; Kennedy, J.; Tzipori, S.; Janda, K.; Allen, K.

    2007-01-01

    The potential for the use of Clostridial neurotoxins as bioweapons makes the development of small-molecule inhibitors of these deadly toxins a top priority. Recently, screening of a random hydroxamate library identified a small-molecule inhibitor of C. botulinum Neurotoxin Serotype A Light Chain (BoNT/A-LC), 4-chlorocinnamic hydroxamate, a derivative of which has been shown to have in vivo efficacy in mice and no toxicity. We describe the X-ray crystal structures of BoNT/A-LC in complexes with two potent small-molecule inhibitors. The structures of the enzyme with 4-chlorocinnamic hydroxamate or 2,4-dichlorocinnamic hydroxamate bound are compared to the structure of the enzyme complexed with L-arginine hydroxamate, an inhibitor with modest affinity. Taken together, this suite of structures provides surprising insights into the BoNT/A-LC active site, including unexpected conformational flexibility at the S1' site that changes the electrostatic environment of the binding pocket. Information gained from these structures will inform the design and optimization of more effective small-molecule inhibitors of BoNT/A-LC.

  5. Hybrid Enzalutamide Derivatives with Histone Deacetylase Inhibitor Activity Decrease Heat Shock Protein 90 and Androgen Receptor Levels and Inhibit Viability in Enzalutamide-Resistant C4-2 Prostate Cancer Cells.

    PubMed

    Rosati, Rayna; Chen, Bailing; Patki, Mugdha; McFall, Thomas; Ou, Siyu; Heath, Elisabeth; Ratnam, Manohar; Qin, Zhihui

    2016-09-01

    Histone deacetylase inhibitors (HDACIs) can disrupt the viability of prostate cancer (PCa) cells through modulation of the cytosolic androgen receptor (AR) chaperone protein heat shock protein 90 (HSP90). However, toxicities associated with their pleiotropic effects could contribute to the ineffectiveness of HDACIs in PCa treatment. We designed hybrid molecules containing partial chemical scaffolds of enzalutamide and suberoylanilide hydroxamic acid (SAHA), with weakened intrinsic pan-HDACI activities, to target HSP90 and AR in enzalutamide-resistant PCa cells. The potency of the new molecules, compounds 2-75 [4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-(7-(hydroxyamino)-7-oxoheptyl)benzamide] and 1005 [(E)-3-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluorophenyl)-N-hydroxyacrylamide], as inhibitors of nuclear and cytosolic histone deacetylases was substantially lower than that of SAHA in cell-free and in situ assays. Compounds 2-75 and 1005 antagonized gene activation by androgen without inducing chromatin association of AR. Enzalutamide had no effect on the levels of AR or HSP90, whereas the hybrid compounds induced degradation of both AR and HSP90, similar to (compound 1005) or more potently than (compound 2-75) SAHA. Similar to SAHA, compounds 2-75 and 1005 decreased the level of HSP90 and induced acetylation in a predicted approximately 55 kDa HSP90 fragment. Compared with SAHA, compound 2-75 induced greater hyperacetylation of the HDAC6 substrate α-tubulin. In contrast with SAHA, neither hybrid molecule caused substantial hyperacetylation of histones H3 and H4. Compounds 2-75 and 1005 induced p21 and caused loss of viability in the enzalutamide-resistant C4-2 cells, with efficacies that were comparable to or better than SAHA. The results suggest the potential of the new compounds as prototype antitumor drugs that would downregulate HSP90 and AR in

  6. Hydantoin based inhibitors of MMP13--discovery of AZD6605.

    PubMed

    De Savi, Chris; Waterson, David; Pape, Andrew; Lamont, Scott; Hadley, Elma; Mills, Mark; Page, Ken M; Bowyer, Jonathan; Maciewicz, Rose A

    2013-08-15

    Piperidine ether and aryl piperazine hydantoins are reported as potent inhibitors of MMP13. A medicinal chemistry campaign focused on replacing the reverse hydroxamate zinc binding group associated with historical inhibitors with a hydantoin zinc binding group then optimising MMP13 potency, solubility and DMPK properties whilst maintaining good selectivity over MMP14. A number of high quality candidates were progressed and following rat and dog safety evaluation, AZD6605 (3m) was identified as a candidate drug. PMID:23810497

  7. Structures of Staphylococcus aureus peptide deformylase in complex with two classes of new inhibitors.

    PubMed

    Lee, Sang Jae; Lee, Seung-Jae; Lee, Seung Kyu; Yoon, Hye-Jin; Lee, Hyung Ho; Kim, Kyeong Kyu; Lee, Bong Jin; Lee, Byung Il; Suh, Se Won

    2012-07-01

    Peptide deformylase (PDF) catalyzes the removal of the formyl group from the N-terminal methionine residue in newly synthesized polypeptides, which is an essential process in bacteria. Four new inhibitors of PDF that belong to two different classes, hydroxamate/pseudopeptide compounds [PMT387 (7a) and PMT497] and reverse-hydroxamate/nonpeptide compounds [PMT1039 (15e) and PMT1067], have been developed. These compounds inhibited the growth of several pathogens involved in respiratory-tract infections, such as Streptococcus pneumoniae, Moraxella catarrhalis and Haemophilus influenzae, and leading nosocomial pathogens such as Staphylococcus aureus and Klebsiella pneumoniae with a minimum inhibitory concentration (MIC) in the range 0.1-0.8 mg ml(-1). Interestingly, the reverse-hydroxamate/nonpeptide compounds showed a 250-fold higher antimicrobial activity towards S. aureus, although the four compounds showed similar K(i) values against S. aureus PDF enzymes, with K(i) values in the 11-85 nM range. To provide a structural basis for the discovery of additional PDF inhibitors, the crystal structures of S. aureus PDF in complex with the four inhibitors were determined at resolutions of 1.90-2.30 Å. The inhibitor-bound structures displayed distinct deviations depending on the inhibitor class. The distance between the Zn(2+) ion and the carbonyl O atom of the hydroxamate inhibitors (or the hydroxyl O atom of the reverse-hydroxamate inhibitors) appears to be correlated to S. aureus inhibition activity. The structural information reported in this study should aid in the discovery of new PDF inhibitors that can be used as novel antibacterial drugs. PMID:22751663

  8. Molecular titanium-hydroxamate complexes as models for TiO2 surface binding.

    PubMed

    Brennan, Bradley J; Chen, Jeffrey; Rudshteyn, Benjamin; Chaudhuri, Subhajyoti; Mercado, Brandon Q; Batista, Victor S; Crabtree, Robert H; Brudvig, Gary W

    2016-02-18

    Hydroxamate binding modes and protonation states have yet to be conclusively determined. Molecular titanium(iv) phenylhydroxamate complexes were synthesized as structural and spectroscopic models, and compared to functionalized TiO2 nanoparticles. In a combined experimental-theoretical study, we find that the predominant binding form is monodeprotonated, with evidence for the chelate mode. PMID:26781247

  9. [The use of hydroxamic acids and sodium nitrate to enhance the antitumor effect of cyclophosphamide].

    PubMed

    Bogatyrenko, T N; Kuropteva, Z V; Sashenkova, T E; Baĭder, L M; Konovalova, N P

    2013-01-01

    It has been showed that the introduction of nitrocompounds (as nitic oxide donors) in to the compositions of cyclophosphamide and hydroxamic acids for curing animals having leukemia P-388 increased duration of life by 290%. Thereby 40% of animals have recovered. The therapeutic dose cyclophosphamide have been reduced by 6 times. PMID:23814833

  10. Salinomycin Hydroxamic Acids: Synthesis, Structure, and Biological Activity of Polyether Ionophore Hybrids.

    PubMed

    Borgström, Björn; Huang, Xiaoli; Chygorin, Eduard; Oredsson, Stina; Strand, Daniel

    2016-06-01

    The polyether ionophore salinomycin has recently gained attention due to its exceptional ability to selectively reduce the proportion of cancer stem cells within a number of cancer cell lines. Efficient single step strategies for the preparation of hydroxamic acid hybrids of this compound varying in N- and O-alkylation are presented. The parent hydroxamic acid, salinomycin-NHOH, forms both inclusion complexes and well-defined electroneutral complexes with potassium and sodium cations via 1,3-coordination by the hydroxamic acid moiety to the metal ion. A crystal structure of an cationic sodium complex with a noncoordinating anion corroborates this finding and, moreover, reveals a novel type of hydrogen bond network that stabilizes the head-to-tail conformation that encapsulates the cation analogously to the native structure. The hydroxamic acid derivatives display down to single digit micromolar activity against cancer cells but unlike salinomycin selective reduction of ALDH(+) cells, a phenotype associated with cancer stem cells was not observed. Mechanistic implications are discussed. PMID:27326340

  11. A `Clicked' Tetrameric Hydroxamic Acid Glycopeptidomimetic Antagonizes Sugar-Lectin Interactions On The Cellular Level

    NASA Astrophysics Data System (ADS)

    Zhang, Hai-Lin; Zang, Yi; Xie, Juan; Li, Jia; Chen, Guo-Rong; He, Xiao-Peng; Tian, He

    2014-07-01

    A tetrameric N-acetyl galactosaminyl (GalNAc) peptidomimetic was constructed by N-acetylation of repeating proline-based hydroxamic acid units, followed by a convergent `click chemistry' coupling. This novel glycopeptidomimetic was determined to effectively antagonize the interaction between a transmembrane hepatic lectin and GalNAc on the cellular level.

  12. Water-Stable, Hydroxamate Anchors for Functionalization of TiO2 Surfaces with Ultrafast Interfacial Electron Transfer

    SciTech Connect

    McNamara, W.R.; Milot, R.L.; Song, H.; Snoeberger III, R.C.; Batista, Victor S.; Schmuttenmaer, C.A.; Brudvig, Gary W; Crabtree, Robert H

    2010-01-01

    A novel class of derivatized hydroxamic acid linkages for robust sensitization of TiO{sub 2} nanoparticles (NPs) under various aqueous conditions is described. The stability of linkages bound to metal oxides under various conditions is important in developing photocatalytic cells which incorporate transition metal complexes for solar energy conversion. In order to compare the standard carboxylate anchor to hydroxamates, two organic dyes differing only in anchoring groups were synthesized and attached to TiO{sub 2} NPs. At acidic, basic, and close to neutral pH, hydroxamic acid linkages resist detachment compared to the labile carboxylic acids. THz spectroscopy was used to compare ultrafast interfacial electron transfer (IET) into the conduction band of TiO{sub 2} for both linkages and found similar IET characteristics. Observable electron injection and stronger binding suggest that hydroxamates are a suitable class of anchors for designing water stable molecules for functionalizing TiO{sub 2}.

  13. Syntheses of hydroxamic acid-containing bicyclic β-lactams via palladium-catalyzed oxidative amidation of alkenes.

    PubMed

    Jobbins, Maria O; Miller, Marvin J

    2014-02-21

    Palladium-catalyzed oxidative amidation has been used to synthesize hydroxamic acid-containing bicyclic β-lactam cores. Oxidative cleavage of the pendant alkene provides access to the carboxylic acid in one step. PMID:24483144

  14. Potent, Selective, and CNS-Penetrant Tetrasubstituted Cyclopropane Class IIa Histone Deacetylase (HDAC) Inhibitors.

    PubMed

    Luckhurst, Christopher A; Breccia, Perla; Stott, Andrew J; Aziz, Omar; Birch, Helen L; Bürli, Roland W; Hughes, Samantha J; Jarvis, Rebecca E; Lamers, Marieke; Leonard, Philip M; Matthews, Kim L; McAllister, George; Pollack, Scott; Saville-Stones, Elizabeth; Wishart, Grant; Yates, Dawn; Dominguez, Celia

    2016-01-14

    Potent and selective class IIa HDAC tetrasubstituted cyclopropane hydroxamic acid inhibitors were identified with high oral bioavailability that exhibited good brain and muscle exposure. Compound 14 displayed suitable properties for assessment of the impact of class IIa HDAC catalytic site inhibition in preclinical disease models. PMID:26819662

  15. The interaction of zinc(II) and hydroxamic acids and a metal-triggered Lossen rearrangement.

    PubMed

    Duchácková, Lucie; Roithová, Jana

    2009-12-14

    The structure and reactivity of a complex of zinc(II), water, acetic acid, and acetohydroxamic acid, in which one of the acids is deprotonated, is investigated by means of mass spectrometry, labeling studies, and density functional calculations to unravel the exceptional binding properties of hydroxamic acids towards zinc-containing enzymes at the molecular level. It is shown that acetohydroxamic acid is deprotonated in the complex, whereas acetic acid is present in its neutral form. The binding energies of the ligands towards zinc increase in the following order: waterhydroxamic acids. Furthermore, coordinatively unsaturated complexes of zinc and acetohydroxamic acid undergo a zinc-assisted Lossen rearrangement followed by elimination of water if acetohydroxamic acid is present as a neutral ligand, or by loss of methylisocyanate if acetohydroxamic acid is deprotonated. PMID:19937618

  16. Consumption and utilization of experimentally altered corn by southern armyworm: Iron, nitrogen, and cyclic hydroxamates.

    PubMed

    Manuwoto, S; Scriber, J M

    1985-11-01

    The effects of differential leaf water, leaf nitrogen and cyclic hydroxamate (DIMBOA) concentrations in corn seedlings were analyzed for a polyphagous insect, the southern armyworm (Spodoptera eridania Cram.). Six different combinations of nutrients and allelochemicals [DIMBOA = 2,4-dihydroxy-7-methoxy(2H)-benzoxazin-3(4H)-one] were generated using two corn genotypes (WF9 and CI3IA) and three fertility regimes (complete nutrient, Fe-deficient, and N-deficient solutions) in the University Biotron. Poorest larval growth was observed in the low-nitrogen treatments (1.2% and 1.7% leaf N) and was the result of both low consumption rates and high metabolic costs (low efficiency of conversion of digested food, ECD). Fastest growth rates were observed forthe larvae fed leaves from the high-nitrogen treatments (4.6% and 4.4% leaf N). It is noteworthy that these treatments also contained the highest concentration of cyclic hydroxamates, which are generally believed to be the primary defensive chemicals mediating resistance against the European corn borer,Ostrinia nubilalis (Hubner). If these hydroxamates do have any deleterious or costly effects (perhaps accounting for a large portion of metabolic expenditures), the high digestibility of the leaf tissue and the increased consumption rates more than compensate, resulting in rapid growth (growth rate = consumption rate × approximate digestibility × efficiency of conversion of the digested food). These studies illustrate that variation in key nutrients and allelochemicals within a single plant species (Zea mays L.) may have significantly different effects upon various potential leaf-chewing caterpillars, such as these armyworms versus corn borers (which cannot handle the cyclic hydroxamates, even if provided with young nutritious leaf tissues). PMID:24311240

  17. Hydroxamate siderophore-promoted reactions between iron(II) and nitroaromatic groundwater contaminants

    NASA Astrophysics Data System (ADS)

    Kim, Dongwook; Duckworth, Owen W.; Strathmann, Timothy J.

    2009-03-01

    Recent studies show that ferrous iron (Fe II), which is often abundant in anaerobic soil and groundwater, is capable of abiotically reducing many subsurface contaminants. However, studies also demonstrate that Fe II redox reactivity in geochemical systems is heavily dependent upon metal speciation. This contribution examines the influence of hydroxamate ligands, including the trihydroxamate siderophore desferrioxamine B (DFOB), on Fe II reactions with nitroaromatic groundwater contaminants (NACs). Experimental results demonstrate that ring-substituted NACs are reduced to the corresponding aniline products in aqueous solutions containing Fe II complexes with DFOB and two monohydroxamate ligands (acetohydroxamic acid and salicylhydroxamic acid). Reaction rates are heavily dependent upon solution conditions and the identities of both the Fe II-complexing hydroxamate ligand and the target NAC. Trends in the observed pseudo-first-order rate constants for reduction of 4-chloronitrobenzene ( kobs, s -1) are quantitatively linked to the formation of Fe II species with standard one-electron reduction potentials, EH0 (Fe III/Fe II), below -0.3 V. Linear free energy relationships correlate reaction rates with the EH0 (Fe III/Fe II) values of different electron-donating Fe II complexes and with the apparent one-electron reduction potentials of different electron-accepting NACs, EH1'(ArNO 2). Experiments describing a redox auto-decomposition mechanism for Fe II-DFOB complexes that occurs at neutral pH and has implications for the stability of hydroxamate siderophores in anaerobic environments are also presented. Results from this study indicate that hydroxamates and other Fe III-stabilizing organic ligands can form highly redox-active Fe II complexes that may contribute to the natural attenuation and remediation of subsurface contaminants.

  18. Growth of Actinobacillus pleuropneumoniae is promoted by exogenous hydroxamate and catechol siderophores.

    PubMed Central

    Diarra, M S; Dolence, J A; Dolence, E K; Darwish, I; Miller, M J; Malouin, F; Jacques, M

    1996-01-01

    Siderophores bind ferric ions and are involved in receptor-specific iron transport into bacteria. Six types of siderophores were tested against strains representing the 12 different serotypes of Actinobacillus pleuropneumoniae. Ferrichrome and bis-catechol-based siderophores showed strong growth-promoting activities for A. pleuropneumoniae in a disk diffusion assay. Most strains of A. pleuropneumoniae tested were able to use ferrichrome (21 of 22 or 95%), ferrichrome A (20 of 22 or 90%), and lysine-based bis-catechol (20 of 22 or 90%), while growth of 36% (8 of 22) was promoted by a synthetic hydroxamate, N5-acetyl-N5-hydroxy-L-ornithine tripeptide. A. pleuropneumoniae serotype 1 (strain FMV 87-682) and serotype 5 (strain 2245) exhibited a distinct yellow halo around colonies on Chrome Azurol S agar plates, suggesting that both strains can produce an iron chelator (siderophore) in response to iron stress. The siderophore was found to be neither a phenolate nor a hydroxamate by the chemical tests of Arnow and Csaky, respectively. This is the first report demonstrating the production of an iron chelator and the use of exogenous siderophores by A. pleuropneumoniae. A spermidine-based bis-catechol siderophore conjugated to a carbacephalosporin was shown to inhibit growth of A. pleuropneumoniae. A siderophore-antibiotic-resistant strain was isolated and shown to have lost the ability to use ferrichrome, synthetic hydroxamate, or catechol-based siderophores when grown under conditions of iron restriction. This observation indicated that a common iron uptake pathway, or a common intermediate, for hydroxamate- and catechol-based siderophores may exist in A. pleuropneumoniae. PMID:8975614

  19. Development and application of versatile bis-hydroxamic acids for catalytic asymmetric oxidation

    PubMed Central

    Barlan, Allan U.; Zhang, Wei; Yamamoto, Hisashi

    2010-01-01

    In this article, we describe the development and preliminary results of our new designed C2-symmetric bis-hydroxamic acid (BHA) ligands and the application of the new ligands for vanadium-catalyzed asymmetric epoxidation of allylic alcohols as well as homoallylic alcohols. From this success we demonstrate the versatile nature of BHA in the molybdenum catalyzed asymmetric oxidation of unfunctionalized olefins and sulfides. PMID:21152351

  20. Investigation on the ZBG-functionality of phenyl-4-yl-acrylohydroxamic acid derivatives as histone deacetylase inhibitors.

    PubMed

    Musso, Loana; Cincinelli, Raffaella; Zuco, Valentina; Zunino, Franco; Nurisso, Alessandra; Cuendet, Muriel; Giannini, Giuseppe; Vesci, Loredana; Pisano, Claudio; Dallavalle, Sabrina

    2015-10-15

    A series of alternative Zn-binding groups were explored in the design of phenyl-4-yl-acrylohydroxamic acid derivatives as histone deacetylase (HDAC) inhibitors. Most of the synthesized compounds were less effective than the parent hydroxamic acid. However, the profile of activity shown by the analog bearing a hydroxyurea head group, makes this derivative promising for further investigation. PMID:26376355

  1. The discovery of novel tartrate-based TNF-[alpha] converting enzyme (TACE) inhibitors

    SciTech Connect

    Rosner, Kristin E.; Guo, Zhuyan; Orth, Peter; Shipps, Jr., Gerald W.; Belanger, David B.; Chan, Tin Yau; Curran, Patrick J.; Dai, Chaoyang; Deng, Yongqi; Girijavallabhan, Vinay M.; Hong, Liwu; Lavey, Brian J.; Lee, Joe F.; Li, Dansu; Liu, Zhidan; Popovici-Muller, Janeta; Ting, Pauline C.; Vaccaro, Henry; Wang, Li; Wang, Tong; Yu, W.; Zhou, G.; Niu, X.; Sun, J.; Kozlowski, J.A.; Lundell, D.J.; Madison, V.; McKittrick, B.; Piwinski, J.J.; Shih, N.Y.; Siddiqui, M. Arshad; Strickland, Corey O.

    2010-09-17

    A novel series of TNF-{alpha} convertase (TACE) inhibitors which are non-hydroxamate have been discovered. These compounds are bis-amides of L-tartaric acid (tartrate) and coordinate to the active site zinc in a tridentate manner. They are selective for TACE over other MMP's. We report the first X-ray crystal structure for a tartrate-based TACE inhibitor.

  2. Recent advances in the discovery of zinc-binding motifs for the development of carbonic anhydrase inhibitors.

    PubMed

    Winum, Jean-Yves; Supuran, Claudiu T

    2015-04-01

    In addition to the sulfonamides and their isosteres, recently novel carbonic anhydrase (CA, EC 4.2.1.1) inhibitors (CAIs) which act by binding to the metal ion from the active site were discovered. Based on the X-ray crystal structure of the CA II-trithiocarbonate adduct, dithiocarbamates, xanthates and thioxanthates were shown to potently inhibit α- and β-CAs. The hydroxamates constitute another class of recently studied CAIs both against mammalian and protozoan enzymes. Another chemotype for which CA inhibitory properties were recently reported is the salicylaldoxime scaffold. X-ray crystal structures were reported for CA II complexed with dithiocarbamates and hydroxamates, whereas the xanthates and salicylaldoximes were investigated by kinetic measurements and docking studies. The dithiocarbamates and the xanthates showed potent antiglaucoma activity in animal models of the disease whereas some hydroxamates inhibited the growth of Trypanosoma cruzii probably by inhibiting the protozoan CA. PMID:24939097

  3. A preliminary study of the hydrolysis of hydroxamic acid complexants in the presence of oxidising metal ions

    NASA Astrophysics Data System (ADS)

    Andrieux, Fabrice P. L.; Boxall, Colin; May, Iain; Taylor, Robin J.

    2010-03-01

    Simple hydroxamic acids (XHAs) are salt free, organic compounds with affinities for cations such as Np4+, Pu4+ and Fe3+. As such they have been identified as suitable reagents for the separation of either Pu and/or Np from U in modified or single cycle Purex based solvent extraction processes designed to meet the emerging requirements of Advanced Fuel Cycles. Acid catalyzed hydrolysis of free XHAs is well known and may impact negatively on reprocessing applications. The hydrolysis of metal-bound XHAs within metal ion-XHA complexes is less understood. Using a model derived for the study of hydroxamic acid hydrolysis in the presence of non-oxidising metal ions (Np (IV) and Fe(III)), we review data pertaining to the hydrolysis of hydroxamic acids in the presence of the oxidising Pu4+ ion, under conditions where the influence of the redox processes may potentially be neglected.

  4. Bisucaberin B, a linear hydroxamate class siderophore from the marine bacterium Tenacibaculum mesophilum.

    PubMed

    Fujita, Masaki J; Nakano, Koji; Sakai, Ryuichi

    2013-01-01

    A siderophore, named bisucaberin B, was isolated from Tenacibaculum mesophilum bacteria separated from a marine sponge collected in the Republic of Palau. Using spectroscopic and chemical methods, the structure of bisucaberin B (1) was clearly determined to be a linear dimeric hydroxamate class siderophore. Although compound 1 is an open form of the known macrocyclic dimer bisucaberin (2), and was previously described as a bacterial degradation product of desferrioxamine B (4), the present report is the first description of the de novo biosynthesis of 1. To the best of our knowledge, compound 1 is the first chemically characterized siderophore isolated from a bacterium belonging to the phylum Bacteroidetes. PMID:23549298

  5. Efficient Route to Highly Water-Soluble Aromatic Cyclic Hydroxamic Acid Ligands

    SciTech Connect

    Seitz, Michael; Raymond, Kenneth N.

    2008-02-06

    2-Hydroxyisoquinolin-1-one (1,2-HOIQO) is a new member of the important class of aromatic cyclic hydroxamic acid ligands which are widely used in metal sequestering applications and metal chelating therapy. The first general approach for the introduction of substituents at the aromatic ring of the chelating moiety is presented. As a useful derivative, the highly water-soluble sulfonic acid has been synthesized by an efficient route that allows general access to 1,2-HOQIO 3-carboxlic acid amides, which are the most relevant for applications.

  6. An enthalpic basis of additivity in biphenyl hydroxamic acid ligands for stromelysin-1

    PubMed Central

    Wilfong, Erin M.; Du, Yu; Toone, Eric J.

    2013-01-01

    Fragment based drug discovery remains a successful tool for pharmaceutical lead discovery. Although based upon the principle of thermodynamic additivity, the underlying thermodynamic basis is poorly understood. A thermodynamic additivity analysis was performed using stromelysin-1 and a series of biphenyl hydroxamate ligands identified through fragment additivity. Our studies suggest that, in this instance, additivity arises from enthalpic effects, while interaction entropies are unfavorable; this thermodynamic behavior is masked by proton transfer. Evaluation of the changes in constant pressure heat capacities during binding suggest that solvent exclusion from the binding site does not account for the dramatic affinity enhancements observed. PMID:22985855

  7. New beginnings for matrix metalloproteinase inhibitors: identification of high-affinity zinc-binding groups.

    PubMed

    Puerta, David T; Lewis, Jana A; Cohen, Seth M

    2004-07-14

    In an effort to identify promising non-hydroxamate inhibitors of matrix metalloproteinases (MMPs), several new zinc-binding groups (ZBGs) based on pyrone, pyrothione, hydroxypyridinone, and hydroxypyridinethione chelators have been examined. Structural studies with tris(pyrazolyl)borate model complexes show that these ligands bind to the MMP active site zinc(II) ion in a bidentate fashion, similar to that found with hydroxamate-based inhibitors. Fluorescence- and colorimetric-based enzyme assays have been used to determine the IC50 values for these ZBGs against MMP-3; mixed O,S-donor ligands were found to be remarkably potent, with IC50 values as much as 700-fold lower than that found for acetohydroxamic acid. Inhibitory activity was found to parallel metal binding affinity as determined in titrations with model complexes. These results demonstrate that MPIs based on new ZBGs are feasible and may indeed improve the overall performance of inhibitors designed against these important medicinal targets. PMID:15237990

  8. A novel collector 2-ethyl-2-hexenoic hydroxamic acid: Flotation performance and adsorption mechanism to ilmenite

    NASA Astrophysics Data System (ADS)

    Xu, Haifeng; Zhong, Hong; Tang, Qing; Wang, Shuai; Zhao, Gang; Liu, Guangyi

    2015-10-01

    In this paper, a novel collector, 2-ethyl-2-hexenoic hydroxamic acid (EHHA) was prepared and characterized by elemental analysis, infrared, 1H NMR, 13C NMR and mass spectra. The flotation performance and adsorption mechanism of EHHA to ilmenite were investigated by micro-flotation tests, density functional theory (DFT) calculations, FTIR spectra, zeta potential and solution chemistry analyses. The micro-flotation results indicated that EHHA exhibited superior flotation performance compared to isooctyl hydroximic acid (IOHA) and octyl hydroxamic acid (OHA), and floated out 84.03% ilmenite at pH 8.0 with 250 mg/L dosage. The analyses of FTIR spectra and zeta potential demonstrated that EHHA might chemisorb onto ilmenite surfaces by form of five-membered chelates. The solution chemistry analyses further inferred that at pH 6.3-10.5, both Fe and Ti species on ilmenite surfaces could chelate EHHA. DFT calculation results implied EHHA owned the strongest affinity to ilmenite among the three C8 hydroximic acids. To discern the sharply improving floatability of ilmenite at pH 8-10, a schematic co-adsorption molecule-ion model of EHHA on ilmenite surfaces was suggested.

  9. Detoxifying carcinogenic polyhalogenated quinones by hydroxamic acids via an unusual double Lossen rearrangement mechanism

    PubMed Central

    Zhu, Ben-Zhan; Zhu, Jun-Ge; Mao, Li; Kalyanaraman, Balaraman; Shan, Guo-Qiang

    2010-01-01

    Hydroxamic acids, which are best-known for their metal-chelating properties in biomedical research, have been found to effectively detoxify the carcinogenic polyhalogenated quinoid metabolites of pentachlorophenol and other persistent organic pollutants. However, the chemical mechanism underlying such detoxication is unclear. Here we show that benzohydroxamic acid (BHA) could dramatically accelerate the conversion of the highly toxic tetrachloro-1, 4-benzoquinone (p-chloranil) to the much less toxic 2,5-dichloro-3, 6-dihydroxy-1, 4-benzoquonine (chloranilic acid), with rate accelerations of up to 150,000-fold. In contrast, no enhancing effect was observed with O-methyl BHA. The major reaction product of BHA was isolated and identified as O-phenylcarbamyl benzohydroxamate. On the basis of these data and oxygen-18 isotope-labeling studies, we proposed that suicidal nucleophilic attack coupled with an unexpected double Lossen rearrangement reaction was responsible for this remarkable acceleration of the detoxication reaction. This is the first report of an unusually mild and facile Lossen-type rearrangement, which could take place under normal physiological conditions in two consecutive steps. Our findings may have broad biological and environmental implications for future research on hydroxamic acids and polyhalogenated quinoid carcinogens, which are two important classes of compounds of major biomedical and environmental interest. PMID:21076034

  10. Betulinic acid derived hydroxamates and betulin derived carbamates are interesting scaffolds for the synthesis of novel cytotoxic compounds.

    PubMed

    Wiemann, Jana; Heller, Lucie; Perl, Vincent; Kluge, Ralph; Ströhl, Dieter; Csuk, René

    2015-12-01

    The betulinic acid-derived hydroxamates 5-18, the amides 19-24, and betulin-derived bis-carbamates 25-28 as well as the carbamates 31-40 and 44-48 were prepared and evaluated for their antiproliferative activity in a photometric sulforhodamine B (SRB) assay against several human cancer cell lines and nonmalignant mouse fibroblasts (NIH 3T3). While for 3-O-acetyl hydroxamic acid 5 EC50 values as low as EC50 = 1.3 μM were found, N,O-bis-alkyl substituted hydroxamates showed lowered cytotoxicity (EC50 = 16-20 μM). In general, hydroxamic acid derivatives showed only reduced selectivity for tumor cells, except for allyl substituted compound 13 (EC50 = 5.9 μM for A2780 human ovarian carcinoma cells and EC50 > 30 μM for nonmalignant mouse fibroblasts). The cytotoxicity of betulinic acid derived amides 19-24 and of betulin derived bis-carbamates 25-28 was low, except for N-ethyl substituted 25. Hexyl substituted 39 showed EC50 = 5.6 μM (518A2 cells) while for mouse fibroblasts EC50 > 30 was determined. PMID:26547057

  11. What Makes Hydroxamate a Promising Anchoring Group in Dye-Sensitized Solar Cells? Insights from Theoretical Investigation.

    PubMed

    Li, Wei; Rego, Luis G C; Bai, Fu-Quan; Wang, Jian; Jia, Ran; Xie, Li-Ming; Zhang, Hong-Xing

    2014-11-20

    We report, from a theoretical point of view, the first comparative study between the highly water-stable hydroxamate and the widely used carboxylate, in addition to the robust phosphate anchors. Theoretical calculations reveal that hydroxamate would be better for photoabsorption. A quantum dynamics description of the interfacial electron transfer (IET), including the underlying nuclear motion effect, is presented. We find that both hydroxamate and carboxylate would have efficient IET character; for phosphate the injection time is significantly longer (several hundred femtoseconds). We also verified that the symmetry of the geometry of the anchoring group plays important roles in the electronic charge delocalization. We conclude that hydroxamate can be a promising anchoring group, as compared to carboxylate and phosphate, due to its better photoabsorption and comparable IET time scale as well as the experimental advantage of water stability. We expect the implications of these findings to be relevant for the design of more efficient anchoring groups for dye-sensitized solar cell (DSSC) application. PMID:26276483

  12. Inhibitory effect of beta-glucosyl-phenolic hydroxamic acids against urease in the presence of microfloral beta-glucosidase.

    PubMed

    Park, J B; Imamura, L; Kobashi, K; Itoh, H; Miyazaki, T; Horisaki, T

    1995-02-01

    Three glucosyl-phenolic hydroxamates, 4-O-(beta-D-glucopyranosyl) benzohydroxamic acid, 4-O-(beta-D-glucopyranosyl)hippuric hydroxamic acid, and 3-[4-O-(beta-D-glucopyranosyl)phenyl]propionohydroxamic acid (Glc-PPHA), were hydrolyzed to their corresponding aglycones by beta-glucosidase of intestinal flora of rat without any major adverse hydrolysis in vitro. Inhibitory potency of these glucosyl-hydroxamates on urease was recovered to the same extent as that of the corresponding aglycone hydroxamates by preincubation for 2h with rat intestinal flora. p-Hydroxyphenylpropionohydroxamic acid inhibited noncompetitively jack-bean urease activity and its glucose-ligated form, Glc-PPHA inhibited it competitively. A single oral dose of Glc-PPHA tended to inhibit urease activity in proximal colon contents of rat at 6 h after administration (p = 0.06). After 14C-urea was orally administered to rat, 14CO2 was collected for to measure the ureolysis in vivo. Expired 14CO2 was limited to 40% by a single oral dose of Glc-PPHA during 6 h, and 75% of intestinal ureolysis was repressed during the first 1 h in the breath test. PMID:7742785

  13. Quinolone-based HDAC inhibitors.

    PubMed

    Balasubramanian, Gopalan; Kilambi, Narasimhan; Rathinasamy, Suresh; Rajendran, Praveen; Narayanan, Shridhar; Rajagopal, Sridharan

    2014-08-01

    HDAC inhibitors emerged as promising drug candidates in combating wide variety of cancers. At present, two of the compounds SAHA and Romidepsin were approved by FDA for cutaneous T-cell lymphoma and many are in various clinical phases. A new quinolone cap structure was explored with hydroxamic acid as zinc-binding group (ZBG). The pan HDAC inhibitory and antiproliferative activities against three human cancer cell lines HCT-116 (colon), NCI-H460 (lung) and U251 (glioblastoma) of the compounds (4a-4w) were evaluated. Introduction of heterocyclic amines in CAP region increased the enzyme inhibitory and antiproliferative activities and few of the compounds tested are metabolically stable in both MLM and HLM. PMID:25019596

  14. Sorption of Pb(ll) by poly(hydroxamic acid) grafted oil palm empty fruit bunch.

    PubMed

    Haron, M J; Tiansin, M; Ibrahim, N A; Kassim, A; Wan Yunus, W M Z; Talebi, S M

    2011-01-01

    This paper describes the sorption of Pb(ll) from aqueous solution. Oil palm empty fruit bunch (OPEFB) fiber was first grafted with poly(methylacrylate) and then treated with hydroxylammonium chloride in alkaline medium to produce hydroxamic acid (PHA) grafted OPEFB. Sorption of Pb(ll) by PHA-OPEFB was maximum at pH 5. The sorption followed the Langmuir model with maximum capacityof 125.0 mg g-1 at 25 degrees C. The sorption process was exothermic, as shown by the negative value of enthalpy change, Delta H0. The free energy change (DeltaG0) for the sorption was negative, showing that the sorption process was spontaneous. A kinetic study showed that the Pb(ll) sorption followed a second order kinetic model. PMID:21866782

  15. Covalency-Driven Dimerization of Plutonium(IV) in a Hydroxamate Complex.

    PubMed

    Silver, Mark A; Cary, Samantha K; Stritzinger, Jared T; Parker, T Gannon; Maron, Laurent; Albrecht-Schmitt, Thomas E

    2016-06-01

    The reaction of formohydroxamic acid [NH(OH)CHO, FHA] with Pu(III) should result in stabilization of the trivalent oxidation state. However, slow oxidation to Pu(IV) occurs, which leads to formation of the dimeric plutonium(IV) formohydroxamate complex Pu2(FHA)8. In addition to being reductants, hydroxamates are also strong π-donor ligands. Here we show that formation of the Pu2(FHA)8 dimer occurs via covalency between the 5f orbitals on plutonium and the π* orbitals of FHA(-) anions, which gives rise to a broad and intense ligand-to-metal charge-transfer feature. Time-dependent density functional theory calculations corroborate this assignment. PMID:27228095

  16. Design, synthesis and biological evaluation of novel hydroxamic acids bearing artemisinin skeleton.

    PubMed

    Ha, Vu Thi; Kien, Vu Tuan; Binh, Le Huy; Tien, Vu Dinh; My, Nguyen Thi Thuy; Nam, Nguyen Hai; Baltas, Michael; Hahn, Hyunggu; Han, Byung Woo; Thao, Do Thi; Vu, Tran Khac

    2016-06-01

    A series of novel hydroxamic acids bearing artemisinin skeleton was designed and synthesized. Some compounds in this series exhibited moderate inhibition against the whole cell HDAC enzymes. Especially, compound 6g displayed potent cytotoxicity against three human cancer cell lines, including HepG2 (liver cancer), MCF-7 (breast cancer) and HL-60 (leukemia cancer), with IC50 values of 2.50, 2.62 and 1.28μg/mL, respectively. Docking studies performed with two potent compounds 6a and 6g using Autodock Vina showed that both compounds bound to HDAC2 with relatively high binding affinities from -7.1 to 7.0kcal/mol compared to SAHA (-7.4kcal/mol). It was found in this research that most of the target compounds seemed to be more cytotoxic toward blood cancer cells (HL-60) than liver (HepG2), and breast (MCF-7) cancer cells. PMID:27018835

  17. Self-assembly and cytotoxicity study of waterwheel-like dinuclear metal complexes: the first metal complexes appended with multiple free hydroxamic acid groups.

    PubMed

    Wang, Wen-Hua; Liu, Wei-Sheng; Wang, Ya-Wen; Li, Yang; Zheng, Li-Fang; Wang, Da-Qi

    2007-02-01

    Two waterwheel-like dinuclear complexes [M(2)(PHA)(4)(H(2)O)(2)] (M = Cu(II) (1), Zn(II) (2); HPHA = phthal-hydroxamic acid) appended with four free hydroxamic acid groups, namely, free hydroxamic acid metal complexes (FHAMCs) have been synthesized and characterized. The crystal structure of complex 1 was determined by single crystal X-ray diffraction, which adopts the paddlewheel motif with four bidentate carboxylate ligands joining two Cu(II) ions. The relative cytotoxicities of compounds 1 and 2 against SMMC-7721 and HO-8910 cell lines are similar and more predominant than HPHA (IC(50): Cu(II)>Zn(II)>HPHA). The synergic effect of the bound water molecules, multiple free hydroxamic acid groups and dimetal active sites with bridging carboxylate may have significant impacts on their pharmacological activity. As the prototype for a new class of hydroxamic acid derivatives, the self-assembly of FHAMCs presents a promising new strategy in designing multiple hydroxamic acids with remarkable bioactivities. PMID:17125839

  18. Probing the "additive effect" in the proline and proline hydroxamic acid catalyzed asymmetric addition of nitroalkanes to cyclic enones.

    PubMed

    Hanessian, Stephen; Govindan, Subramaniyan; Warrier, Jayakumar S

    2005-11-01

    The effect of chirality and steric bulk of 2,5-disubstituted piperazines as additives in the conjugate addition of 2-nitropropane to cyclohexenone, catalyzed by l-proline, was investigated. Neither chirality nor steric bulk affects the enantioselectivity of addition, which gives 86-93% ee in the presence of achiral and chiral nonracemic 2,5-disubstituted piperazines. Proline hydroxamic acid is shown for the first time to be an effective organocatalyst in the same Michael reaction. PMID:16189834

  19. Tenacibactins A-D, hydroxamate siderophores from a marine-derived bacterium, Tenacibaculum sp. A4K-17.

    PubMed

    Jang, Jae-Hyuk; Kanoh, Kaneo; Adachi, Kyoko; Matsuda, Satoru; Shizuri, Yoshikazu

    2007-04-01

    Four new hydroxamate siderophores, tenacibactins A-D (1-4), were isolated from a culture broth of the marine-derived bacterium Tenacibaculum sp. A4K-17. The structures of these tenacibactins were determined by NMR analyses and ESIMS/MS experiments. The iron-binding (chelating) activity of 1-4 was evaluated by the chrome azurol sulfonate (CAS) assay. PMID:17319723

  20. Synthesis and Evaluation of 2-Alkylthio-4-(N-substituted sulfonamide)pyrimidine Hydroxamic Acids as Anti-myeloma Agents.

    PubMed

    Xiang, Jinbao; Leung, Crystal; Zhang, Zhuoqi; Hu, Cassie; Geng, Chao; Liu, Lili; Yi, Lang; Li, Zhiwei; Berenson, James; Bai, Xu

    2016-03-01

    A series of pyrimidine hydroxamic acids with a sulfide substituent at the second position and a sulfonamide substituent at the fourth position have been synthesized and evaluated for their activity against human myeloma cell line RPMI 8226. Several compounds exhibited significant anti-cancer potency. It was found that representative compound 6a selectively killed cancerous but not normal cells. Moreover, compound 6a was effective in causing apoptosis in RPMI 8226 cells and exhibited promising HDAC-inhibitory activities. PMID:26518472

  1. Coordination compounds of hafnium(IV) with some N-substituted derivatives of unsaturated hydroxamic acids

    SciTech Connect

    Stratulat, A.A.; Batyr, D.G.

    1987-05-01

    Coordination compounds of hafnium(IV) with N-o(or m)-X-phenylacryl- and methacrylhydroxamic acids with the general formula (Hf/XC/sub 6/H/sub 4/-N(O)-C(O)-R//sub 4/), where X = 4-CH/sub 3/, H, 4-Cl, 4-Br, 4-CH/sub 3/C(O), 4-CH=CH/sub 2/, 4-CH/sub 3/OC(O), 3-CH/sub 3/, 3-Cl, and 3-Br, and R = CH=CH/sub 2/ and C(CH/sub 3/)=CH/sub 2/, have been synthesized and characterized. The type of coordination of the organic ligands and the structure of the complexes have been established on the basis of the data from IR, electronic, and PMR spectra. It has been shown that the complexation process involves the replacement of the proton of the hydroxyl group of the hydroxamic grouping by a metal ion and the coordination of the oxygen atom of the carbonyl group. The coordination compounds obtained have been assigned a square-antiprismatic structure. The introduction of a methyl radical into the vinyl grouping R results in a significant increase in the strength of the complex.

  2. Hematologic Response to Vorinostat Treatment in Relapsed Myeloid Leukemia of Down Syndrome.

    PubMed

    Scheer, Carina; Kratz, Christian; Witt, Olaf; Creutzig, Ursula; Reinhardt, Dirk; Klusmann, Jan-Henning

    2016-09-01

    Children with Down syndrome are at high risk to develop myeloid leukemia (ML-DS). Despite their excellent prognosis, children with ML-DS particularly suffer from severe therapy-related toxicities and for relapsed ML-DS the cure rates are very poor. Here we report the clinical course of one child with ML-DS treated with the histone deacetylase (HDAC) inhibitor vorinostat (suberoylanilide hydroxamic acid) after second relapse. The child had previously received conventional chemotherapy and stem cell transplantation, yet showed a remarkable clinical and hematologic response. Thus, HDAC inhibitor may represent an effective class of drugs for the treatment of ML-DS. PMID:27191354

  3. Bioactive conformation of stromelysin inhibitors determined by transferred nuclear Overhauser effects.

    PubMed Central

    Gonnella, N C; Bohacek, R; Zhang, X; Kolossváry, I; Paris, C G; Melton, R; Winter, C; Hu, S I; Ganu, V

    1995-01-01

    The transferred nuclear Overhauser effect has been used to determine the biologically active conformations of two stromelysin inhibitors. Both inhibitors used in this study were hydroxamic acids generated via chemical synthesis. These structures, representing the conformation of each inhibitor bound to stromelysin, superimposed with excellent agreement. The study also provided information on the shape and orientation of the S2' and S1' pockets of the enzyme relative to thermolysin. Comparisons were made between stromelysin and thermolysin inhibitors to critically examine thermolysin as a template for stromelysin-inhibitor design. The enzyme-bound conformations of these stromelysin inhibitors were determined for use as a template in conformationally restricted drug design. Images Fig. 4 Fig. 5 Fig. 6 Fig. 7 PMID:7831311

  4. Arylsulfonamide inhibitors of aggrecanases as potential therapeutic agents for osteoarthritis: synthesis and biological evaluation.

    PubMed

    Nuti, Elisa; Santamaria, Salvatore; Casalini, Francesca; Yamamoto, Kazuhiro; Marinelli, Luciana; La Pietra, Valeria; Novellino, Ettore; Orlandini, Elisabetta; Nencetti, Susanna; Marini, Anna Maria; Salerno, Silvia; Taliani, Sabrina; Da Settimo, Federico; Nagase, Hideaki; Rossello, Armando

    2013-04-01

    Aggrecanases, in particular aggrecanase-2 (ADAMTS-5), are considered the principal proteases responsible for aggrecan degradation in osteoarthritis. For this reason, considerable effort has been put on the discovery and development of aggrecanase inhibitors able to slow down or halt the progression of osteoarthritis. We report herein the synthesis and biological evaluation of a series of arylsulfonamido-based hydroxamates as aggrecanase inhibitors. Compound 18 was found to have a nanomolar activity for ADAMTS-5, ADAMTS-4 and MMP-13 and high selectivity over MMP-1 and MMP-14. Furthermore, this compound proved to be effective in blocking ex vivo cartilage degradation without having effect on cell cytotoxicity. PMID:23376997

  5. FhuD1, a Ferric Hydroxamate-binding Lipoprotein in Staphylococcus aureus - A case of gene duplication and lateral transfer

    SciTech Connect

    Sebulsky, M. Tom; Speziali, Craig D.; Shilton, Brian H.; Edgell, David R.

    2010-11-16

    Staphylococcus aureus can utilize ferric hydroxamates as a source of iron under iron-restricted growth conditions. Proteins involved in this transport process are: FhuCBG, which encodes a traffic ATPase; FhuD2, a post-translationally modified lipoprotein that acts as a high affinity receptor at the cytoplasmic membrane for the efficient capture of ferric hydroxamates; and FhuD1, a protein with similarity to FhuD2. Gene duplication likely gave rise to fhuD1 and fhuD2. While the genomic locations of fhuCBG and fhuD2 in S. aureus strains are conserved, both the presence and the location of fhuD1 are variable. The apparent redundancy of FhuD1 led us to examine the role of this protein. We demonstrate that FhuD1 is expressed only under conditions of iron limitation through the regulatory activity of Fur. FhuD1 fractions with the cell membrane and binds hydroxamate siderophores but with lower affinity than FhuD2. Using small angle x-ray scattering, the solution structure of FhuD1 resembles that of FhuD2, and only a small conformational change is associated with ferrichrome binding. FhuD1, therefore, appears to be a receptor for ferric hydroxamates, like FhuD2. Our data to date suggest, however, that FhuD1 is redundant to FhuD2 and plays a minor role in hydroxamate transport. However, given the very real possibility that we have not yet identified the proper conditions where FhuD1 does provide an advantage over FhuD2, we anticipate that FhuD1 serves an enhanced role in the transport of untested hydroxamate siderophores and that it may play a prominent role during the growth of S. aureus in its natural environments.

  6. Consecutive enzymatic modification of ornithine generates the hydroxamate moieties of the siderophore erythrochelin.

    PubMed

    Robbel, Lars; Helmetag, Verena; Knappe, Thomas A; Marahiel, Mohamed A

    2011-07-12

    Biosynthesis of the hydroxamate-type siderophore erythrochelin requires the generation of δ-N-acetyl-δ-N-hydroxy-L-ornithine (L-haOrn), which is incorporated into the tetrapeptide at positions 1 and 4. Bioinformatic analysis revealed the FAD-dependent monooxygenase EtcB and the bifunctional malonyl-CoA decarboxylase/acetyltransferase Mcd to be putatively involved in the generation of L-haOrn. To investigate if EtcB and Mcd constitute a two-enzyme pathway for the biosynthesis of L-haOrn, they were produced in a recombinant manner and subjected to biochemical studies in vitro. Hydroxylation assays employing recombinant EtcB gave rise to δ-N-hydroxy-L-ornithine (L-hOrn) and confirmed the enzyme to be involved in building block assembly. Acetylation assays were carried out by incubating L-hOrn with recombinant Mcd and malonyl-CoA as the acetyl group donor. Substrate turnover was increased by substituting malonyl-CoA with acetyl-CoA, bypassing the decarboxylation reaction which represents the rate-limiting step. Consecutive enzymatic synthesis of L-haOrn was accomplished in coupled assays employing both the L-ornithine hydroxylase and Mcd. In summary, a biosynthetic route for the generation of δ-N-acetyl-δ-N-hydroxy-L-ornithine starting from L-ornithine has been established in vitro by tandem action of the FAD-dependent monooxygenase EtcB and the bifunctional malonyl-CoA decarboxylase/acetyltransferase Mcd. PMID:21650455

  7. Regio- and stereochemically controlled formation of hydroxamic acids from indium triflate-mediated nucleophilic ring-opening reactions with acylnitroso-Diels–Alder adducts

    PubMed Central

    Yang, Baiyuan; Miller, Marvin J.

    2010-01-01

    Treatment of acylnitroso-Diels–Alder [2.2.1] bicyclic adducts 2a–b with indium triflate in an alcohol solvent induces ring opening reactions to afford monocyclic anti-1,2-, anti-1,4- and syn-1,4-hydroxamic acids with good to excellent regio- and stereoselectivity (up to 7:86:7). Treatment of [2.2.2] bicyclic nitroso adducts 2c–d under similar reaction conditions generates only anti-1,2- and anti-1,4-hydroxamic acids with anti-1,4-product predominant (up to 17:83). PMID:20209116

  8. Synthesis and metabolism of inhibitors of ribonucleotide reductase

    SciTech Connect

    Smith, F.T.

    1985-01-01

    In an effort to prepare more effective inhibitors of ribo-nucleotide reductase a series of 2-substituted-4,6-dihydroxypyrimidines was prepared via the appropriately substituted benzamidine. None of the compounds exhibited in vivo activity against L1210 leukemia. No further testing was performed. In order to investigate the metabolism of 3,4-dihydroxybenzohydroxamic acid, a known inhibitor of ribonucleotide reductase, radiolabeled 3,4-dihydroxybenzohydroxamic acid was synthesized by a modification of the procedure of Pichat and Tostain. /sup 14/C-3,4-Dihydroxybenzoic acid was converted to the methyl ester and subsequently reacted with hydroxylamine to give the hydroxamic acid. /sup 14/C-3,4-Dihydroxybenzohydroxamic acid was given i.p. to Sprague-Dawley rats. Excretion occurred mainly (72%) via the urine. HPLC coupled with GC/MS analyses showed that the compound was excreted mainly unchanged. The compound was metabolized to 3,4-dihydroxybenzamide, 4-methoxy-3-hydroxybenzohydroxamic acid, and 4-hydroxy-3-methoxybenzohydroxamic acid. HPLC analysis also showed the lack of formation of any glucuronide or sulfate conjugates through either the hydroxamic acid or catechol functionalities.

  9. High stability and high efficiency chemiluminescent acridinium compounds obtained from 9-acridine carboxylic esters of hydroxamic and sulphohydroxamic acids.

    PubMed

    Renotte, R; Sarlet, G; Thunus, L; Lejeune, R

    2000-01-01

    A series of hydroxamic acids and sulphohydroxamic acids were prepared and linked to 9-acridinecarboxylic acid through a pseudo-ester function. After N-methylation of the heterocyclic ring, the different compounds were tested for their chemiluminescent properties. Substituents on the hydroxamic functions have shown various effects (steric or electronic) on the luminescence yield or stability of the molecule. The most interesting derivatives were selected in terms of chemical stability and chemiluminescence efficiency. 9-[(N-hydroxysuccinimidyl-4-oxo-4-N-phenylaminobutanoate)N-carb oxylat e]-10-methyl-acridinium (FA6), 9-(N-phenylpivalamide-N-carboxylate)-10-methylacridinium (FA17) and 9-(N-phenylpivalamide N-carboxylate)-10-carboxymethyl-acridinium (FA18) iodomercurates are very promising as chemiluminescent labels. These compounds can be detected at very low levels (10(-16)-10(-17) mol/L) and in our stability evaluation, FA6, FA17 and FA18 showed similar results to the acridinium ester DMAE. Their half-lives at 20 degrees C are greater than 2 weeks. PMID:11038489

  10. Hydroxamate-Stimulated O2 Uptake in Roots of Pisum sativum and Zea mays, Mediated by a Peroxidase 1

    PubMed Central

    Brouwer, Koos Spreen; van Valen, Ties; Day, David A.; Lambers, Hans

    1986-01-01

    Low concentrations of salicylhydroxamic acid (<5 millimolar) stimulate O2 uptake in intact roots of Pisum sativum. We demonstrate that the hydroxamate-stimulated O2 uptake does not reside in the mitochondria. We also show that the hydroxamate-stimulated O2 uptake is due to the activation of a peroxidase catalyzing reduction of O2. This peroxidase, which can use both NADH and NADPH as a substrate, is stimulated by low concentrations of monophenols, e.g. salicylhydroxamic acid and 2-methoxyphenol. It is inhibited by high (20 millimolar) concentrations of salicylhydroxamic acid, cyanide, and scavengers of the superoxide free radical ion, e.g. ascorbate, gentisic acid, and catechol. In the presence of gentisic acid, O2 uptake by intact pea roots was no longer stimulated by low concentrations of salicylhydroxamic acid. The consequence of the present finding for in vivo respiration measurements is that the use of low concentrations of salicylhydroxamic acid and uncoupler is reliable only in the presence of a suitable superoxide free radical scavenger which prevents activation of the peroxidase. It also confirms that high concentrations of salicylhydroxamic acid (20-25 millimolar) can be safely used in short-term experiments to assess the activity of the alternative path in intact roots. PMID:16664999

  11. Probing the structure-activity relationship of endogenous histone deacetylase complexes with immobilized peptide-inhibitors.

    PubMed

    Sindlinger, Julia; Bierlmeier, Jan; Geiger, Lydia-Christina; Kramer, Katharina; Finkemeier, Iris; Schwarzer, Dirk

    2016-05-01

    Histone deacetylases (HDACs) are key regulators of numerous cellular proteins by removing acetylation marks from modified lysine residues. Peptide-based HDAC probes containing α-aminosuberic acid ω-hydroxamate have been established as useful tools for investigating substrate selectivity and composition of endogenous HDAC complexes in cellular lysates. Here we report a structure-activity study of potential HDAC-probes containing derivatives of the hydroxamate moieties. While most of these probes did not recruit significant amounts of endogenous HDACs from cellular lysates, peptides containing Nε-acetyl-Nε-hydroxy-L-lysine served as HDAC probe. The recruitment efficiency varied between HDACs and was generally lower than that of α-aminosuberic acid ω-hydroxamate probes, but showed a similar global interaction profile. These findings indicate that Nε-acetyl-Nε-hydroxy-L-lysine might be a useful tool for investigations on HDAC complexes and the development of HDAC inhibitors. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd. PMID:27071932

  12. Benzyl and Methyl Fatty Hydroxamic Acids Based on Palm Kernel Oil as Chelating Agent for Liquid-Liquid Iron(III) Extraction

    PubMed Central

    Haron, Md Jelas; Jahangirian, Hossein; Silong, Sidik; Yusof, Nor Azah; Kassim, Anuar; Rafiee-Moghaddam, Roshanak; Mahdavi, Behnam; Peyda, Mazyar; Abdollahi, Yadollah; Amin, Jamileh

    2012-01-01

    Liquid-liquid iron(III) extraction was investigated using benzyl fatty hydroxamic acids (BFHAs) and methyl fatty hydroxamic acids (MFHAs) as chelating agents through the formation of iron(III) methyl fatty hydroxamate (Fe-MFHs) or iron(III) benzyl fatty hydroxamate (Fe-BFHs) in the organic phase. The results obtained under optimized conditions, showed that the chelating agents in hexane extract iron(III) at pH 1.9 were realized effectively with a high percentage of extraction (97.2% and 98.1% for MFHAs and BFHAs, respectively). The presence of a large amount of Mg(II), Ni(II), Al(III), Mn(II) and Co(II) ions did affect the iron(III) extraction. Finally stripping studies for recovering iron(III) from organic phase (Fe-MFHs or Fe-BFHs dissolved in hexane) were carried out at various concentrations of HCl, HNO3 and H2SO4. The results showed that the desired acid for recovery of iron(III) was 5 M HCl and quantitative recovery of iron(III) was achieved from Fe(III)-MFHs and Fe(III)-BFHs solutions in hexane containing 5 mg/L of Fe(III). PMID:22408444

  13. Ultra-fast photo-patterning of hydroxamic acid layers adsorbed on TiAlN: The challenge of modeling thermally induced desorption

    NASA Astrophysics Data System (ADS)

    Hemgesberg, Maximilian; Schütz, Simon; Müller, Christine; Schlörholz, Matthias; Latzel, Harald; Sun, Yu; Ziegler, Christiane; Thiel, Werner R.

    2012-10-01

    Long-chain n-alkyl terminated hydroxamic acids (HA) are used for the modification of titanium aluminum nitride (TiAlN) surfaces. HA coatings improve the hydrophobicity of this wear resistant and industrially relevant ceramic. Therefore, HAs with different structural properties are evaluated with respect to their wear resistance and their thermal desorption properties. In order to find new coatings for rewritable offset printing plates, the changes in the surface polarity, composition, and morphology are analyzed by contact angle measurements, X-ray photoemission spectroscopy (XPS), and scanning force microscopy (SFM), respectively. The results are referenced to the strongly bonding molecule n-dodecyl phosphonate (PO11M), which has been used for surface hydrophobization before but proved difficult to remove due to the high laser outputs required for thermal desorption. It is found that for certain HAs, an equally good hydrophobization compared to PO11M can be achieved. Contact angles obtained for different hydroxamic acid coatings can be correlated to their modes of adsorption. Only for selected HA species, resistance to mechanical wear is sufficient for further investigations. Photo-patterning of these hydroxamic acid layers is achieved using a high energy IR laser beam at different energy inputs. Fitting of the obtained data and further evaluation using finite element analysis (FEM) calculations reveal significantly reduced energy consumption of about 20% for the removal of a specific hydroxamic acid coating from the ceramic surface compared to PO11M.

  14. Inhibitors Incorporating Zinc-Binding Groups Target the GlcNAc-PI de-N-acetylase in Trypanosoma brucei, the Causative Agent of African Sleeping Sickness

    PubMed Central

    Abdelwahab, Nuha Z; Crossman, Arthur T; Sullivan, Lauren; Ferguson, Michael A J; Urbaniak, Michael D

    2012-01-01

    Disruption of glycosylphosphatidylinositol biosynthesis is genetically and chemically validated as a drug target against the protozoan parasite Trypanosoma brucei, the causative agent of African sleeping sickness. The N-acetylglucosamine-phosphatidylinositol de-N-acetylase (deNAc) is a zinc metalloenzyme responsible for the second step of glycosylphosphatidylinositol biosynthesis. We recently reported the synthesis of eight deoxy-2-C-branched monosaccharides containing carboxylic acid, hydroxamic acid, or N-hydroxyurea substituents at the C2 position that may act as zinc-binding groups. Here, we describe the synthesis of a glucocyclitol-phospholipid incorporating a hydroxamic acid moiety and report the biochemical evaluation of the monosaccharides and the glucocyclitol-phospholipid as inhibitors of the trypanosome deNAc in the cell-free system and against recombinant enzyme. Monosaccharides with carboxylic acid or hydroxamic acid substituents were found to be the inhibitors of the trypanosome deNAc with IC50 values 0.1–1.5 mm, and the glucocyclitol-phospholipid was found to be a dual inhibitor of the deNAc and the α1-4-mannose transferase with an apparent IC50 = 19 ± 0.5 μm. PMID:22222041

  15. Identification of new snake venom metalloproteinase inhibitors using compound screening and rational Peptide design.

    PubMed

    Villalta-Romero, Fabián; Gortat, Anna; Herrera, Andrés E; Arguedas, Rebeca; Quesada, Javier; de Melo, Robson Lopes; Calvete, Juan J; Montero, Mavis; Murillo, Renato; Rucavado, Alexandra; Gutiérrez, José María; Pérez-Payá, Enrique

    2012-07-12

    The majority of snakebite envenomations in Central America are caused by the viperid species Bothrops asper, whose venom contains a high proportion of zinc-dependent metalloproteinases that play a relevant role in the pathogenesis of hemorrhage characteristic of these envenomations. Broad metalloproteinase inhibitors, such as the peptidomimetic hydroxamate Batimastat, have been shown to inhibit snake venom metalloproteinases (SVMP). However, the difficulty in having open public access to Batimastat and similar molecules highlights the need to design new inhibitors of SVMPs that could be applied in the treatment of snakebite envenomations. We have chosen the SVMP BaP1 as a model to search for new inhibitors using different strategies, that is, screening of the Prestwick Chemical Library and rational peptide design. Results from these approaches provide clues on the structural requirements for efficient BaP1 inhibition and pave the way for the design of new inhibitors of SVMP. PMID:24900507

  16. Identification of New Snake Venom Metalloproteinase Inhibitors Using Compound Screening and Rational Peptide Design

    PubMed Central

    2012-01-01

    The majority of snakebite envenomations in Central America are caused by the viperid species Bothrops asper, whose venom contains a high proportion of zinc-dependent metalloproteinases that play a relevant role in the pathogenesis of hemorrhage characteristic of these envenomations. Broad metalloproteinase inhibitors, such as the peptidomimetic hydroxamate Batimastat, have been shown to inhibit snake venom metalloproteinases (SVMP). However, the difficulty in having open public access to Batimastat and similar molecules highlights the need to design new inhibitors of SVMPs that could be applied in the treatment of snakebite envenomations. We have chosen the SVMP BaP1 as a model to search for new inhibitors using different strategies, that is, screening of the Prestwick Chemical Library and rational peptide design. Results from these approaches provide clues on the structural requirements for efficient BaP1 inhibition and pave the way for the design of new inhibitors of SVMP. PMID:24900507

  17. Valproic Acid as a Potential Inhibitor of Plasmodium falciparum Histone Deacetylase 1 (PfHDAC1): An in Silico Approach

    PubMed Central

    Elbadawi, Mohamed A. Abdallah; Awadalla, Mohamed Khalid Alhaj; Abdel Hamid, Muzamil Mahdi; Mohamed, Magdi Awadalla; Awad, Talal Ahmed

    2015-01-01

    A new Plasmodium falciparum histone deacetylase1 (PfHDAC1) homology model was built based on the highest sequence identity available template human histone deacetylase 2 structure. The generated model was carefully evaluated for stereochemical accuracy, folding correctness and overall structure quality. All evaluations were acceptable and consistent. Docking a group of hydroxamic acid histone deacetylase inhibitors and valproic acid has shown binding poses that agree well with inhibitor-bound histone deacetylase-solved structural interactions. Docking affinity dG scores were in agreement with available experimental binding affinities. Further, enzyme-ligand complex stability and reliability were investigated by running 5-nanosecond molecular dynamics simulations. Thorough analysis of the simulation trajectories has shown that enzyme-ligand complexes were stable during the simulation period. Interestingly, the calculated theoretical binding energies of the docked hydroxamic acid inhibitors have shown that the model can discriminate between strong and weaker inhibitors and agrees well with the experimental affinities reported in the literature. The model and the docking methodology can be used in screening virtual libraries for PfHDAC1 inhibitors, since the docking scores have ranked ligands in accordance with experimental binding affinities. Valproic acid calculated theoretical binding energy suggests that it may inhibit PfHDAC1. PMID:25679451

  18. 1,3,4-Oxadiazole-containing histone deacetylase inhibitors: anticancer activities in cancer cells.

    PubMed

    Valente, Sergio; Trisciuoglio, Daniela; De Luca, Teresa; Nebbioso, Angela; Labella, Donatella; Lenoci, Alessia; Bigogno, Chiara; Dondio, Giulio; Miceli, Marco; Brosch, Gerald; Del Bufalo, Donatella; Altucci, Lucia; Mai, Antonello

    2014-07-24

    We describe 1,3,4-oxadiazole-containing hydroxamates (2) and 2-aminoanilides (3) as histone deacetylase inhibitors. Among them, 2t, 2x, and 3i were the most potent and selective against HDAC1. In U937 leukemia cells, 2t was more potent than SAHA in inducing apoptosis, and 3i displayed cell differentiation with a potency similar to MS-275. In several acute myeloid leukemia (AML) cell lines, as well as in U937 cells in combination with doxorubicin, 3i showed higher antiproliferative effects than SAHA. PMID:24972008

  19. Breaking the dogma of the metal-coordinating carboxylate group in integrin ligands: introducing hydroxamic acids to the MIDAS to tune potency and selectivity.

    PubMed

    Heckmann, Dominik; Laufer, Burkhardt; Marinelli, Luciana; Limongelli, Vittorio; Novellino, Ettore; Zahn, Grit; Stragies, Roland; Kessler, Horst

    2009-01-01

    A suitable substitute: All integrin receptors bind their ligands, which contain an aspartate residue, in the metal-ion- dependent adhesion site (MIDAS). So far all attempts to replace the carboxyl group of aspartate with other, pharmacologically favorable isosteric groups have failed. Now it has been shown that a hydroxamic acid group can replace the carboxyl group; the resulting ligand retains its high binding activity. The picture shows one such ligand in the binding site of alphavbeta3. PMID:19343753

  20. Hydroxamic acid interactions with solvated cerium hydroxides in the flotation of monazite and bastnäsite-Experiments and DFT study

    NASA Astrophysics Data System (ADS)

    Sarvaramini, A.; Azizi, D.; Larachi, F.

    2016-11-01

    Density functional theory (DFT) simulations and experiments were performed to clarify the interaction mechanisms between hydroxamic acid collectors and cerium hydroxides during the flotation of bastnäsite and monazite minerals. These minerals showed considerable floatability at moderately alkaline pH which was related to the adsorption of hydroxamic acids on their surfaces as confirmed by vibrational spectroscopic and zeta potential measurements. DFT simulations showed that at moderately alkaline pH, the interactions between solvated Ce(OH)2+ and Ce(OH)2+ and heptyl-hydroxamic acid (HHA) anions resulted in the formation of, respectively, [Ce(OH)(HHA)x(H2O)y]2-x (x[y = ] = 1[6],2[3],3[1]) and [Ce(OH)2(HHA)x(H2O)y]1-x (x[y = ] = 1[5],2[1],3[0]) complexes. The collector anions were found to interact directly through formation of two covalent bonds between their two polar-head oxygen atoms and cerium in the hydroxide complexes. However, formation of such new bonds resulted in breakage of a few covalent/electrostatic bonds between cerium and water molecules initially present in the first hydration shell of the rare-earth metal cation. Building up in the electric double layer of the semi-soluble minerals, these complexes, and by extension, those from other rare-earth elements belonging to monazite and bastnäsite, are speculated to play a role in the interactions between rare-earth minerals and hydroxamic acid collectors.

  1. Identification and quantification of hydroxamic acids in maize seedling root tissue and impact on western corn rootworm (Coleoptera: Chrysomelidae) larval development.

    PubMed

    Davis, C S; Ni, X; Quisenberry, S S; Foster, J E

    2000-06-01

    Hydroxamic acid content was analyzed in the root tissue of four maize, Zea mays L., lines using high-performance liquid chromatography (HPLC) and related to western corn rootworm, Diabrotica virgifera virgifera LeConte, larval development and survivorship. Maize lines evaluated included Mp710 (PI 596627), MpSWCB-4, (PI 550498), Sc213 (PI 548792), and Dk580 (DeKalb commercial hybrid). Maize plants from each line were grown in test tubes containing a transparent agarose gel medium in a growth chamber. After 8 d of growth, root tissue of each line was harvested and hydroxamic acid content analyzed using HPLC. Three hydroxamic acids, 2,4-dihydroxy-7-methoxy-1,4-benzoxazin-3-one (DIMBOA), 6-methoxybenzoxazolinone (MBOA), and 2,4-dihydroxy-1,4-benzoxazin-3-one (DIBOA), were identified in the maize roots tested. DIMBOA concentration was quantified and ranged from 246.37 +/- 70.53 micrograms to 91.84 +/- 49.82 micrograms DIMBOA per gram of root tissue. No significant difference was found among lines in D. v. virgifera larval development and survivorship. PMID:10902360

  2. Iron chelating active packaging: Influence of competing ions and pH value on effectiveness of soluble and immobilized hydroxamate chelators.

    PubMed

    Ogiwara, Yoshiko; Roman, Maxine J; Decker, Eric A; Goddard, Julie M

    2016-04-01

    Many packaged foods utilize synthetic chelators (e.g. ethylenediaminetetraacetic acid, EDTA) to inhibit iron-promoted oxidation or microbial growth which would result in quality loss. To address consumer demands for all natural products, we have previously developed a non-migratory iron chelating active packaging material by covalent immobilization of polyhydroxamate and demonstrated its efficacy in delaying lipid oxidation. Herein, we demonstrate the ability of this hydroxamate-functionalized iron chelating active packaging to retain iron chelating capacity; even in the presence of competing ions common in food. Both immobilized and soluble hydroxamate chelators retained iron chelating capacity in the presence of calcium, magnesium, and sodium competing ions, although at pH 5.0 the presence of calcium reduced immobilized hydroxamate iron chelation. A strong correlation was found between colorimetric and mass spectral analysis of iron chelation by the chelating packaging material. Such chelating active packaging may support reducing additive use in product formulations, while retaining quality and shelf life. PMID:26593563

  3. Identification of the KDM2/7 Histone Lysine Demethylase Subfamily Inhibitor and its Antiproliferative Activity

    PubMed Central

    2013-01-01

    Histone Nε-methyl lysine demethylases KDM2/7 have been identified as potential targets for cancer therapies. On the basis of the crystal structure of KDM7B, we designed and prepared a series of hydroxamate analogues bearing an alkyl chain. Enzyme assays revealed that compound 9 potently inhibits KDM2A, KDM7A, and KDM7B, with IC50s of 6.8, 0.2, and 1.2 μM, respectively. While inhibitors of KDM4s did not show any effect on cancer cells tested, the KDM2/7-subfamily inhibitor 9 exerted antiproliferative activity, indicating the potential for KDM2/7 inhibitors as anticancer agents. PMID:23964788

  4. Peptide deformylase inhibitors as potent antimycobacterial agents.

    PubMed

    Teo, Jeanette W P; Thayalan, Pamela; Beer, David; Yap, Amelia S L; Nanjundappa, Mahesh; Ngew, Xinyi; Duraiswamy, Jeyaraj; Liung, Sarah; Dartois, Veronique; Schreiber, Mark; Hasan, Samiul; Cynamon, Michael; Ryder, Neil S; Yang, Xia; Weidmann, Beat; Bracken, Kathryn; Dick, Thomas; Mukherjee, Kakoli

    2006-11-01

    Peptide deformylase (PDF) catalyzes the hydrolytic removal of the N-terminal formyl group from nascent proteins. This is an essential step in bacterial protein synthesis, making PDF an attractive target for antibacterial drug development. Essentiality of the def gene, encoding PDF from Mycobacterium tuberculosis, was demonstrated through genetic knockout experiments with Mycobacterium bovis BCG. PDF from M. tuberculosis strain H37Rv was cloned, expressed, and purified as an N-terminal histidine-tagged recombinant protein in Escherichia coli. A novel class of PDF inhibitors (PDF-I), the N-alkyl urea hydroxamic acids, were synthesized and evaluated for their activities against the M. tuberculosis PDF enzyme as well as their antimycobacterial effects. Several compounds from the new class had 50% inhibitory concentration (IC50) values of <100 nM. Some of the PDF-I displayed antibacterial activity against M. tuberculosis, including MDR strains with MIC90 values of <1 microM. Pharmacokinetic studies of potential leads showed that the compounds were orally bioavailable. Spontaneous resistance towards these inhibitors arose at a frequency of < or =5 x 10(-7) in M. bovis BCG. DNA sequence analysis of several spontaneous PDF-I-resistant mutants revealed that half of the mutants had acquired point mutations in their formyl methyltransferase gene (fmt), which formylated Met-tRNA. The results from this study validate M. tuberculosis PDF as a drug target and suggest that this class of compounds have the potential to be developed as novel antimycobacterial agents. PMID:16966397

  5. Rational Design Synthesis and Evaluation of New Selective Inhibitors of Microbial Class II (Zinc Dependent) Fructose Bis-phosphate Aldolases

    SciTech Connect

    R Daher; M Coincon; M Fonvielle; P Gest; M Guerin; M Jackson; J Sygusch; M Therisod

    2011-12-31

    We report the synthesis and biochemical evaluation of several selective inhibitors of class II (zinc dependent) fructose bis-phosphate aldolases (Fba). The products were designed as transition-state analogues of the catalyzed reaction, structurally related to the substrate fructose bis-phosphate (or sedoheptulose bis-phosphate) and based on an N-substituted hydroxamic acid, as a chelator of the zinc ion present in active site. The compounds synthesized were tested on class II Fbas from various pathogenic microorganisms and, by comparison, on a mammalian class I Fba. The best inhibitor shows Ki against class II Fbas from various pathogens in the nM range, with very high selectivity (up to 105). Structural analyses of inhibitors in complex with aldolases rationalize and corroborate the enzymatic kinetics results. These inhibitors represent lead compounds for the preparation of new synthetic antibiotics, notably for tuberculosis prophylaxis.

  6. Fluorescence quenching and bonding properties of some hydroxamic acid derivatives by iron(III) and manganese(II).

    PubMed

    Senthilnithy, R; De Costa, M D P; Gunawardhana, H D

    2009-01-01

    Spectrophotometric investigations of highly fluorescent metal chelating molecules are of relevance due to their potential application in novel, selective fluorescence-based sensors. Benzene and naphthalene chromophores are highly fluorescent while hydroxamic acids are widely used as ligands for complexation of transition metals. In order to develop fluorescence probes, several phenyl derivatives of N-phenylbenzohydroxamic acid and an aminodihydroxamic acid linked with a naphthalene chromophore were synthesized and their selective ionophoric properties towards iron(III) and manganese(II) ions were investigated using fluorescence and absorption spectroscopy. Both methods confirm the formation of 1:1 and 1:2 complexes for iron(III) and a 1:1 complex for manganese(II). The complex that is formed depends on the concentration of the ligand and pH of the medium. The amino dihydroxamic acid exhibits a prominent selectivity towards iron(III) with a two-step 1:1 and 1:2 quenching mechanism at pH 3 and towards manganese(II) with a 1:1 quenching mechanism at a probe concentration of 1 x 10(-5) mol dm(-3) at pH 9.5 The logarithm of overall formation constants of 1:1 and 1:2 complexes of iron(III) were estimated as 3.30 and 9.05, respectively. PMID:18800360

  7. Charting the mechanism and reactivity of zirconium oxalate with hydroxamate ligands using density functional theory: implications in new chelate design.

    PubMed

    Holland, Jason P; Vasdev, Neil

    2014-07-14

    The reaction of [(89)Zr(C2O4)4](4-) with the tris-hydroxamate ligand desferrioxamine B (DFO) provides the basis of radiolabelling biological vectors such as antibodies and proteins with the radionuclide (89)Zr for positron emission tomography imaging. In this work, density functional theory methods were used to investigate the mechanism of reaction from [Zr(C2O4)4](4-) to Zr(MeAHA)4 by ligand substitution with N-methyl acetohydroxamate (MeAHA). Calculations were performed under simulated basic and acidic conditions. Ligand substitution under basic conditions was found to be thermodynamically feasible with an overall calculated change in solvation free energy, ΔGsol = -97 kJ mol(-1) using the B3LYP/DGDZVP methodology and a water continuum solvation model. In contrast, an acid-mediated mechanism of ligand substitution was found to be thermodynamically non-feasible. Molecular orbital analysis provides a rationale for the difference in thermodynamic stability between [Zr(C2O4)4](4-) and Zr(MeAHA)4. Overall, the DFT calculations are consistent with observed experimental (89)Zr-radiolabelling reactions and suggest that computational methods may prove useful in designing novel chelates for increasing the thermodynamic and kinetic stability of (89)Zr-complexes in vivo. PMID:24722728

  8. Molecular characterization of Haemophilus parasuis ferric hydroxamate uptake (fhu) genes and constitutive expression of the FhuA receptor.

    PubMed

    del Río, Maria Luisa; Navas, Jesús; Martín, Ana Judith; Gutiérrez, César B; Rodríguez-Barbosa, José-Ignacio; Rodríguez Ferri, Elías F

    2006-01-01

    Bacteria have evolved a set of highly specialized proteins to capture iron in iron-depleted environments. The acquisition and uptake of iron present in the extracellular milieu of eukaryotic organisms is indispensable for the growth and survival of microbial pathogens in the course of infection. Haemophilus parasuis is the causative agent of Glässer disease, which is responsible for considerable financial losses in pig-rearing worldwide. To gain insight into the mechanisms involved in siderophore-mediated iron uptake in H. parasuis, genes in the H. parasuis ferric hydroxamate uptake (Fhu) region were amplified in the work being reported here. As has been described in A. pleuropneumoniae, an Fhu genomic region was also present in H. parasuis, being composed of four potential consecutive open reading frames (ORF) designated as fhuC, fhuD, fhuB, and fhuA, respectively. By immunoblotting, using a cross-reactive polyclonal antibody raised against Actinobacillus pleuropneumoniae FhuA protein, it was demonstrated that this protein was constitutively expressed in H. parasuis and its level of expression was not modified under conditions of restricted iron availability. This is the first report describing the presence of the fhu genes in H. parasuis. Our results indicate that FhuA protein expression is not affected under iron-restricted conditions, however, it is one of the targets of the humoral immune response. PMID:16336924

  9. Inhibitors of histone deacetylase as antitumor agents: A critical review.

    PubMed

    Manal, Mohammed; Chandrasekar, M J N; Gomathi Priya, Jeyapal; Nanjan, M J

    2016-08-01

    Histone deacetylase (EC 3.5.1.98 - HDAC) is an amidohydrolase involved in deacetylating the histone lysine residues for chromatin remodeling and thus plays a vital role in the epigenetic regulation of gene expression. Due to its aberrant activity and over expression in several forms of cancer, HDAC is considered as a potential anticancer drug target. HDAC inhibitors alter the acetylation status of histone and non-histone proteins to regulate various cellular events such as cell survival, differentiation and apoptosis in tumor cells and thus exhibit anticancer activity. Till date, four drugs, namely Vorinostat (SAHA), Romidepsin (FK-228), Belinostat (PXD-101) and Panobinostat (LBH-589) have been granted FDA approval for cancer and several HDAC inhibitors are currently in various phases of clinical trials, either as monotherapy and/or in combination with existing/novel anticancer agents. Regardless of this, today scientific efforts have fortified the quest for newer and novel HDAC inhibitors that show isoform selectivity. This review focuses on the chemistry of the molecules of two classes of HDAC inhibitors, namely short chain fatty acids and hydroxamic acids, investigated so far as novel therapeutic agents for cancer. PMID:27239721

  10. Proteasome inhibitors.

    PubMed

    Teicher, Beverly A; Tomaszewski, Joseph E

    2015-07-01

    Proteasome inhibitors have a 20 year history in cancer therapy. The first proteasome inhibitor, bortezomib (Velcade, PS-341), a break-through multiple myeloma treatment, moved rapidly through development from bench in 1994 to first approval in 2003. Bortezomib is a reversible boronic acid inhibitor of the chymotrypsin-like activity of the proteasome. Next generation proteasome inhibitors include carfilzomib and oprozomib which are irreversible epoxyketone proteasome inhibitors; and ixazomib and delanzomib which are reversible boronic acid proteasome inhibitors. Two proteasome inhibitors, bortezomib and carfilzomib are FDA approved drugs and ixazomib and oprozomib are in late stage clinical trials. All of the agents are potent cytotoxics. The disease focus for all the proteasome inhibitors is multiple myeloma. This focus arose from clinical observations made in bortezomib early clinical trials. Later preclinical studies confirmed that multiple myeloma cells were indeed more sensitive to proteasome inhibitors than other tumor cell types. The discovery and development of the proteasome inhibitor class of anticancer agents has progressed through a classic route of serendipity and scientific investigation. These agents are continuing to have a major impact in their treatment of hematologic malignancies and are beginning to be explored as potential treatment agent for non-cancer indications. PMID:25935605

  11. Copper(II)-catalyzed room temperature aerobic oxidation of hydroxamic acids and hydrazides to acyl-nitroso and azo intermediates, and their Diels-Alder trapping.

    PubMed

    Chaiyaveij, Duangduan; Cleary, Leah; Batsanov, Andrei S; Marder, Todd B; Shea, Kenneth J; Whiting, Andrew

    2011-07-01

    CuCl(2), in the presence of a 2-ethyl-2-oxazoline ligand, is an effective catalyst for the room temperature, aerobic oxidation of hydroxamic acids and hydrazides, to acyl-nitroso and azo dienophiles respectively, which are efficiently trapped in situ via both inter- and intramolecular hetero-Diels-Alder reactions with dienes. Both inter- and intramolecular variants of the Diels-Alder reaction are suitable under the reaction conditions using a variety of solvents. Under the same conditions, an acyl hydrazide was also oxidized to give an acyl-azo dienophile which was trapped intramolecularly by a diene. PMID:21644530

  12. Dissecting structure-activity-relationships of crebinostat: Brain penetrant HDAC inhibitors for neuroepigenetic regulation.

    PubMed

    Ghosh, Balaram; Zhao, Wen-Ning; Reis, Surya A; Patnaik, Debasis; Fass, Daniel M; Tsai, Li-Huei; Mazitschek, Ralph; Haggarty, Stephen J

    2016-02-15

    Targeting chromatin-mediated epigenetic regulation has emerged as a potential avenue for developing novel therapeutics for a wide range of central nervous system disorders, including cognitive disorders and depression. Histone deacetylase (HDAC) inhibitors have been pursued as cognitive enhancers that impact the regulation of gene expression and other mechanisms integral to neuroplasticity. Through systematic modification of the structure of crebinostat, a previously discovered cognitive enhancer that affects genes critical to memory and enhances synaptogenesis, combined with biochemical and neuronal cell-based screening, we identified a novel hydroxamate-based HDAC inhibitor, here named neurinostat, with increased potency compared to crebinostat in inducing neuronal histone acetylation. In addition, neurinostat was found to have a pharmacokinetic profile in mouse brain modestly improved over that of crebinostat. This discovery of neurinostat and demonstration of its effects on neuronal HDACs adds to the available pharmacological toolkit for dissecting the molecular and cellular mechanisms of neuroepigenetic regulation in health and disease. PMID:26804233

  13. FptA, the Fe(III)-pyochelin receptor of Pseudomonas aeruginosa: a phenolate siderophore receptor homologous to hydroxamate siderophore receptors.

    PubMed Central

    Ankenbauer, R G; Quan, H N

    1994-01-01

    The Pseudomonas aeruginosa siderophore pyochelin is structurally unique among siderophores and possesses neither hydroxamate- nor catecholate-chelating groups. The structural gene encoding the 75-kDa outer membrane Fe(III)-pyochelin receptor FptA has been isolated by plasmid rescue techniques and sequenced. The N-terminal amino acid sequence of the isolated FptA protein corresponded to that deduced from the nucleotide sequence of the fptA structural gene. The mature FptA protein has 682 amino acids and a molecular mass of 75,993 Da and has considerable overall homology with the hydroxamate siderophore receptors FpvA of P. aeruginosa, PupA and PupB of Pseudomonas putida, and FhuE of Escherichia coli. This observation indicates that homologies between siderophore receptors are an unreliable predictor of siderophore ligand class recognition by a given receptor. The fptA gene was strongly regulated by iron; fptA transcription was totally repressed by 30 microM FeCl3, as determined by Northern (RNA) blotting. The promoter of the fptA gene contained the sequence 5'-ATAATGATAAGCATTATC-3', which matches the consensus E. coli Fur-binding site at 17 of 18 positions. The -10 promoter region and transcriptional start site of the fptA gene reside within this Fur-binding site. Images PMID:8288523

  14. Quantitative Analysis of Global Proteome and Lysine Acetylome Reveal the Differential Impacts of VPA and SAHA on HL60 Cells.

    PubMed

    Zhu, Xiaoyu; Liu, Xin; Cheng, Zhongyi; Zhu, Jun; Xu, Lei; Wang, Fengsong; Qi, Wulin; Yan, Jiawei; Liu, Ning; Sun, Zimin; Liu, Huilan; Peng, Xiaojun; Hao, Yingchan; Zheng, Nan; Wu, Quan

    2016-01-01

    Valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA) are both HDAC inhibitors (HDACi). Previous studies indicated that both inhibitors show therapeutic effects on acute myeloid leukaemia (AML), while the differential impacts of the two different HDACi on AML treatment still remains elusive. In this study, using 3-plex SILAC based quantitative proteomics technique, anti-acetyllysine antibody based affinity enrichment, high resolution LC-MS/MS and intensive bioinformatic analysis, the quantitative proteome and acetylome in SAHA and VPA treated AML HL60 cells were extensively studied. In total, 5,775 proteins and 1,124 lysine acetylation sites were successfully obtained in response to VAP and SAHA treatment. It is found that VPA and SAHA treatment differently induced proteome and acetylome profiling in AML HL60 cells. This study revealed the differential impacts of VPA and SAHA on proteome/acetylome in AML cells, deepening our understanding of HDAC inhibitor mediated AML therapeutics. PMID:26822725

  15. Quantitative Analysis of Global Proteome and Lysine Acetylome Reveal the Differential Impacts of VPA and SAHA on HL60 Cells

    PubMed Central

    Zhu, Xiaoyu; Liu, Xin; Cheng, Zhongyi; Zhu, Jun; Xu, Lei; Wang, Fengsong; Qi, Wulin; Yan, Jiawei; Liu, Ning; Sun, Zimin; Liu, Huilan; Peng, Xiaojun; Hao, Yingchan; Zheng, Nan; Wu, Quan

    2016-01-01

    Valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA) are both HDAC inhibitors (HDACi). Previous studies indicated that both inhibitors show therapeutic effects on acute myeloid leukaemia (AML), while the differential impacts of the two different HDACi on AML treatment still remains elusive. In this study, using 3-plex SILAC based quantitative proteomics technique, anti-acetyllysine antibody based affinity enrichment, high resolution LC-MS/MS and intensive bioinformatic analysis, the quantitative proteome and acetylome in SAHA and VPA treated AML HL60 cells were extensively studied. In total, 5,775 proteins and 1,124 lysine acetylation sites were successfully obtained in response to VAP and SAHA treatment. It is found that VPA and SAHA treatment differently induced proteome and acetylome profiling in AML HL60 cells. This study revealed the differential impacts of VPA and SAHA on proteome/acetylome in AML cells, deepening our understanding of HDAC inhibitor mediated AML therapeutics. PMID:26822725

  16. Novel inhibitors of brain, neuronal, and basophilic anandamide amidohydrolase.

    PubMed

    De Petrocellis, L; Melck, D; Ueda, N; Maurelli, S; Kurahashi, Y; Yamamoto, S; Marino, G; Di Marzo, V

    1997-02-01

    Mammalian brain as well as mouse neuroblastoma (N18TG2) and rat basophilic leukaemia (RBL) cells were previously shown to contain "anandamide amidohydrolase', a membrane-bound enzyme sensitive to serine and cysteine protease inhibitors and catalyzing the hydrolysis of the endogenous cannabimimetic metabolite, anandamide (arachidonoyl-ethanolamide). With the aim of developing novel inhibitors of this enzyme, we synthesized three arachidonic acid (AA) analogues, i.e. arachidonoyl-diazo-methyl-ketone (ADMK), ara-chidonoyl-chloro-methyl-ketone (ACMK) and O-acetyl-arachidonoyl-hydroxamate (AcAHA), by adding to the fatty acid moiety three functional groups previously used to synthesize irreversible inhibitors of serine and cysteine proteases. The three compounds were purified and characterized by proton nuclear magnetic resonance and electron impact mass spectrometry. Their effect was tested on anandamide amidohydrolase partially purified from N18TG2 and RBL-1 cells and porcine brain. Pre-treatment of the enzyme with each compound produced a significant inhibition, with ADMK being the most potent (IC50 = 3, 2 and 6 microM) and AcAHA the weakest (IC50 = 34, 15 and 25 microM) inhibitors. The inactivated enzyme regained its full activity when chromatographed by anion-exchange chromatography, suggesting that none of the compounds inhibited the amidohydrolase in a covalent manner. Accordingly, Lineweaver-Burk profiles showed competitive inhibition by each compound. Conversely, the irreversible inhibitor of cytosolic phospholipase As, methyl-arachidonoyl-fluoro-phosphonate (MAFP), covalently inhibited the amidohydrolase. MAFP was active at concentrations 10(3) times lower than those reported for phospholipase A2 inhibition, and is the most potent anandamide amidohydrolase inhibitor so far described (IC50 = 1-3 nM). MAFP, ADMK and ACMK, probably by inhibiting anandamide degradation, produced an apparent increase of the in vitro formation of anandamide from its biosynthetic

  17. tert-Butylcarbamate-containing histone deacetylase inhibitors: apoptosis induction, cytodifferentiation, and antiproliferative activities in cancer cells.

    PubMed

    Valente, Sergio; Trisciuoglio, Daniela; Tardugno, Maria; Benedetti, Rosaria; Labella, Donatella; Secci, Daniela; Mercurio, Ciro; Boggio, Roberto; Tomassi, Stefano; Di Maro, Salvatore; Novellino, Ettore; Altucci, Lucia; Del Bufalo, Donatella; Mai, Antonello; Cosconati, Sandro

    2013-05-01

    Herein we report novel pyrrole- and benzene-based hydroxamates (8, 10) and 2'-aminoanilides (9, 11) bearing the tert-butylcarbamate group at the CAP moiety as histone deacetylase (HDAC) inhibitors. Compounds 8 b and 10 c selectively inhibited HDAC6 at the nanomolar level, whereas the other hydroxamates effected an increase in acetyl-α-tubulin levels in human acute myeloid leukemia U937 cells. In the same cell line, compounds 8 b and 10 c elicited 18.4 and 21.4 % apoptosis, respectively (SAHA: 16.9 %), and the pyrrole anilide 9 c displayed the highest cytodifferentiating effect (90.9 %). In tests against a wide range of various cancer cell lines to determine its antiproliferative effects, compound 10 c exhibited growth inhibition from sub-micromolar (neuroblastoma LAN-5 and SH-SY5Y cells, chronic myeloid leukemia K562 cells) to low-micromolar (lung H1299 and A549, colon HCT116 and HT29 cancer cells) concentrations. In HT29 cells, 10 c increased histone H3 acetylation, and decreased the colony-forming potential of the cancer cells by up to 60 %. PMID:23526814

  18. CFTR Inhibitors

    PubMed Central

    Verkman, Alan S.; Synder, David; Tradtrantip, Lukmanee; Thiagarajah, Jay R.; Anderson, Marc O.

    2014-01-01

    The cystic fibrosis transmembrane conductance regulator (CFTR) protein is a cAMP-regulated Cl− channel whose major function is to facilitate epithelial fluid secretion. Loss-of-function mutations in CFTR cause the genetic disease cystic fibrosis. CFTR is required for transepithelial fluid transport in certain secretory diarrheas, such as cholera, and for cyst expansion in autosomal dominant polycystic kidney disease. High-throughput screening has yielded CFTR inhibitors of the thiazolidinone, glycine hydrazide and quinoxalinedione chemical classes. The glycine hydrazides target the extracellular CFTR pore, whereas the thiazolidinones and quinoxalinediones act at the cytoplasmic surface. These inhibitors have been widely used in cystic fibrosis research to study CFTR function at the cell and organ levels. The most potent CFTR inhibitor has IC50 of approximately 4 nM. Studies in animal models support the development of CFTR inhibitors for antisecretory therapy of enterotoxin-mediated diarrheas and polycystic kidney disease. PMID:23331030

  19. Pyrido[2,3-d]pyrimidin-5-ones: A Novel Class of Antiinflammatory Macrophage Colony-Stimulating Factor-1 Receptor Inhibitors

    SciTech Connect

    Huang, Hui; Hutta, Daniel A.; Rinker, James M.; Hu, Huaping; Parsons, William H.; Schubert, Carsten; DesJarlais, Renee L.; Crysler, Carl S.; Chaikin, Margery A.; Donatelli, Robert R.; Chen, Yanmin; Cheng, Deping; Zhou, Zhao; Yurkow, Edward; Manthey, Carl L.; Player, Mark R.

    2010-10-01

    A series of pyrido[2,3-d]pyrimidin-5-ones has been synthesized and evaluated as inhibitors of the kinase domain of macrophage colony-stimulating factor-1 receptor (FMS). FMS inhibitors may be useful in treating rheumatoid arthritis and other chronic inflammatory diseases. Structure-based optimization of the lead amide analogue 10 led to hydroxamate analogue 37, which possessed excellent potency and an improved pharmacokinetic profile. During the chronic phase of streptococcal cell wall-induced arthritis in rats, compound 37 (10, 3, and 1 mg/kg) was highly effective at reversing established joint swelling. In an adjuvant-induced arthritis model in rats, 37 prevented joint swelling partially at 10 mg/kg. In this model, osteoclastogenesis and bone erosion were prevented by low doses (1 or 0.33 mg/kg) that had minimal impact on inflammation. These data underscore the potential of FMS inhibitors to prevent erosions and reduce symptoms in rheumatoid arthritis.

  20. The effects of a novel aliphatic-chain hydroxamate derivative WMJ-S-001 in HCT116 colorectal cancer cell death.

    PubMed

    Huang, Yu-Han; Huang, Shiu-Wen; Hsu, Ya-Fen; Ou, George; Huang, Wei-Jan; Hsu, Ming-Jen

    2015-01-01

    Hydroxamate derivatives have attracted considerable attention due to their broad pharmacological properties and have been extensively investigated. We recently demonstrated that WMJ-S-001, a novel aliphatic hydroxamate derivative, exhibits anti-inflammatory and anti-angiogenic activities. In this study, we explored the underlying mechanisms by which WMJ-S-001 induces HCT116 colorectal cancer cell death. WMJ-S-001 inhibited cell proliferation and induced cell apoptosis in HCT116 cells. These actions were associated with AMP-activated protein kinase (AMPK) and p38 mitogen-activated protein kinase (MAPK) activation, p53 phosphorylation and acetylation, as well as the modulation of p21(cip/Waf1), cyclin D1, survivin and Bax. AMPK-p38MAPK signaling blockade reduced WMJ-S-001-induced p53 phosphorylation. Transfection with AMPK dominant negative mutant (DN) reduced WMJ-S-001's effects on p53 and Sp1 binding to the survivn promoter region. Transfection with HDAC3-Flag or HDAC4-Flag also abrogated WMJ-S-001's enhancing effect on p53 acetylation. WMJ-S-001's actions on p21(cip/Waf1), cyclin D1, survivin, Bax were reduced in p53-null HCT116 cells. Furthermore, WMJ-S-001 was shown to suppress the growth of subcutaneous xenografts of HCT116 cells in vivo. In summary, the death of HCT116 colorectal cancer cells exposed to WMJ-S-001 may involve AMPK-p38MAPK-p53-survivin cascade. These results support the role of WMJ-S-001 as a potential drug candidate and warrant the clinical development in the treatment of cancer. PMID:26510776

  1. Development of novel ferulic acid derivatives as potent histone deacetylase inhibitors.

    PubMed

    Wang, Fang; Lu, Wen; Zhang, Tao; Dong, Jinyun; Gao, Hongping; Li, Pengfei; Wang, Sicen; Zhang, Jie

    2013-11-15

    Histone deacetylase inhibitors (HDACIs) offer a promising strategy for cancer therapy. The discovery of potent ferulic acid-based HDACIs with hydroxamic acid or 2-aminobenzamide group as zinc binding group was reported. The halogeno-acetanilide was introduced as novel surface recognition moiety (SRM). The majority of title compounds displayed potent HDAC inhibitory activity. In particular, FA6 and FA16 exhibited significant enzymatic inhibitory activities, with IC50 values of 3.94 and 2.82 μM, respectively. Furthermore, these compounds showed moderate antiproliferative activity against a panel of human cancer cells. FA17 displayed promising profile as an antitumor candidate. The results indicated that these ferulic acid derivatives could serve as promising lead compounds for further optimization. PMID:24095016

  2. [Proteasome inhibitor].

    PubMed

    Yagi, Hideo

    2014-06-01

    The ubiquitin-proteasome system plays an essential role in degradation of eukaryotic intracellular protein, including cell cycle regulation, cell growth and proliferation, and survival. Cancer cells generally have higher level of proteasome activity compared with normal cells, suggesting proteasome inhibition could be therapeutic target in oncology. Bortezomib, the first proteasome inhibitor introduced into the clinic, is approved for the treatment of patients with multiple myeloma (MM). Although it was approved as single agent in the relapsed setting, bortezomib is now predominantly used in combination with conventional and novel targeted agents because bortezomib has demonstrated additive and synergistic activity in preclinical studies. Recently, several second-generation proteasome inhibitors, such as carfilzomib and MLN9708, have been developed and entered into clinical trials. These agents were investigated in frontline MM in combination with lenalidomide and low-dose dexamethasone. These studies demonstrated positive efficacy and safety, and it is expected that they will be approved in near future. PMID:25016815

  3. 2-Benzazolyl-4-Piperazin-1-Ylsulfonylbenzenecarbohydroxamic Acids as Novel Selective Histone Deacetylase-6 Inhibitors with Antiproliferative Activity

    PubMed Central

    Wang, Lei; Kofler, Marina; Brosch, Gerald; Melesina, Jelena; Sippl, Wolfgang; Martinez, Elisabeth D.; Easmon, Johnny

    2015-01-01

    We have screened our compound collection in an established cell based assay that measures the derepression of an epigenetically silenced transgene, the locus derepression assay. The screen led to the identification of 4-[4-(1-methylbenzimidazol-2-yl)piperazin-1-yl]sulfonylbenzenecarbohydroxamic acid (9b) as an active which was found to inhibit HDAC1. In initial structure activity relationships study, the 1-methylbenzimidazole ring was replaced by the isosteric heterocycles benzimidazole, benzoxazole, and benzothiazole and the position of the hydroxamic acid substituent on the phenyl ring was varied. Whereas compounds bearing a para substituted hydroxamic acid (9a-d) were active HDAC inhibitors, the meta substituted analogues (8a-d) were appreciably inactive. Compounds 9a-d selectively inhibited HDAC6 (IC50 = 0.1–1.0μM) over HDAC1 (IC50 = 0.9–6μM) and moreover, also selectively inhibited the growth of lung cancer cells vs. patient matched normal cells. The compounds induce a cell cycle arrest in the S-phase while induction of apoptosis is neglible as compared to controls. Molecular modeling studies uncovered that the MM-GBSA energy for interaction of 9a-d with HDAC6 was higher than for HDAC1 providing structural rationale for the HDAC6 selectivity. PMID:26698121

  4. Histone deacetylase inhibitor pracinostat in doublet therapy: a unique strategy to improve therapeutic efficacy and to tackle herculean cancer chemoresistance.

    PubMed

    Ganai, Shabir Ahmad

    2016-09-01

    Context Histone deacetylase inhibitors (HDACi) have shown promising results in neurodegeneration and cancer. Hydroxamate HDACi, including vorinostat, have shown encouraging results in haematological malignancies, but the poor pharmacokinetic of these inhibitors leads to insufficient tumour concentration limiting their application against solid malignancies. Objective This article deals with novel HDAC inhibitor pracinostat (SB939) and delineates its therapeutic role in solid and haematological malignancies. The article provides rigorous details about the underlying molecular mechanisms modulated by pracinostat to exert cytotoxic effect. The article further highlights the doublet therapy that may be used to tackle monotonous cancer chemoresistance. Methods Both old and the latest literature on pracinostat was retrieved from diverse sources, such as PubMed, Science Direct, Springer Link, general Google search using both pracinostat and SB939 keywords in various ways: after thorough evaluation the topic which can fulfil the current gap was chosen. Results Pracinostat shows potent anticancer activity against both solid and haematological malignancies compared to the FDA-approved drug vorinostat. This marvellous inhibitor has better physicochemical, pharmaceutical and pharmacokinetic properties than the defined inhibitor vorinostat. Pracinostat has  >100-fold more affinity towards HDACs compared to other zinc-dependent metalloenzymes and shows maximum efficacy when used in doublet therapy. Conclusion Pracinostat shows potent anticancer activity even against therapeutically challenging cancers when used in doublet therapy. However, the triplet combination studies of the defined inhibitor that may prove even more beneficial are still undone, emphasizing the desperate need of further research in the defined gap. PMID:26853619

  5. Concerted Amidation of Activated Esters: Reaction Path and Origins of Selectivity in the Kinetic Resolution of Cyclic Amines via N-Heterocyclic Carbenes and Hydroxamic Acid Cocatalyzed Acyl Transfer

    PubMed Central

    2015-01-01

    The N-heterocyclic carbene and hydroxamic acid cocatalyzed kinetic resolution of cyclic amines generates enantioenriched amines and amides with selectivity factors up to 127. In this report, a quantum mechanical study of the reaction mechanism indicates that the selectivity-determining aminolysis step occurs via a novel concerted pathway in which the hydroxamic acid plays a key role in directing proton transfer from the incoming amine. This modality was found to be general in amide bond formation from a number of activated esters including those generated from HOBt and HOAt, reagents that are broadly used in peptide coupling. For the kinetic resolution, the proposed model accurately predicts the faster reacting enantiomer. A breakdown of the steric and electronic control elements shows that a gearing effect in the transition state is responsible for the observed selectivity. PMID:25050843

  6. Designed Inhibitors of Insulin-Degrading Enzyme Regulate the Catabolism and Activity of Insulin

    SciTech Connect

    Leissring, Malcolm A.; Malito, Enrico; Hedouin, Sabrine; Reinstatler, Lael; Sahara, Tomoko; Abdul-Hay, Samer O.; Choudhry, Shakeel; Maharvi, Ghulam M.; Fauq, Abdul H.; Huzarska, Malwina; May, Philip S.; Choi, Sungwoon; Logan, Todd P.; Turk, Benjamin E.; Cantley, Lewis C.; Manolopoulou, Marika; Tang, Wei-Jen; Stein, Ross L.; Cuny, Gregory D.; Selkoe, Dennis J.

    2010-09-20

    Insulin is a vital peptide hormone that is a central regulator of glucose homeostasis, and impairments in insulin signaling cause diabetes mellitus. In principle, it should be possible to enhance the activity of insulin by inhibiting its catabolism, which is mediated primarily by insulin-degrading enzyme (IDE), a structurally and evolutionarily distinctive zinc-metalloprotease. Despite interest in pharmacological inhibition of IDE as an attractive anti-diabetic approach dating to the 1950s, potent and selective inhibitors of IDE have not yet emerged. We used a rational design approach based on analysis of combinatorial peptide mixtures and focused compound libraries to develop novel peptide hydroxamic acid inhibitors of IDE. The resulting compounds are {approx} 10{sup 6} times more potent than existing inhibitors, non-toxic, and surprisingly selective for IDE vis-a-vis conventional zinc-metalloproteases. Crystallographic analysis of an IDE-inhibitor complex reveals a novel mode of inhibition based on stabilization of IDE's 'closed,' inactive conformation. We show further that pharmacological inhibition of IDE potentiates insulin signaling by a mechanism involving reduced catabolism of internalized insulin. Conclusions/Significance: The inhibitors we describe are the first to potently and selectively inhibit IDE or indeed any member of this atypical zinc-metalloprotease superfamily. The distinctive structure of IDE's active site, and the mode of action of our inhibitors, suggests that it may be possible to develop inhibitors that cross-react minimally with conventional zinc-metalloproteases. Significantly, our results reveal that insulin signaling is normally regulated by IDE activity not only extracellularly but also within cells, supporting the longstanding view that IDE inhibitors could hold therapeutic value for the treatment of diabetes.

  7. Speciation, liquid-liquid extraction, sequential separation, preconcentration, transport and ICP-AES determination of Cr(III), Mo(VI) and W(VI) with calix-crown hydroxamic acid in high purity grade materials and environmental samples.

    PubMed

    Agrawal, Y K; Sharma, K R

    2005-07-15

    A new functionalized calix[6]crown hydroxamic acid is reported for the speciation, liquid-liquid extraction, sequential separation and trace determination of Cr(III), Mo(VI) and W(VI). Chromium(III), molybdenum(VI) and tungsten(VI) are extracted at pH 4.5, 1.5M HCl and 6.0M HCl, respectively with calixcrown hydroxamic acid (37,38,39,40,41,42-hexahydroxy7,25,31-calix[6]crown hydroxamic acid) in chloroform in presence of large number of cations and anions. The extraction mechanism is investigated. The various extraction parameters, appropriate pH/M HCl, choice of solvent, effect of the reagent concentration, temperature and distribution constant have been studied. The speciation, preconcentration and kinetic of transport has been investigated. The maximum transport is observed 35, 45 and 30min for chromium(III), molybdenum(VI) and tungsten(IV), respectively. For trace determination the extracts were directly inserted into the plasma for inductively coupled plasma atomic emission spectrometry, ICP-AES, measurements of chromium, molybdenum and tungsten which increase the sensitivity by 30-fold, with detection limits of 3ngml(-1). The method is applied for the determination of chromium, molybdenum and tungsten in high purity grade ores, biological and environmental samples. The chromium was recovered from the effluent of electroplating industries. PMID:18970144

  8. Impact of the uranium (VI) speciation in mineralised urines on its extraction by calix[6]arene bearing hydroxamic groups used in chromatography columns.

    PubMed

    Baghdadi, S; Bouvier-Capely, C; Ritt, A; Peroux, A; Fevrier, L; Rebiere, F; Agarande, M; Cote, G

    2015-11-01

    Actinides determination in urine samples is part of the analyses performed to monitor internal contamination in case of an accident or a terrorist attack involving nuclear matter. Mineralisation is the first step of any of these analyses. It aims at reducing the sample volume and at destroying all organic compounds present. The mineralisation protocol is usually based on a wet ashing step, followed by actinides co-precipitation and a furnace ashing step, before redissolution and the quantification of the actinides by the appropriate techniques. Amongst the existing methods to perform the actinides co-precipitation, alkali-earth (typically calcium) precipitation is widely used. In the present work, the extraction of uranium(VI), plutonium(IV) and americium(III) from the redissolution solutions (called "mineralised urines") on calix[6]arene columns bearing hydroxamic groups was investigated as such an extraction is a necessary step before their determination by ICP-MS or alpha spectrometry. Difficulties were encountered in the transfer of uranium(VI) from raw to mineralised urines, with yield of transfer ranging between 0% and 85%, compared to about 90% for Pu and Am, depending on the starting raw urines. To understand the origin of such a difficulty, the speciation of uranium (VI) in mineralised urines was investigated by computer simulation using the MEDUSA software and the associated HYDRA database, compiled with recently published data. These calculations showed that the presence of phosphates in the "mineralised urines" leads to the formation of strong uranyl-phosphate complexes (such as UO2HPO4) which compete with the uranium (VI) extraction by the calix[6]arene bearing hydroxamic groups. The extraction constant of uranium (VI) by calix[6]arene bearing hydroxamic groups was determined in a 0.04 mol L(-1) sodium nitrate solution (logK=4.86±0.03) and implemented in an extraction model taking into account the speciation in the aqueous phase. This model allowed to

  9. Non-coding nucleotides and amino acids near the active site regulate peptide deformylase expression and inhibitor susceptibility in Chlamydia trachomatis.

    PubMed

    Bao, Xiaofeng; Pachikara, Niseema D; Oey, Christopher B; Balakrishnan, Amit; Westblade, Lars F; Tan, Ming; Chase, Theodore; Nickels, Bryce E; Fan, Huizhou

    2011-09-01

    Chlamydia trachomatis, an obligate intracellular bacterium, is a highly prevalent human pathogen. Hydroxamic-acid-based matrix metalloprotease inhibitors can effectively inhibit the pathogen both in vitro and in vivo, and have exhibited therapeutic potential. Here, we provide genome sequencing data indicating that peptide deformylase (PDF) is the sole target of the inhibitors in this organism. We further report molecular mechanisms that control chlamydial PDF (cPDF) expression and inhibition efficiency. In particular, we identify the σ⁶⁶-dependent promoter that controls cPDF gene expression and demonstrate that point mutations in this promoter lead to resistance by increasing cPDF transcription. Furthermore, we show that substitution of two amino acids near the active site of the enzyme alters enzyme kinetics and protein stability. PMID:21719536

  10. Autophagy inhibitors.

    PubMed

    Pasquier, Benoit

    2016-03-01

    Autophagy is a lysosome-dependent mechanism of intracellular degradation. The cellular and molecular mechanisms underlying this process are highly complex and involve multiple proteins, including the kinases ULK1 and Vps34. The main function of autophagy is the maintenance of cell survival when modifications occur in the cellular environment. During the past decade, extensive studies have greatly improved our knowledge and autophagy has exploded as a research field. This process is now widely implicated in pathophysiological processes such as cancer, metabolic, and neurodegenerative disorders, making it an attractive target for drug discovery. In this review, we will summarize the different types of inhibitors that affect the autophagy machinery and provide some potential therapeutic perspectives. PMID:26658914

  11. HDAC inhibition radiosensitizes human normal tissue cells and reduces DNA Double-Strand Break repair capacity.

    PubMed

    Purrucker, Jan C; Fricke, Andreas; Ong, Mei Fang; Rübe, Christian; Rübe, Claudia E; Mahlknecht, Ulrich

    2010-01-01

    HDAC inhibitors (HDACi) are gaining increasing attention in the treatment of cancer, particularly in view of their therapeutic effectiveness and assumed mild toxicity profile. While numerous studies have investigated the role of HDACi in tumor cells, little is known about their effects on normal tissue cells. We studied the effect of suberoylanilide hydroxamic acid (SAHA), MS275, sodium-butyrate and valproic acid in healthy human fibroblasts and found HDACi-treatment to go along with increased radiosensitivity and reduced DSB repair capacity. In view of the potential genotoxic effects of HDACi-treatment, particularly when being administered long-term for chronic disease or when given to children, to women of childbearing age or their partners or in combination with radiotherapy, an extensive education of patients and prescribing physicians as well as a stringent definition of clinical indications is urgently required. PMID:19956891

  12. Screening Novel SAHA Derivatives as Anti-lung Carcinoma Agents: Synthesis, Biological Evaluation, Docking Studies and Further Mechanism Research between Apoptosis and Autophagy.

    PubMed

    Huang, Weibin; Zhang, Song; Yang, Zhicheng; Feng, Binghong

    2015-01-01

    Four suberoylanilide hydroxamic acid (SAHA) derivatives (N34, N4I, N4B, N24) were designed and synthesized on the basis of our previous studies on N25. Assays for anti-proliferative activity and histone deacetylase (HDAC) activity were performed against human lung cancer (SPC-A-1, LTEP-a-2, NCI-H1650) and normal lung cells (MRC-5), which were compared with those of SAHA. Molecular docking was used to theoretically confirm the receptor-binding ability of N34. Ultimately, N34 was validated as the best HDAC inhibitor candidate. Furthermore, the effects of N34 on the levels of apoptosis- and autophagy-associated proteins caspase-3, caspase-9, Bcl-2 and Beclin-1 in SPC-A-1 cells were evaluated. N34 exerted more evident effects on human lung cancer than the other three SAHA derivatives did. PMID:26118711

  13. Evidence for Hydroxamate Siderophores and Other N-Containing Organic Compounds Controlling (239,240)Pu Immobilization and Remobilization in a Wetland Sediment.

    PubMed

    Xu, Chen; Zhang, Saijin; Kaplan, Daniel I; Ho, Yi-Fang; Schwehr, Kathleen A; Roberts, Kimberly A; Chen, Hongmei; DiDonato, Nicole; Athon, Matthew; Hatcher, Patrick G; Santschi, Peter H

    2015-10-01

    Pu concentrations in wetland surface sediments collected downstream of a former nuclear processing facility in F-Area of the Savannah River Site (SRS), USA, were ∼2.5 times greater than those measured in the associated upland aquifer sediments; similarly, the Pu concentration solid/water ratios were orders of magnitude greater in the wetland than in the low-organic matter content aquifer soils. Sediment Pu concentrations were correlated to total organic carbon and total nitrogen contents and even more strongly to hydroxamate siderophore (HS) concentrations. The HS were detected in the particulate or colloidal phases of the sediments but not in the low molecular weight fractions (<1000 Da). Macromolecules which scavenged the majority of the potentially mobile Pu were further separated from the bulk mobile organic matter fraction ("water extract") via an isoelectric focusing experiment (IEF). An electrospray ionization Fourier-transform ion cyclotron resonance ultrahigh resolution mass spectrometry (ESI FTICR-MS) spectral comparison of the IEF extract and a siderophore standard (desferrioxamine; DFO) suggested the presence of HS functionalities in the IEF extract. This study suggests that while HS are a very minor component in the sediment particulate/colloidal fractions, their concentrations greatly exceed those of ambient Pu, and HS may play an especially important role in Pu immobilization/remobilization in wetland sediments. PMID:26313339

  14. Ethyl 2-cyano-2-(2-nitrobenzenesulfonyloxyimino)acetate (o-NosylOXY): a recyclable coupling reagent for racemization-free synthesis of peptide, amide, hydroxamate, and ester.

    PubMed

    Dev, Dharm; Palakurthy, Nani Babu; Thalluri, Kishore; Chandra, Jyoti; Mandal, Bhubaneswar

    2014-06-20

    Ubiquitousness of amide and ester functionality makes coupling reactions extremely important. Although numerous coupling reagents are available, methods of preparation of the common and efficient reagents are cumbersome. Those reagents generate a substantial amount of chemical waste and lack recyclability. Ethyl 2-cyano-2-(2-nitrobenzenesulfonyloxyimino)acetate (o-NosylOXY), the first member of a new generation of coupling reagents, produces byproducts that can be easily recovered and reused for the synthesis of the same reagent, making the method more environmentally friendly and cost-effective. The synthesis of amides, hydroxamates, peptides, and esters using this reagent is described. The synthesis of the difficult sequences, for example, the islet amyloid polypeptide (22-27) fragment (with a C-terminal Gly, H-Asn-Phe-Gly-Ala-Ile-Leu-Gly-NH2) and acyl carrier protein (65-74) fragment (H-Val-Gln-Ala-Ala-Ile-Asp-Tyr-Ile-Asn-Gly-OH), following the solid-phase peptide synthesis (SPPS) protocol and Amyloid β (39-42) peptide (Boc-Val-Val-IIe-Ala-OMe), following solution-phase strategy is demonstrated. Remarkable improvement is noticed with respect to reaction time, yield, and retention of stereochemistry. A mechanistic investigation and recyclability are also described. PMID:24849944

  15. A new class of potent reversible inhibitors of metallo-proteinases: C-terminal thiol-peptides as zinc-coordinating ligands.

    PubMed

    Peters, K; Jahreis, G; Kotters, E M

    2001-10-01

    A number of substrate analogous peptides containing a phosphoramidate, phosphonate ester, hydroxamate, carboxylate or sulfhydryl group are known to be inhibitors of thermolysin and other metalloproteinases. According to the specificity, most of the inhibitors mimic the prime site of the active center. Hitherto, peptidyl derivatives with a thiol group at the C-terminus have not been described. We have synthesized the protected cysteamides Ac-Ala-Ala-CA-SH and Z-Aa1-Aa2-CA-SH (Aa1: Ala, Pro; Aa2: Ala, Leu). The binding of these thiol peptide inhibitors to the metalloproteinases is characterized first by the coordination of the thiolate group of the inhibitor to the catalytic zinc ion and second by the subsite interaction of the peptide ligand in the active site of the enzyme. All peptide derivatives were competitive inhibitors of the zinc metalloproteinase thermolysin. The strongest inhibition was found with Z-Pro-Leu-CA-SH (Ki = 30 microM). Substitution of the N-protecting benzyloxycarbonyl residue towards the acetyl group in the peptide inhibitor, the inhibition constant decreased about 25 times. PMID:11916139

  16. Identification of Jumonji AT-Rich Interactive Domain 1A Inhibitors and Their Effect on Cancer Cells

    PubMed Central

    2015-01-01

    Jumonji AT-rich interactive domain 1A (JARID1A), one of the jumonji C domain-containing histone demethylase (JHDM) family members, plays key roles in cancer cell proliferation and development of drug tolerance. Therefore, selective JARID1A inhibitors are potential anticancer agents. In this study, we searched for cell-active JARID1A inhibitors by screening hydroxamate compounds in our in-house library and the structural optimization based on docking study of the hit-compound to a homology model of JARID1A. As a result, we identified compound 6j, which selectively inhibits JARID1A over three other JHDM family members. Compound 7j, a prodrug form of compound 6j, induced a selective increase in the level of trimethylation of histone H3 lysine 4, a substrate of JARID1A. Furthermore, compound 7j synergistically enhanced A549 human lung cancer cell growth inhibition induced by vorinostat, a histone deacetylase inhibitor. These findings support the idea that JARID1A inhibitors have potential as anticancer agents. PMID:26101571

  17. Chemical intervention in bacterial lignin degradation pathways: Development of selective inhibitors for intradiol and extradiol catechol dioxygenases.

    PubMed

    Sainsbury, Paul D; Mineyeva, Yelena; Mycroft, Zoe; Bugg, Timothy D H

    2015-06-01

    Bacterial lignin degradation could be used to generate aromatic chemicals from the renewable resource lignin, provided that the breakdown pathways can be manipulated. In this study, selective inhibitors of enzymatic steps in bacterial degradation pathways were developed and tested for their effects upon lignin degradation. Screening of a collection of hydroxamic acid metallo-oxygenase inhibitors against two catechol dioxygenase enzymes, protocatechuate 3,4-dioxygenase (3,4-PCD) and 2,3-dihydroxyphenylpropionate 1,2-dioxygenase (MhpB), resulted in the identification of selective inhibitors D13 for 3,4-PCD (IC50 15μM) and D3 for MhpB (IC50 110μM). Application of D13 to Rhodococcus jostii RHA1 in minimal media containing ferulic acid led to the appearance of metabolic precursor protocatechuic acid at low concentration. Application of 1mM disulfiram, an inhibitor of mammalian aldehyde dehydrogenase, to R. jostii RHA1, gave rise to 4-carboxymuconolactone on the β-ketoadipate pathway, whereas in Pseudomonas fluorescens Pf-5 disulfiram treatment gave rise to a metabolite found to be glycine betaine aldehyde. PMID:25984987

  18. Phosphinic peptides, the first potent inhibitors of astacin, behave as extremely slow-binding inhibitors.

    PubMed Central

    Yiallouros, I; Vassiliou, S; Yiotakis, A; Zwilling, R; Stöcker, W; Dive, V

    1998-01-01

    A series of phosphinic pseudo-peptides varying in length and composition have been designed as inhibitors of the crayfish zinc endopeptidase astacin, the prototype of the astacin family and of the metzincin superfamily of metalloproteinases. The most efficient phosphinic peptide, fluorenylmethyloxycarbonyl-Pro-Lys-PhePsi(PO2CH2)Ala-P ro-Leu-Val, binds to astacin with a Ki value of 42 nM, which is about three orders of magnitude below the corresponding values for previously used hydroxamic acid derivatives. However, the rate constants for association (kon = 96.8 M-1.s-1) and dissociation (koff = 4.1 x 10(-6) s-1) are evidence for the extremely slow binding behaviour of this compound. N-terminally or C-terminally truncated phosphinic analogues of this parent molecule are much less potent, indicating a critical role of the peptide size on the potency. In particular, omission of the N-terminal proline residue leads to a 40-fold increase in Ki which is mostly due to a 75-fold higher koff value. These findings are consistent with the previously solved crystal structure of astacin complexed with one of the phosphinic peptides, benzyloxycarbonyl-Pro-Lys-PhePsi(PO2CH2)Ala-Pro-O-methyl, Ki = 14 microM [Grams, Dive, Yiotakis, Yiallouros, Vassiliou, Zwilling, Bode and Stöcker (1996) Nature Struct. Biol. 3, 671-675]. This structure also reveals that the phosphinic group binds to the active site as a transition-state analogue. The extremely slow binding behaviour of the phosphinic peptides is discussed in the light of the conformational changes involving a unique 'tyrosine switch' in the structure of astacin upon inhibitor binding. The phosphinic peptides may provide a rational basis for the design of drugs directed towards other members of the astacin family which, like bone morphogenetic protein 1 (BMP1; i.e. the procollagen C-proteinase), have become targets of pharmacological research. PMID:9531473

  19. Evaluation of histone deacetylase inhibitors (HDACi) as therapeutic leads for human African trypanosomiasis (HAT).

    PubMed

    Carrillo, Angela K; Guiguemde, W Armand; Guy, R Kiplin

    2015-08-15

    Two of the histone deacetylases, TbDAC1 and TbDAC3, have been reported to be essential genes in trypanosomes. Therefore, we tested the activity of a panel of human histone deacetylase inhibitors (HDACi) for their ability to block proliferation of Trypanosoma brucei brucei. Among the HDACi's, the hydroxamic acid derivatives panobinostat and belinostat exhibited potency that appeared to make them viable candidates for development due to their reported pharmacokinetic characteristics. However, cellular pharmacodynamic analysis demonstrated that these drugs were unable to kill cultured parasites at exposures seen in patients at their tolerated doses and additionally failed to show any synergistic effects in combination with pentamidine, suramin, melarsoprol, or nifurtimox. Analysis of the potency of the entire HDACi panel revealed no correlations between potency against any human HDAC isoform and inhibition of T. brucei proliferation, suggesting that the trypanosome histone deacetylases possess a unique specificity. These studies confirmed that HDAC inhibitors have potential as leads against human African trypanosomiasis but that none of the current clinical candidates can be directly repurposed. Therefore, development of HDACi's with appropriate specificity and potency may be a viable route to a new class of anti-trypanosomal drugs. PMID:25637120

  20. A fluorescence polarization binding assay to identify inhibitors of flavin-dependent monooxygenases.

    PubMed

    Qi, Jun; Kizjakina, Karina; Robinson, Reeder; Tolani, Karishma; Sobrado, Pablo

    2012-06-01

    N-Hydroxylating monooxygenases (NMOs) are essential for pathogenesis in fungi and bacteria. NMOs catalyze the hydroxylation of sine and ornithine in the biosynthesis of hydroxamate-containing siderophores. Inhibition of kynurenine monooxygenase (KMO), which catalyzes the conversion of kynurenine to 3-hydroxykynurenine, alleviates neurodegenerative disorders such as Huntington's and Alzheimer's diseases and brain infections caused by the parasite Trypanosoma brucei. These enzymes are examples of flavin-dependent monooxygenases, which are validated drug targets. Here, we describe the development and optimization of a fluorescence polarization assay to identify potential inhibitors of flavin-dependent monooxygenases. Fluorescently labeled ADP molecules were synthesized and tested. An ADP-TAMRA chromophore bound to KMO with a K(d) value of 0.60 ± 0.05 μM and to the NMOs from Aspergillus fumigatus and Mycobacterium smegmatis with K(d) values of 2.1 ± 0.2 and 4.0 ± 0.2 μM, respectively. The assay was tested in competitive binding experiments with substrates and products of KMO and an NMO. Furthermore, we show that this assay can be used to identify inhibitors of NMOs. A Z' factor of 0.77 was calculated, and we show that the assay exhibits good tolerance to temperature, incubation time, and dimethyl sulfoxide concentration. PMID:22410281

  1. Proton pump inhibitors

    MedlinePlus

    Proton pump inhibitors (PPIs) are medicines that work by reducing the amount of stomach acid made by glands in ... Proton pump inhibitors are used to: Relieve symptoms of acid reflux, or gastroesophageal reflux disease (GERD). This is a ...

  2. Histone deacetylase inhibition modulates indoleamine 2,3-dioxygenase–dependent DC functions and regulates experimental graft-versus-host disease in mice

    PubMed Central

    Reddy, Pavan; Sun, Yaping; Toubai, Tomomi; Duran-Struuck, Raimon; Clouthier, Shawn G.; Weisiger, Elizabeth; Maeda, Yoshinobu; Tawara, Isao; Krijanovski, Oleg; Gatza, Erin; Liu, Chen; Malter, Chelsea; Mascagni, Paolo; Dinarello, Charles A.; Ferrara, James L.M.

    2008-01-01

    Histone deacetylase (HDAC) inhibitors are antitumor agents that also have antiinflammatory properties. However, the mechanisms of their immunomodulatory functions are not known. We investigated the mechanisms of action of 2 HDAC inhibitors, suberoylanilide hydroxamic acid (SAHA) and ITF 2357, on mouse DC responses. Pretreatment of DCs with HDAC inhibitors significantly reduced TLR-induced secretion of proinflammatory cytokines, suppressed the expression of CD40 and CD80, and reduced the in vitro and in vivo allostimulatory responses induced by the DCs. In addition, injection of DCs treated ex vivo with HDAC inhibitors reduced experimental graft-versus-host disease (GVHD) in a murine allogeneic BM transplantation model. Exposure of DCs to HDAC inhibitors increased expression of indoleamine 2,3-dioxygenase (IDO), a suppressor of DC function. Blockade of IDO in WT DCs with siRNA and with DCs from IDO-deficient animals caused substantial reversal of HDAC inhibition–induced in vitro suppression of DC-stimulated responses. Direct injection of HDAC inhibitors early after allogeneic BM transplantation to chimeric animals whose BM-derived cells lacked IDO failed to protect from GVHD, demonstrating an in vivo functional role for IDO. Together, these data show that HDAC inhibitors regulate multiple DC functions through the induction of IDO and suggest that they may represent a novel class of agents to treat immune-mediated diseases. PMID:18568076

  3. The new low-toxic histone deacetylase inhibitor S-(2) induces apoptosis in various acute myeloid leukaemia cells

    PubMed Central

    Cellai, C; Balliu, M; Laurenzana, A; Guandalini, L; Matucci, R; Miniati, D; Torre, E; Nebbioso, A; Carafa, V; Altucci, L; Romanelli, M N; Paoletti, F

    2012-01-01

    Abstract Histone deacetylase inhibitors (HDACi) induce tumour cell cycle arrest and/or apoptosis, and some of them are currently used in cancer therapy. Recently, we described a series of powerful HDACi characterized by a 1,4-benzodiazepine (BDZ) ring hybridized with a linear alkyl chain bearing a hydroxamate function as Zn++-chelating group. Here, we explored the anti-leukaemic properties of three novel hybrids, namely the chiral compounds (S)-2 and (R)-2, and their non-chiral analogue 4, which were first comparatively tested in promyelocytic NB4 cells. (S)-2 and partially 4– but not (R)-2 – caused G0/G1 cell-cycle arrest by up-regulating cyclin G2 and p21 expression and down-regulating cyclin D2 expression, and also apoptosis as assessed by cell morphology and cytofluorimetric assay, histone H2AX phosphorylation and PARP cleavage. Notably, these events were partly prevented by an anti-oxidant. Moreover, novel HDACi prompted p53 and α-tubulin acetylation and, consistently, inhibited HDAC1 and 6 activity. The rank order of potency was (S)-2 > 4 > (R)-2, reflecting that of other biological assays and addressing (S)-2 as the most effective compound capable of triggering apoptosis in various acute myeloid leukaemia (AML) cell lines and blasts from patients with different AML subtypes. Importantly, (S)-2 was safe in mice (up to 150 mg/kg/week) as determined by liver, spleen, kidney and bone marrow histopathology; and displayed negligible affinity for peripheral/central BDZ-receptors. Overall, the BDZ-hydroxamate (S)-2 showed to be a low-toxic HDACi with powerful anti-proliferative and pro-apototic activities towards different cultured and primary AML cells, and therefore of clinical interest to support conventional anti-leukaemic therapy. PMID:22004558

  4. The new low-toxic histone deacetylase inhibitor S-(2) induces apoptosis in various acute myeloid leukaemia cells.

    PubMed

    Cellai, C; Balliu, M; Laurenzana, A; Guandalini, L; Matucci, R; Miniati, D; Torre, E; Nebbioso, A; Carafa, V; Altucci, L; Romanelli, M N; Paoletti, F

    2012-08-01

    Histone deacetylase inhibitors (HDACi) induce tumour cell cycle arrest and/or apoptosis, and some of them are currently used in cancer therapy. Recently, we described a series of powerful HDACi characterized by a 1,4-benzodiazepine (BDZ) ring hybridized with a linear alkyl chain bearing a hydroxamate function as Zn(++)--chelating group. Here, we explored the anti-leukaemic properties of three novel hybrids, namely the chiral compounds (S)-2 and (R)-2, and their non-chiral analogue 4, which were first comparatively tested in promyelocytic NB4 cells. (S)-2 and partially 4--but not (R)-2--caused G0/G1 cell-cycle arrest by up-regulating cyclin G2 and p21 expression and down-regulating cyclin D2 expression, and also apoptosis as assessed by cell morphology and cytofluorimetric assay, histone H2AX phosphorylation and PARP cleavage. Notably, these events were partly prevented by an anti-oxidant. Moreover, novel HDACi prompted p53 and α-tubulin acetylation and, consistently, inhibited HDAC1 and 6 activity. The rank order of potency was (S)-2 > 4 > (R)-2, reflecting that of other biological assays and addressing (S)-2 as the most effective compound capable of triggering apoptosis in various acute myeloid leukaemia (AML) cell lines and blasts from patients with different AML subtypes. Importantly, (S)-2 was safe in mice (up to 150 mg/kg/week) as determined by liver, spleen, kidney and bone marrow histopathology; and displayed negligible affinity for peripheral/central BDZ-receptors. Overall, the BDZ-hydroxamate (S)-2 showed to be a low-toxic HDACi with powerful anti-proliferative and pro-apototic activities towards different cultured and primary AML cells, and therefore of clinical interest to support conventional anti-leukaemic therapy. PMID:22004558

  5. Solution structure of the catalytic domain of human stromelysin complexed with a hydrophobic inhibitor.

    PubMed Central

    Van Doren, S. R.; Kurochkin, A. V.; Hu, W.; Ye, Q. Z.; Johnson, L. L.; Hupe, D. J.; Zuiderweg, E. R.

    1995-01-01

    Stromelysin, a representative matrix metalloproteinase and target of drug development efforts, plays a prominent role in the pathological proteolysis associated with arthritis and secondarily in that of cancer metastasis and invasion. To provide a structural template to aid the development of therapeutic inhibitors, we have determined a medium-resolution structure of a 20-kDa complex of human stromelysin's catalytic domain with a hydrophobic peptidic inhibitor using multinuclear, multidimensional NMR spectroscopy. This domain of this zinc hydrolase contains a mixed beta-sheet comprising one antiparallel strand and four parallel strands, three helices, and a methionine-containing turn near the catalytic center. The ensemble of 20 structures was calculated using, on average, 8 interresidue NOE restraints per residue for the 166-residue protein fragment complexed with a 4-residue substrate analogue. The mean RMS deviation (RMSD) to the average structure for backbone heavy atoms is 0.91 A and for all heavy atoms is 1.42 A. The structure has good stereochemical properties, including its backbone torsion angles. The beta-sheet and alpha-helices of the catalytic domains of human stromelysin (NMR model) and human fibroblast collagenase (X-ray crystallographic model of Lovejoy B et al., 1994b, Biochemistry 33:8207-8217) superimpose well, having a pairwise RMSD for backbone heavy atoms of 2.28 A when three loop segments are disregarded. The hydroxamate-substituted inhibitor binds across the hydrophobic active site of stromelysin in an extended conformation. The first hydrophobic side chain is deeply buried in the principal S'1 subsite, the second hydrophobic side chain is located on the opposite side of the inhibitor backbone in the hydrophobic S'2 surface subsite, and a third hydrophobic side chain (P'3) lies at the surface. PMID:8580839

  6. 4-(1-Ethyl-4-anisyl-imidazol-5-yl)-N-hydroxycinnamide – A new pleiotropic HDAC inhibitor targeting cancer cell signalling and cytoskeletal organisation

    SciTech Connect

    Mahal, Katharina; Kahlen, Philip; Biersack, Bernhard; Schobert, Rainer

    2015-08-15

    Histone deacetylases (HDAC) which play a crucial role in cancer cell proliferation are promising drug targets. However, HDAC inhibitors (HDACi) modelled on natural hydroxamic acids such as trichostatin A frequently lead to resistance or even an increased agressiveness of tumours. As a workaround we developed 4-(1-ethyl-4-anisyl-imidazol-5-yl)-N-hydroxycinnamide (etacrox), a hydroxamic acid that combines HDAC inhibition with synergistic effects of the 4,5-diarylimidazole residue. Etacrox proved highly cytotoxic against a panel of metastatic and resistant cancer cell lines while showing greater specificity for cancer over non-malignant cells when compared to the approved HDACi vorinostat. Like the latter, etacrox and the closely related imidazoles bimacroxam and animacroxam acted as pan-HDACi yet showed some specificity for HDAC6. Akt signalling and interference with nuclear beta-catenin localisation were elicited by etacrox at lower concentrations when compared to vorinostat. Moreover, etacrox disrupted the microtubule and focal adhesion dynamics of cancer cells and inhibited the proteolytic activity of prometastatic and proangiogenic matrix metalloproteinases. As a consequence, etacrox acted strongly antimigratory and antiinvasive against various cancer cell lines in three-dimensional transwell invasion assays and also antiangiogenic in vivo with respect to blood vessel formation in the chorioallantoic membrane assay. These pleiotropic effects and its water-solubility and tolerance by mice render etacrox a promising new HDACi candidate. - Graphical abstract: A novel histone deacetylase inhibitor with pleiotropic anticancer effects. - Highlights: • Etacrox is a new HDACi with cytotoxic, antiangiogenic and antiinvasive activity. • Etacrox causes aberrant cancer cell signalling and cytoskeletal reorganisation. • Pro-metastatic and angiogenic matrix metalloproteinases are inhibited by etacrox. • Etacrox impairs blood vessel maturation in vivo and cancer cell

  7. Drug forecast – the peptide deformylase inhibitors as antibacterial agents

    PubMed Central

    Guay, David R P

    2007-01-01

    The relatively rapid development of microbial resistance after the entry of every new antimicrobial into the marketplace necessitates a constant supply of new agents to maintain effective pharmacotherapy. Despite extensive efforts to identify novel lead compounds from molecular targets, only the peptide deformylase inhibitors (PDIs) have shown any real promise, with some advancing to phase I human trials. Bacterial peptide deformylase, which catalyzes the removal of the N-formyl group from N-terminal methionine following translation, is essential for bacterial protein synthesis, growth, and survival. The majority of PDIs are pseudopeptide hydroxamic acids and two of these (IV BB-83698 and oral NVP LBM-415) entered phase I human trials. However, agents to the present have suffered from major potential liabilities. Their in vitro activity has been limited to gram-positive aerobes and some anaerobes and has been quite modest against the majority of such species (MIC90 values ranging from 1–8 mg/L). They have exerted bacteriostatic, not bacteriocidal, activity, thus reducing their potential usefulness in the management of serious infections in the immunocompromised. The relative ease with which microorganisms have been able to develop resistance and the multiple available mechanisms of resistance (mutations in fmt, defB, folD genes; AcrAB/TolC efflux pump; overexpression of peptide deformylase) are worrisome. These could portend a short timespan of efficacy after marketing. Despite these current liabilities, further pursuit of more potent and broader spectrum PDIs which are less susceptible to bacterial mechanisms of resistance is still warranted. PMID:18472972

  8. [Inhibitors of xanthine oxidoreductase].

    PubMed

    Okamoto, Ken

    2008-04-01

    Inhibitors of xanthine oxidoreductase decrease production of uric acid, thus they act as hypouricemic drugs. Allopurinol, a prototypical xanthine oxidoreductase inhibitor, has been widely prescribed for treatment of gout and hyperuricemia. However, severe side effects of allopurinol may occur in patients with renal insufficiency. Recently, novel nonpurine selective inhibitors of xanthine oxidoreductase have been developed as potential alternatives to allopurinol. They have different inhibition mechanisms, utilizing the enzyme structure and the reaction mechanism. Such variation of the inhibition mechanism affects/in vivo/hypouricemic effects of the inhibitors. PMID:18409526

  9. Potent dual inhibitors of Plasmodium falciparum M1 and M17 aminopeptidases through optimization of S1 pocket interactions.

    PubMed

    Drinkwater, Nyssa; Vinh, Natalie B; Mistry, Shailesh N; Bamert, Rebecca S; Ruggeri, Chiara; Holleran, John P; Loganathan, Sasdekumar; Paiardini, Alessandro; Charman, Susan A; Powell, Andrew K; Avery, Vicky M; McGowan, Sheena; Scammells, Peter J

    2016-03-01

    Malaria remains a global health problem, and though international efforts for treatment and eradication have made some headway, the emergence of drug-resistant parasites threatens this progress. Antimalarial therapeutics acting via novel mechanisms are urgently required. Plasmodium falciparum M1 and M17 are neutral aminopeptidases which are essential for parasite growth and development. Previous work in our group has identified inhibitors capable of dual inhibition of PfA-M1 and PfA-M17, and revealed further regions within the protease S1 pockets that could be exploited in the development of ligands with improved inhibitory activity. Herein, we report the structure-based design and synthesis of novel hydroxamic acid analogues that are capable of potent inhibition of both PfA-M1 and PfA-M17. Furthermore, the developed compounds potently inhibit Pf growth in culture, including the multi-drug resistant strain Dd2. The ongoing development of dual PfA-M1/PfA-M17 inhibitors continues to be an attractive strategy for the design of novel antimalarial therapeutics. PMID:26807544

  10. Novel corrosion inhibitor technology

    SciTech Connect

    Van de Ven, P.; Fritz, P.; Pellet, R.

    1999-11-01

    A novel, patented corrosion inhibitor technology has been identified for use in heat transfer applications such as automotive and heavy-duty coolant. The new technology is based on a low-toxic, virtually depletion-free carboxylic acid corrosion inhibitor package that performs equally well in mono ethylene glycol and in less toxic propylene glycol coolants. An aqueous inhibitor concentrate is available to provide corrosion protection where freezing protection is not an issue. In the present paper, this inhibitor package is evaluated in the different base fluids: mono ethylene glycol, mono propylene glycol and water. Results are obtained in both standardized and specific corrosion tests as well as in selected field trials. These results indicate that the inhibitor package remains effective and retains the benefits previously identified in automotive engine coolant applications: excellent corrosion protection under localized conditions, general corrosion conditions as well as at high temperature.

  11. Proteomic profiling of human colon cancer cells treated with the histone deacetylase inhibitor belinostat.

    PubMed

    Beck, Hans Christian; Petersen, Jørgen; Nielsen, Søren Jensby; Morsczeck, Christian; Morszeck, Christian; Jensen, Peter B; Sehested, Maxwell; Grauslund, Morten

    2010-08-01

    The anticancer drug belinostat is a hydroxamate histone deacetylase inhibitor that has shown significant antitumour activity in various tumour models and also in clinical trials. In this study, we utilized a proteomic approach in order to evaluate the effect of this drug on protein expression in the human colon cancer cell line HCT116. Protein extracts from untreated HCT116 cells, and cells grown for 24 h in the presence of 1 and 10 muM belinostat were analysed by 2-D gel electrophoresis. Proteins were visualized by colloidal Coomassie blue staining and quantitative analysis of gel images revealed 45 unique differentially expressed proteins that were identified by LC-MSMS analysis. Among these proteins, of particular interest are the downregulated proteins nucleophosmin and stratifin, and the upregulated proteins nucleolin, gelsolin, heterogeneous nuclear ribonucleoprotein K, annexin 1, and HSP90B that all were related to the proto-oncogene proteins p53, Myc, activator protein 1, and c-fos protein. The modulation of these proteins is consistent with the observations that belinostat is able to inhibit clonogenic cell growth of HCT116 cells and the biological role of these proteins will be discussed. PMID:20717991

  12. Synthesis and biological evaluation of enantiomerically pure glyceric acid derivatives as LpxC inhibitors.

    PubMed

    Tangherlini, Giovanni; Torregrossa, Tullio; Agoglitta, Oriana; Köhler, Jens; Melesina, Jelena; Sippl, Wolfgang; Holl, Ralph

    2016-03-01

    Inhibitors of the UDP-3-O-[(R)-3-hydroxymyristoyl]-N-acetylglucosamine deacetylase (LpxC) represent a promising class of novel antibiotics, selectively combating Gram-negative bacteria. In order to elucidate the impact of the hydroxymethyl groups of diol (S,S)-4 on the inhibitory activity against LpxC, glyceric acid ethers (R)-7a, (S)-7a, (R)-7b, and (S)-7b, lacking the hydroxymethyl group in benzylic position, were synthesized. The compounds were obtained in enantiomerically pure form by a chiral pool synthesis and a lipase-catalyzed enantioselective desymmetrization, respectively. The enantiomeric hydroxamic acids (R)-7b (Ki=230nM) and (S)-7b (Ki=390nM) show promising enzyme inhibition. However, their inhibitory activities do not substantially differ from each other leading to a low eudismic ratio. Generally, the synthesized glyceric acid derivatives 7 show antibacterial activities against two Escherichia coli strains exceeding the ones of their respective regioisomes 6. PMID:26827141

  13. Screening of telomerase inhibitors.

    PubMed

    Kleideiter, Elke; Piotrowska, Kamilla; Klotz, Ulrich

    2007-01-01

    Shortening of telomeres prevents cells from uncontrolled proliferation. Progressive telomere shortening occurs at each cell division until a critical telomeric length is reached. Telomerase expression is switched off after embryonic differentiation in most normal cells, but it is expressed in a very high percentage of tumors of different origin. Thus, telomerase is regarded as the best tumor marker and a promising novel molecular target for cancer treatment. Therefore, different strategies to inhibit telomerase have been developed. However, systematic screening of telomerase inhibitors has not been performed to compare their therapeutic potential. We propose a suitable strategy for estimation of the therapeutic potential of telomerase inhibitors, which is based on a systematic screening of different inhibitors in the same cell system. From the long list of compounds discussed in the literature, we have selected four telomerase inhibitors of different structure and mode of action: BRACO19 (G-quadruplex-interactive compound), BIBR1532 (non-nucleosidic reverse transcriptase inhibitor), 2'-O-methyl RNA, and peptide nucleic acids (PNAs; hTR antisense oligonucleotides). To determine minimal effective concentrations for telomerase inhibition, telomerase activity was measured using the cell-free telomerase repeat amplification protocol (TRAP) assay. We also tested inhibitors in long-term cell-culture experiments by exposing A-549 cells to non-cytotoxic concentrations of inhibitors for a period of 99 days. Subsequently, telomerase activity of A-549 cells was investigated using the TRAP assay, and telomere length of samples was assessed by telomere restriction fragment (TRF) Southern blot analysis. PMID:18369824

  14. Disarming an Electrophilic Warhead: Retaining Potency in Tyrosine Kinase Inhibitor (TKI)-Resistant CML Lines While Circumventing Pharmacokinetic Liabilities.

    PubMed

    Ali, Ahmed M; Gómez-Biagi, Rodolfo F; Rosa, David A; Lai, Ping-Shan; Heaton, William L; Park, Ji Sung; Eiring, Anna M; Vellore, Nadeem A; de Araujo, Elvin D; Ball, Dan P; Shouksmith, Andrew E; Patel, Ami B; Deininger, Michael W; O'Hare, Thomas; Gunning, Patrick T

    2016-04-19

    Pharmacologic blockade of the activation of signal transducer and activator of transcription 3 (STAT3) in tyrosine kinase inhibitor (TKI)-resistant chronic myeloid leukemia (CML) cell lines characterized by kinase-independent resistance was shown to re-sensitize CML cells to TKI therapy, suggesting that STAT3 inhibitors in combination with TKIs are an effective combinatorial therapeutic for the treatment of CML. Benzoic acid- and hydroxamic acid-based STAT3 inhibitors SH-4-054 and SH-5-007, developed previously in our laboratory, demonstrated promising activity against these resistant CML cell lines. However, pharmacokinetic studies in murine models (CD-1 mice) revealed that both SH-4-054 and SH-5-007 are susceptible to glutathione conjugation at the para position of the pentafluorophenyl group via nucleophilic aromatic substitution (SN Ar). To determine whether the electrophilicity of the pentafluorophenyl sulfonamide could be tempered, an in-depth structure-activity relationship (SAR) study of the SH-4-054 scaffold was conducted. These studies revealed that AM-1-124, possessing a 2,3,5,6-tetrafluorophenylsulfonamide group, retained STAT3 protein affinity (Ki =15 μm), as well as selectivity over STAT1 (Ki >250 μm). Moreover, in both hepatocytes and in in vivo pharmacokinetic studies (CD-1 mice), AM-1-124 was found to be dramatically more stable than SH-4-054 (t1/2 =1.42 h cf. 10 min, respectively). AM-1-124 is a promising STAT3-targeting inhibitor with demonstrated bioavailability, suitable for evaluation in preclinical cancer models. PMID:27028877

  15. Selenium-containing analogs of SAHA induce cytotoxicity in lung cancer cells.

    PubMed

    Karelia, Nilkamal; Desai, Dhimant; Hengst, Jeremy A; Amin, Shantu; Rudrabhatla, Sairam V; Yun, Jong

    2010-11-15

    Cancer therapy has moved beyond conventional chemotherapeutics to more mechanism-based targeted approaches. Studies demonstrate that histone deacetylase (HDAC) is a promising target for anticancer agents. Numerous, structurally diverse, hydroxamic acid derivative, HDAC inhibitors have been reported and have been shown to induce growth arrest, differentiation, autophagy, and/or apoptotic cell death by inhibiting multiple signaling pathways in cancer cells. Suberoylanilide hydroxamic acid (SAHA) has emerged as an effective anticancer therapeutic agent and was recently approved by the FDA for the treatment of advanced cutaneous T-cell lymphoma. In our previous study, we reported the development of the novel, potent, selenium-containing HDAC inhibitors (SelSA-1 and SelSA-2). In this study, the effects of SelSA-1 and SelSA-2 on signaling pathways and cytotoxicity were compared with the known HDAC inhibitor, SAHA, in lung cancer cell lines. After 24 h of treatment, SelSA-1 and SelSA-2 inhibited lung cancer cell growth to a greater extent than SAHA in a dose-dependent manner with IC(50) values at low micromolar concentrations. SelSA-1 and SelSA-2 inhibited ERK and PI3K-AKT signaling pathways while simultaneously increasing in autophagy in A549 cells in a time dependent manner. This preliminary study demonstrates the effectiveness of the selenium-containing analogs of SAHA, SelSA-1, and SelSA-2, as HDAC inhibitors and provides insight into the improvement and/or development of these analogs as a therapeutic approach for the treatment of lung cancer. PMID:20855208

  16. Selenium-Containing Analogs of SAHA Induce Cytotoxicity in Lung Cancer Cells

    PubMed Central

    Karelia, Nilkamal; Desai, Dhimant; Hengst, Jeremy A.; Amin, Shantu; Rudrabhatla, Sairam V.; Yun, Jong

    2010-01-01

    Cancer therapy has moved beyond conventional chemotherapeutics to more mechanism-based targeted approaches. Studies demonstrate that histone deacetylase (HDAC) is a promising target for anticancer agents. Numerous, structurally diverse, hydroxamic acid derivative, HDAC inhibitors have been reported and have been shown to induce growth arrest, differentiation, autophagy and/or apoptotic cell death by inhibiting multiple signaling pathways in cancer cells. Suberoylanilide hydroxamic acid (SAHA) has emerged as an effective anticancer therapeutic agent and was recently approved by the FDA for the treatment of advanced cutaneous T- cell lymphoma. In our previous study, we reported the development of the novel, potent, selenium containing HDAC inhibitors (SelSA-1 and SelSA-2). In this study, the effects of SelSA-1 and SelSA-2 on signaling pathways and cytotoxicity were compared with the known HDAC inhibitor, SAHA, in lung cancer cell lines. After 24 hours of treatment, SelSA-1 and SelSA-2 inhibited lung cancer cell growth to a greater extent than SAHA in a dose-dependent manner with IC50 values at low micromolar concentrations. SelSA-1 and SelSA-2 inhibited ERK and PI3K-AKT signaling pathways while simultaneously increasing in autophagy in A549 cells in a time dependent manner. This preliminary study demonstrates the effectiveness of the selenium-containing analogs of SAHA, SelSA-1 and SelSA-2, as HDAC inhibitors and provides insight into the improvement and/or development of these analogs as a therapeutic approach for the treatment of lung cancer. PMID:20855208

  17. Differences in Expression of Key DNA Damage Repair Genes after Epigenetic-Induced BRCAness Dictate Synthetic Lethality with PARP1 Inhibition.

    PubMed

    Wiegmans, Adrian P; Yap, Pei-Yi; Ward, Ambber; Lim, Yi Chieh; Khanna, Kum Kum

    2015-10-01

    The triple-negative breast cancer (TNBC) subtype represents a cancer that is highly aggressive with poor patient outcome. Current preclinical success has been gained through synthetic lethality, targeting genome instability with PARP inhibition in breast cancer cells that harbor silencing of the homologous recombination (HR) pathway. Histone deacetylase inhibitors (HDACi) are a class of drugs that mediate epigenetic changes in expression of HR pathway genes. Here, we compare the activity of the pan-HDAC inhibitor suberoylanilide hydroxamic acid (SAHA), the class I/IIa HDAC inhibitor valproic acid (VPA), and the HDAC1/2-specific inhibitor romidepsin (ROMI) for their capability to regulate DNA damage repair gene expression and in sensitizing TNBC to PARPi. We found that two of the HDACis tested, SAHA and ROMI, but not VPA, indeed inhibit HR repair and that RAD51, BARD1, and FANCD2 represent key proteins whose inhibition is required for HDACi-mediated therapy with PARP inhibition in TNBC. We also observed that restoration of BRCA1 function stabilizes the genome compared with mutant BRCA1 that results in enhanced polyploid population after combination treatment with HDACi and PARPi. Furthermore, we found that overexpression of the key HR protein RAD51 represents a mechanism for this resistance, promoting aberrant repair and the enhanced polyploidy observed. These findings highlight the key components of HR in guiding synthetic lethality with PARP inhibition and support the rationale for utilizing the novel combination of HDACi and PARPi against TNBC in the clinical setting. PMID:26294743

  18. Synthetic inhibitors of elastase.

    PubMed

    Edwards, P D; Bernstein, P R

    1994-03-01

    For more than two decades investigators around the world, in both academic and industrial institutions, have been developing inhibitors of human neutrophil elastase. A number of very elegant and insightful strategies have been reported. In the case of reversible peptidic inhibitors, this has resulted in the identification of some extremely potent compounds with dissociation constants in the 10(-11) M range. This is quite an accomplishment considering that these low molecular-weight inhibitors are only tri- and tetrapeptides. In the case of the heterocyclic-based inhibitors, the challenge of balancing the heterocycle's inherent reactivity and aqueous stability with the stability of the enzyme-inhibitor adduct has been meet by either using a latent, reactive functionality which is only activated within the enzyme, or by incorporating features which selectively obstruct deacylation but have little effect on the enzyme acylation step. The underlying goal of this research has been the identification of agents to treat diseases associated with HNE. Several animal models have been developed for evaluating the in vivo activity of elastase inhibitors, and compounds have been shown to be effective in all of these models by the intravenous, intratrachael or oral routes of administration. However, only a very small percentage of compounds have possessed all the necessary properties, including lack of toxicity, for progression into the clinic. The peptidyl TFMK ICI 200,880 (25-12) has many of the desired characteristics of a drug to treat the diseases associated with HNE: chemical stability, in vitro and in vivo activity, a long duration of action, and adequate metabolic stability. Currently ICI 200,880 is the only low molecular-weight HNE inhibitor known to be undergoing clinical trials, and may be the compound which finally demonstrates the clinical utility of a synthetic HNE inhibitor. PMID:8189835

  19. [STAT3 inhibitor].

    PubMed

    Kitamura, Toshio

    2011-01-01

    Clinical efficacies of various molecular-targeted drugs have been recently demonstrated. Most of these drugs are kinase inhibitors. A most successful drug Glivec is an inhibitor of Bcr-Abl fusion kinase, derived from a well-known causative chromosome translocation of chronic myeloid leukemia(CML). Although other kinase inhibitors have also proved to be useful in the therapy of malignant diseases including an ALK inhibitor for lung carcinomas, a general problem of kinase inhibitors is their lowspecificities. Therefore, the complication of these drugs must be overcome. Recently, trials to develop moleculartargeted therapy whose targets are molecules other than kinases have also been promising. Among molecular targets, STAT3 has attracted a great deal of researchers' attention because it is constitutively activated in most malignant tumors and plays important roles in carcinogenesis. This article summarizes the current situation and problems to be solved with STAT3 inhibitors as well as our recent findings on the molecular mechanisms of STAT3 activation. PMID:21368456

  20. Aromatase and its inhibitors.

    PubMed

    Brodie, A; Lu, Q; Long, B

    1999-01-01

    Inhibitors of aromatase (estrogen synthetase) have been developed as treatment for postmenopausal breast cancer. Both steroidal substrate analogs, type I inhibitors, which inactivate the enzyme and non-steroidal competitive reversible, type II inhibitors, are now available. 4-hydroxyandrostenedione (4-OHA), the first selective aromatase inhibitor, has been shown to reduce serum estrogen concentrations and cause complete and partial responses in approximately 25% of patients with hormone responsive disease who have relapsed from previous endocrine treatment. Letrozole (CGS 20, 269) and anastrozole (ZN 1033) have been recently approved for treatment. Both suppress serum estrogen levels to the limit of assay detection. Letrozole has been shown to be significantly superior to megace in overall response rates and time to treatment failure, whereas anastrozole was found to improve survival in comparison to megace. Both were better tolerated than the latter. The potential of aromatase within the breast as a significant source of estrogen mediating tumor proliferation and which might determine the outcome of inhibitor treatment was explored. Using immunocytochemistry and in situ hybridization, aromatase and mRNAarom was detected mainly in the epithelial cells of the terminal ductal lobular units (TDLU) of the normal breast and also in breast tumor epithelial cells as well as some stromal cells. Increase in proliferation, measured by increased thymidine incorporation into DNA and by PCNA immunostaining in response to testosterone was observed in histocultures of breast cancer samples. This effect could be inhibited by 4-OHA and implies that intratumoral aromatase has functional significance. An intratumoral aromatase model in the ovariectomized nude mouse was developed which simulated the hormone responsive postmenopausal breast cancer patient. This model also allows evaluation of the efficacy of aromatase inhibitors and antiestrogens in tumors of estrogen receptor positive

  1. Small-molecule caspase inhibitors

    NASA Astrophysics Data System (ADS)

    Zhenodarova, S. M.

    2010-02-01

    The review considers low-molecular weight inhibitors of caspases, cysteine proteases being key contributors to apoptosis (programmed cell death). The inhibitors with aspartic acid residues or various heterocyclic systems (both synthetic and natural) are covered. Their possible mechanisms of action are discussed. Data on inhibitor structure-activity relationship studies are systematically surveyed. The interactions of the non-peptide fragments of an inhibitor with the enzymes are examined. Examples of the use of some inhibitors for apoptosis suppression are provided.

  2. SGLT2 inhibitors.

    PubMed

    Dardi, I; Kouvatsos, T; Jabbour, S A

    2016-02-01

    Diabetes mellitus is a serious health issue and an economic burden, rising in epidemic proportions over the last few decades worldwide. Although several treatment options are available, only half of the global diabetic population achieves the recommended or individualized glycemic targets. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new class of antidiabetic agents with a novel insulin-independent action. SGLT2 is a transporter found in the proximal renal tubules, responsible for the reabsorption of most of the glucose filtered by the kidney. Inhibition of SGLT2 lowers the blood glucose level by promoting the urinary excretion of excess glucose. Due to their insulin-independent action, SGLT2 inhibitors can be used with any degree of beta-cell dysfunction or insulin resistance, related to a very low risk of hypoglycemia. In addition to improving glycemic control, SGLT2 inhibitors have been associated with a reduction in weight and blood pressure when used as monotherapy or in combination with other antidiabetic agents in patients with type 2 diabetes mellitus (T2DM). Treatment with SGLT2 inhibitors is usually well tolerated; however, they have been associated with an increased incidence of urinary tract and genital infections, although these infections are usually mild and easy to treat. SGLT2 inhibitors are a promising new option in the armamentarium of drugs for patients with T2DM. PMID:26362302

  3. Cholinesterase inhibitors from botanicals

    PubMed Central

    Ahmed, Faiyaz; Ghalib, Raza Murad; Sasikala, P.; Ahmed, K. K. Mueen

    2013-01-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disease, wherein a progressive loss of cholinergic synapses occurs in hippocampus and neocortex. Decreased concentration of the neurotransmitter, acetylcholine (ACh), appears to be critical element in the development of dementia, and the most appropriate therapeutic approach to treat AD and other form of dementia is to restore acetylcholine levels by inhibiting both major form of cholinesterase: Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Consequently, researches have focused their attention towards finding cholinesterase inhibitors from natural products. A large number of such inhibitors have been isolated from medicinal plants. This review presents a comprehensive account of the advances in field of cholinesterase inhibitor phytoconstituents. The structures of some important phytoconstituents (collected through www.Chemspider.com) are also presented and the scope for future research is discussed. PMID:24347920

  4. Cholinesterase inhibitors from botanicals.

    PubMed

    Ahmed, Faiyaz; Ghalib, Raza Murad; Sasikala, P; Ahmed, K K Mueen

    2013-07-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disease, wherein a progressive loss of cholinergic synapses occurs in hippocampus and neocortex. Decreased concentration of the neurotransmitter, acetylcholine (ACh), appears to be critical element in the development of dementia, and the most appropriate therapeutic approach to treat AD and other form of dementia is to restore acetylcholine levels by inhibiting both major form of cholinesterase: Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Consequently, researches have focused their attention towards finding cholinesterase inhibitors from natural products. A large number of such inhibitors have been isolated from medicinal plants. This review presents a comprehensive account of the advances in field of cholinesterase inhibitor phytoconstituents. The structures of some important phytoconstituents (collected through www.Chemspider.com) are also presented and the scope for future research is discussed. PMID:24347920

  5. Oncogenic K-ras confers SAHA resistance by up-regulating HDAC6 and c-myc expression.

    PubMed

    Wang, Qun; Tan, Rong; Zhu, Xin; Zhang, Yi; Tan, Zhiping; Su, Bing; Li, Yu

    2016-03-01

    Histone deacetylase inhibitors (HDIs) represent a new class of anticancer drugs. Suberoylanilide hydroxamic acid (SAHA), the first HDI approved for the treatment of cutaneous T cell lymphoma (CTCL), is currently being tested in clinical trials for other cancers. However, SAHA has been ineffective against solid tumors in many clinical trials. A better understanding of molecular mechanisms of SAHA resistance may provide the basis for improved patient selection and the enhancement of clinical efficacy. Here we demonstrate that oncogenic K-ras contributes to SAHA resistance by upregulating HDAC6 and c-myc expression. We find that the high levels of HDAC6 expression are associated with activated K-ras mutant in colon cancer patients. And expressions of HDAC6 and c-myc are increased in fibroblasts transformed with activated K-ras. Surprisingly, we find that activated K-ras transformed cells are more resistant to SAHA inhibition on cell growth and anchorage-independent colony formation. We show that a K-ras inhibitor sensitizes K-ras mutated lung cancer cells to SAHA induced growth inhibition. We also find that mutant K-ras induces HDAC6 expression by a MAP kinase dependent pathway. Our study suggests that combined treatment with SAHA and K-ras inhibitors may represent an effective strategy to overcome SAHA resistance. PMID:26848526

  6. SCL/TAL1-mediated transcriptional network enhances megakaryocytic specification of human embryonic stem cells.

    PubMed

    Toscano, Miguel G; Navarro-Montero, Oscar; Ayllon, Veronica; Ramos-Mejia, Veronica; Guerrero-Carreno, Xiomara; Bueno, Clara; Romero, Tamara; Lamolda, Mar; Cobo, Marien; Martin, Francisco; Menendez, Pablo; Real, Pedro J

    2015-01-01

    Human embryonic stem cells (hESCs) are a unique in vitro model for studying human developmental biology and represent a potential source for cell replacement strategies. Platelets can be generated from cord blood progenitors and hESCs; however, the molecular mechanisms and determinants controlling the in vitro megakaryocytic specification of hESCs remain elusive. We have recently shown that stem cell leukemia (SCL) overexpression accelerates the emergence of hemato-endothelial progenitors from hESCs and promotes their subsequent differentiation into blood cells with higher clonogenic potential. Given that SCL participates in megakaryocytic commitment, we hypothesized that it may potentiate megakaryopoiesis from hESCs. We show that ectopic SCL expression enhances the emergence of megakaryocytic precursors, mature megakaryocytes (MKs), and platelets in vitro. SCL-overexpressing MKs and platelets respond to different activating stimuli similar to their control counterparts. Gene expression profiling of megakaryocytic precursors shows that SCL overexpression renders a megakaryopoietic molecular signature. Connectivity Map analysis reveals that trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA), both histone deacetylase (HDAC) inhibitors, functionally mimic SCL-induced effects. Finally, we confirm that both TSA and SAHA treatment promote the emergence of CD34(+) progenitors, whereas valproic acid, another HDAC inhibitor, potentiates MK and platelet production. We demonstrate that SCL and HDAC inhibitors are megakaryopoiesis regulators in hESCs. PMID:25292191

  7. Oncogenic K-ras confers SAHA resistance by up-regulating HDAC6 and c-myc expression

    PubMed Central

    Zhang, Yi; Tan, Zhiping; Su, Bing; Li, Yu

    2016-01-01

    Histone deacetylase inhibitors (HDIs) represent a new class of anticancer drugs. Suberoylanilide hydroxamic acid (SAHA), the first HDI approved for the treatment of cutaneous T cell lymphoma (CTCL), is currently being tested in clinical trials for other cancers. However, SAHA has been ineffective against solid tumors in many clinical trials. A better understanding of molecular mechanisms of SAHA resistance may provide the basis for improved patient selection and the enhancement of clinical efficacy. Here we demonstrate that oncogenic K-ras contributes to SAHA resistance by upregulating HDAC6 and c-myc expression. We find that the high levels of HDAC6 expression are associated with activated K-ras mutant in colon cancer patients. And expressions of HDAC6 and c-myc are increased in fibroblasts transformed with activated K-ras. Surprisingly, we find that activated K-ras transformed cells are more resistant to SAHA inhibition on cell growth and anchorage-independent colony formation. We show that a K-ras inhibitor sensitizes K-ras mutated lung cancer cells to SAHA induced growth inhibition. We also find that mutant K-ras induces HDAC6 expression by a MAP kinase dependent pathway. Our study suggests that combined treatment with SAHA and K-ras inhibitors may represent an effective strategy to overcome SAHA resistance. PMID:26848526

  8. Protein protease inhibitors in insects and comparison with mammalian inhibitors.

    PubMed

    Eguchi, M

    1993-01-01

    1. Studies on insect protein protease inhibitors are summarized. Biochemical, genetic and physiological investigations of the silkworm are performed. 2. In addition, the properties and characteristics of fungal protease inhibitors from the silkworm (Bombyx mori) are described and their importance as defensive functions is emphasized. 3. This review also concerns comparative and evolutionary studies of protease inhibitors from various sources. 4. The biological significance of inhibitors is discussed in view of the extensive experimental results. PMID:8365101

  9. Inhibitors of rhomboid proteases.

    PubMed

    Wolf, Eliane V; Verhelst, Steven H L

    2016-03-01

    Rhomboid proteases form one of the most widespread families of intramembrane proteases. They utilize a catalytic serine-histidine dyad located several Å below the surface of the membrane for substrate hydrolysis. Multiple studies have implicated rhomboid proteases in biologically and medically relevant processes. Several assays have been developed that are able to monitor rhomboid activity. With the aid of these assays, different types of inhibitors have been found, all based on electrophiles that covalently react with the active site machinery. Although the currently available inhibitors have limited selectivity and moderate potency, they can function as research tools and as starting point for the development of activity-based probes, which are reagents that can specifically detect active rhomboid species. Structural studies on complexes of inhibitors with the Escherichia coli rhomboid GlpG have provided insight into how substrate recognition may occur. Future synthetic efforts, aided by high-throughput screening or structure-based design, may lead to more potent and selective inhibitors for this interesting family of proteases. PMID:26166068

  10. Sunflower trypsin inhibitor-1.

    PubMed

    Korsinczky, Michael L J; Schirra, Horst Joachim; Craik, David J

    2004-10-01

    SFTI-1 is a bicyclic 14 amino acid peptide that was originally isolated from the seeds of the sunflower Helianthus annuus. It is a potent inhibitor of trypsin, with a sub-nanomolar K(i) value and is homologous to the active site region of the well-known family of serine protease inhibitors known as the Bowman-Birk trypsin inhibitors. It has a cyclic backbone that is cross-braced by a single disulfide bridge and a network of hydrogen bonds that result in a well-defined structure. SFTI-1 is amenable to chemical synthesis, allowing for the creation of synthetic variants. Alterations to the structure such as linearising the backbone or removing the disulfide bridge do not reduce the potency of SFTI-1 significantly, and minimising the peptide to as few as nine residues results in only a small decrease in reactivity. The creation of linear variants of SFTI-1 also provides a tool for investigating putative linear precursor peptides. The mechanism of biosynthesis of SFTI-1 is not yet known but it seems likely that it is a gene-coded product that has arisen from a precursor protein that may be evolutionarily related to classic Bowman-Birk inhibitors. PMID:15544530