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Amir Azam - One of the best experts on this subject based on the ideXlab platform.
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synthesis and antiamoebic activity of metronidazole Thiosemicarbazone analogues
European Journal of Medicinal Chemistry, 2008Co-Authors: Mohammad Abid, Subhash Mohan Agarwal, Amir AzamAbstract:Repeated treatment of Entamoeba histolytica infection with commonly used antiamoebic drugs results in not only increasing the toxicity potential but also leads to the development of clinical resistance. Thus new effective agents with less toxicity against amoebiasis are urgently required. With this view, metronidazole Thiosemicarbazone analogues 1-11 were synthesized wherein thioamide moiety was substituted by different cyclic and aromatic amines. These compounds were screened against HM1:IMSS strain of E. histolytica parasite cultured in vitro and the sensitivity of the parasite to the metronidazole Thiosemicarbazones was evaluated using the microdilution method. Eight compounds (1-4, 7-9 and 11) were found better inhibitors of E. histolytica growth since IC50 values elicited by these compounds were much lower than metronidazole with compound 4 showing the most promising antiamoebic activity (IC50=0.56 microM). The study suggests the beneficial potential of these leads that need to be further explored in order to discover and develop better and yet safer therapeutic agents for amoebiasis.
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novel pd ii complexes of 1 n substituted 3 phenyl 2 pyrazoline derivatives and evaluation of antiamoebic activity
European Journal of Medicinal Chemistry, 2008Co-Authors: Kakul Husain, Mohammad Abid, Amir AzamAbstract:Cyclization of Mannich base with N(4)-substituted thiosemicarbazides by different aliphatic, aromatic and cyclic amines afforded a series of new 1-N-substituted cyclised pyrazoline analogues of Thiosemicarbazones (PYZ-TSC) 1-10. Reaction of [Pd(DMSO)(2)Cl(2)] with pyrazoline derivatives led to new palladium(II) complexes [Pd(PYZ-TSC)Cl(2)] 1a-10a. The structures of all the compounds were characterized by spectroscopic methods. It was concluded that the pyrazoline Thiosemicarbazone derivatives have two chelating arms, one attached at the 2-position of the pyrazole ring (that is, N donor) and other (S donor) linked to the Thiosemicarbazone branch. The determination of antiamoebic activity of all the compounds was done using HM1:IMSS strain of Entamoeba histolytica, among all the complexes, 8a showed the most promising IC(50)=0.37 microM vs. IC(50)=1.81 microM of metronidazole, the reference drug. MTT assay showed that the compounds are non-toxic to human kidney epithelial cell line.
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novel bidentate complexes of cu ii derived from 5 nitrofuran 2 carboxaldehyde Thiosemicarbazones with antiamoebic activity against e histolytica
European Journal of Medicinal Chemistry, 2005Co-Authors: Sangita Sharma, Fehmida Naqvi, Fareeda Athar, Mannar R Maurya, Amir AzamAbstract:Abstract The novel analogues of 5-nitrofuran-2-carboxaldehyde Thiosemicarbazones 1 – 10 were synthesized and their copper(II) complexes 1a – 10a were obtained by means of coordination with cupric chloride. All these compounds have been characterized by elemental analysis, IR, electronic spectra and thermogravimetric patterns while ligands have also been characterized by 1 H NMR spectral studies. These copper complexes are bidentate and possess octahedral geometry around Cu(II) ion. Their antiamoebic activities were carried out to ascertain their effectiveness in comparison to their corresponding Thiosemicarbazones. A number of these complexes possess noteworthy potencies towards HK-9 strain of Entamoeba histolytica in vitro . The complexes 2a – 7a , 9a and 10a showed less IC 50 value than metronidazole, the drug of choice for amoebiasis. Moreover, complexes 2a and 9a have shown the most promising antiamoebic activities (IC 50 = 0.38 μM of 2a and IC 50 = 0.34 μM of 9a versus IC 50 = 1.81 μM of metronidazole). These results indicate that the metallated Thiosemicarbazone may be lead molecule to inhibit growth of E. histolytica .
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synthesis characterization and in vitro antiamoebic activity of 5 nitrothiophene 2 carboxaldehyde Thiosemicarbazones and their palladium ii and ruthenium ii complexes
European Journal of Medicinal Chemistry, 2004Co-Authors: Shailendra Kumar Singh, Neelam Bharti, Fehmida Naqvi, Amir AzamAbstract:Synthesis of new Palladium(II) and Ruthenium(II) complexes of the type, [Pd(L)Cl(2)] and [Ru(eta(4)-C(8)H(12))(L)Cl(2)] [where, L = Thiosemicarbazones derived from 5-nitrothiophene-2-carboxaldehyde and cycloalkylaminothiocarbonyl hydrazines] have been isolated by the reaction of [Pd(DMSO)(2)Cl(2)] and [Ru(eta(4)-C(8)H(12))(CH(3)CN)(2)Cl(2)] with 5-nitrothiophene-2-carboxaldehyde Thiosemicarbazones. The spectral data revealed that the Thiosemicarbazones act as bidentate ligands, making use of thionic sulphur and the azomethine nitrogen atom for coordination to the central metal ion. Microdilution method was used for the assessment of antiamoebic activity of all the compounds against HK-9 strain of Entamoeba histolytica. Among all the Thiosemicarbazones, 5-NT-4-BPTSCN (3) showed significant antiamoebic activity (IC(50) - 2.56 microM). Enhancement of antiamoebic activity resulted by introducing palladium and ruthenium metals in the Thiosemicarbazone moiety. All the Pd(II) and Ru(II) complexes of 5-nitrothiophene-2-carboxaldehyde Thiosemicarbazones were found more active then their respective ligands. The complexes 1a-4a, 1b and 3b showed antiamoebic activity.
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Synthesis and in vitro antiprotozoal activity of 5-nitrothiophene-2-carboxaldehyde Thiosemicarbazone derivatives
Bioorganic & Medicinal Chemistry Letters, 2002Co-Authors: Neelam Bharti, Fehmida Naqvi, Kakul Husain, M.t Gonzalez Garza, Delia E. Cruz-vega, Jorge Castro-garza, Benito D. Mata-cárdenas, Amir AzamAbstract:Abstract Several Thiosemicarbazone derivatives of 5-nitrothiophene-2-carboxaldehyde were prepared by the simple process in which N 4 -Thiosemicarbazone moiety was replaced by aliphatic, arylic and cyclic amine. Among these Thiosemicarbazones compound 11 showed significant antiamoebic activity whereas compound 3 was more active antitrichomonal than the reference drug.
Heloisa Beraldo - One of the best experts on this subject based on the ideXlab platform.
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pyridine derived Thiosemicarbazones and their tin iv complexes with antifungal activity against candida spp
European Journal of Medicinal Chemistry, 2011Co-Authors: Gabrieli L Parrilha, Jeferson G Da Silva, Ludmila Ferreira Gouveia, Alan K Gasparoto, Roberta P Dias, Willian R Rocha, Daniel Assis Santos, Nivaldo L Speziali, Heloisa BeraldoAbstract:Abstract [(n-Bu)Sn(2Ac4oClPh)Cl2] (1), [(n-Bu)Sn(2Ac4oFPh)Cl2] (2), [(n-Bu)Sn(2Ac4oNO2Ph)Cl2] (3), [(n-Bu)Sn(2Bz4oClPh)Cl2] (4), [(n-Bu)Sn(2Bz4oFPh)Cl2] (5) and [(n-Bu)Sn(2Bz4oNO2Ph)Cl2] (6) were obtained by reacting [(n-Bu)SnCl3] with 2-acetylpyridine-N(4)-orthochlorophenyl Thiosemicarbazone (H2Ac4oClPh), 2-acetylpyridine-N(4)-orthofluorphenyl Thiosemicarbazone (H2Ac4oFPh), 2-acetylpyridine-N(4)-orthonitrophenyl Thiosemicarbazone (H2Ac4oNO2Ph), and with the corresponding 2-benzoylpyridine-derived Thiosemicarbazones (H2Bz4oClPh, H2ABz4oFPh and H2Bz4oNO2Ph). The antifungal activity of the studied compounds was evaluated against several Candida species. Upon coordination of H2Bz4oNO2Ph to tin in complex (6) the antifungal activity increased three times against Candida albicans and Candida krusei and six times against Candida glabrata and Candida parapsilosis. The minimum inhibitory concentration (MIC) values of H2Ac4oNO2Ph and its complex (3) against C. albicans, C. parapsilosis and C. glabrata are similar to that of fluconazole. All studied compounds were more active than fluconazole against C. krusei.
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copper ii complexes with 2 pyridineformamide derived Thiosemicarbazones spectral studies and toxicity against artemia salina
Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 2009Co-Authors: Karina S O Ferraz, Solange M S V Wardell, James L Wardell, Sonia R W Louro, Heloisa BeraldoAbstract:The copper(II) complexes [Cu(H2Am4DH)Cl2] (1), [Cu(H2Am4Me)Cl2] (2), [Cu(H2Am4Et)Cl2] (3) and [Cu(2Am4Ph)Cl] (4) with 2-pyridineformamide Thiosemicarbazone (H2Am4DH) and its N(4)-methyl (H2Am4Me), N(4)-ethyl (H2Am4Et) and N(4)-phenyl (H2Am4Ph) derivatives were studied by means of infrared and EPR spectral techniques. The crystal structure of 4 was determined. The studied compounds proved to be toxic to Artemia salina, suggesting that they could present cytotoxic activity against solid tumors. Among the free Thiosemicarbazones H2Am4Ph presented higher toxicity than all other compounds, which showed comparable effects. In the case of complexes 2 and 3 toxicity is probably attributable to the complex as an entity or to a synergistic effect involving the Thiosemicarbazone and copper. H2Am4Ph and complexes 2 and 3 revealed to be the most promising compounds as potential antineoplasic agents.
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2 pyridinoformamide derived Thiosemicarbazones and their iron iii complexes potential antineoplastic activity
Polyhedron, 2008Co-Authors: Angelica E Graminha, Sonia R W Louro, Felipe S Vilhena, Alzir A Batista, Roberta L Ziolli, Leticia R Teixeira, Heloisa BeraldoAbstract:Abstract The iron(III) complexes [Fe(2Am4DH)2]Cl (1), [Fe(2Am4Me)2]Cl (2) and [Fe(2Am4Et)2]Cl (3) with 2-pyridineformamide Thiosemicarbazone (H2Am4DH) and its N(4)-methyl (H2Am4Me) and N(4)-ethyl (H2Am4Et) derivatives were obtained and characterized by means microanalyses, infrared and EPR spectra. The electrochemical behavior of the complexes was investigated. The Thiosemicarbazones and complexes (1) and (2) presented toxicity against Artemia salina at low concentrations. Since this bioassay has a good correlation with cytotoxic activity in human solid tumors, the studied compounds present potential pharmacological applications.
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coordination to copper ii strongly enhances the in vitro antimicrobial activity of pyridine derived n 4 tolyl Thiosemicarbazones
Polyhedron, 2007Co-Authors: Isolda C Mendes, Juliana P Moreira, Antonio S Mangrich, Solange P Balena, Bernardo L Rodrigues, Heloisa BeraldoAbstract:Abstract Five copper(II) complexes with N(4)-ortho, N(4)-meta and N(4)-para-tolyl Thiosemicarbazones derived from 2-formyl and 2-acetylpyridine were obtained and thoroughly characterized. The crystal structure of N(4)-meta-tolyl-2-acetylpyridine Thiosemicarbazone (H2Ac4mT) was determined, as well as that of its copper(II) complex [Cu(2Ac4mT)Cl], which contains an anionic ligand and a chloride in the coordination sphere of the metal. The in vitro antimicrobial activities of all Thiosemicarbazones and their copper(II) complexes were tested against Salmonella typhimurium and Candida albicans. Upon coordination a substantial decrease in the minimum inhibitory concentration, from 225 to 1478 μmol L−1 for the Thiosemicarbazones to 5–30 μmol L−1 for the complexes was observe against the growth of Salmonella typhimurium and from 0.7–26 to 0.3–7 μmol L−1 against the growth of C. albicans, suggesting that complexation to copper(II) could be an interesting strategy of dose reduction.
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copper ii and nickel ii complexes of the bis n 3 substituted Thiosemicarbazones of phenylglyoxal and 1 phenylpropane 1 2 dione
Transition Metal Chemistry, 1997Co-Authors: Heloisa Beraldo, Susan B Kaisner, Jennifer D Turner, Issam S Billeh, Janeice S Ives, Douglas X WestAbstract:Copper(II) and nickel(II) complexes of phenylglyoxal and phenylpropane-1,2-dione bis{N(3)-methyl-, bis{N(3)-dimethyl-, bis{piperidylThiosemicarbazone} have been prepared and studied spectroscopically. The six bis(Thiosemicarbazones) have been characterized by their melting points, as well as i.r., electronic and 1H-n.m.r. spectra. The four-coordinate copper(II) complexes have been studied by e.s.r. spectroscopy, and the copper(II) and nickel(II) complexes by spectroscopic techniques mentioned above. Upon formation of these complexes, the loss of protons from each Thiosemicarbazone moiety occurs, and the bis(Thiosemicarbazones) coordinate to the metal centres as dianionic, tetradentate N2S2 ligands.
Zaklina Kovacevic - One of the best experts on this subject based on the ideXlab platform.
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targeting the metastasis suppressor n myc downstream regulated gene 1 with novel di 2 pyridylketone Thiosemicarbazones suppression of tumor cell migration and cell collagen adhesion by inhibiting focal adhesion kinase paxillin signaling
Molecular Pharmacology, 2016Co-Authors: Xiongzhi Wangpu, Zaklina Kovacevic, Sumit Sahni, Sharleen V Menezes, Fei Yue, Kyung Chan Park, Michael L H Huang, Minhua Zheng, Des R RichardsonAbstract:Metastasis is a complex process that is regulated by multiple signaling pathways, with the focal adhesion kinase (FAK)/paxillin pathway playing a major role in the formation of focal adhesions and cell motility. N-myc downstream regulated gene-1 (NDRG1) is a potent metastasis suppressor in many solid tumor types, including prostate and colon cancer. Considering the antimetastatic effect of NDRG1 and the crucial involvement of the FAK/paxillin pathway in cellular migration and cell-matrix adhesion, we assessed the effects of NDRG1 on this important oncogenic pathway. In the present study, NDRG1 overexpression and silencing models of HT29 colon cancer and DU145 prostate cancer cells were used to examine the activation of FAK/paxillin signaling and the formation of focal adhesions. The expression of NDRG1 resulted in a marked and significant decrease in the activating phosphorylation of FAK and paxillin, whereas silencing of NDRG1 resulted in an opposite effect. The expression of NDRG1 also inhibited the formation of focal adhesions as well as cell migration and cell-collagen adhesion. Incubation of cells with novel Thiosemicarbazones, namely di-2-pyridylketone 4,4-dimethyl-3-Thiosemicarbazone and di-2-pyridylketone 4-cyclohexyl-4-methyl-3-Thiosemicarbazone, that upregulate NDRG1 also resulted in decreased phosphorylation of FAK and paxillin. The ability of these Thiosemicarbazones to inhibit cell migration and metastasis could be mediated, at least in part, through the FAK/paxillin pathway.
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the metastasis suppressor n myc downstream regulated gene 1 ndrg1 down regulates the erbb family of receptors to inhibit downstream oncogenic signaling pathways
Journal of Biological Chemistry, 2016Co-Authors: Zaklina Kovacevic, Darius J. R. Lane, Donghun Bae, Danuta S Kalinowski, Sumit Sahni, Sharleen V Menezes, Des R RichardsonAbstract:N-MYC downstream-regulated gene-1 (NDRG1) is a potent growth and metastasis suppressor that acts through its inhibitory effects on a wide variety of cellular signaling pathways, including the TGF-β pathway, protein kinase B (AKT)/PI3K pathway, RAS, etc. To investigate the hypothesis that its multiple effects could be regulated by a common upstream effector, the role of NDRG1 on the epidermal growth factor receptor (EGFR) and other members of the ErbB family, namely human epidermal growth factor receptor 2 (HER2) and human epidermal growth factor receptor 3 (HER3), was examined. We demonstrate that NDRG1 markedly decreased the expression and activation of EGFR, HER2, and HER3 in response to the epidermal growth factor (EGF) ligand, while also inhibiting formation of the EGFR/HER2 and HER2/HER3 heterodimers. In addition, NDRG1 also decreased activation of the downstream MAPKK in response to EGF. Moreover, novel anti-tumor agents of the di-2-pyridylketone class of Thiosemicarbazones, namely di-2-pyridylketone 4,4-dimethyl-3-Thiosemicarbazone and di-2-pyridylketone 4-cyclohexyl-4-methyl-3-Thiosemicarbazone, which markedly up-regulate NDRG1, were found to inhibit EGFR, HER2, and HER3 expression and phosphorylation in cancer cells. However, the mechanism involved appeared dependent on NDRG1 for di-2-pyridylketone 4,4-dimethyl-3-Thiosemicarbazone, but was independent of this metastasis suppressor for di-2-pyridylketone 4-cyclohexyl-4-methyl-3-Thiosemicarbazone. This observation demonstrates that small structural changes in Thiosemicarbazones result in marked alterations in molecular targeting. Collectively, these results reveal a mechanism for the extensive downstream effects on cellular signaling attributed to NDRG1. Furthermore, this study identifies a novel approach for the treatment of tumors resistant to traditional EGFR inhibitors.
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Novel Mechanism of Cytotoxicity for the Selective Selenosemicarbazone, 2‑Acetylpyridine 4,4-Dimethyl-3-selenosemicarbazone (Ap44mSe): Lysosomal Membrane Permeabilization
2016Co-Authors: Zaynab Al-eisawi, Christian Stefani, Patric J. Jansson, Akanksha Arvind, Philip C. Sharpe, Maram T. Basha, George M. Iskander, Naresh Kumar, Zaklina Kovacevic, Darius J. R. LaneAbstract:Selenosemicarbazones show marked antitumor activity. However, their mechanism of action remains unknown. We examined the medicinal chemistry of the selenosemicarbazone, 2-acetylpyridine 4,4-dimethyl-3-selenosemicarbazone (Ap44mSe), and its iron and copper complexes to elucidate its mechanisms of action. Ap44mSe demonstrated a pronounced improvement in selectivity toward neoplastic relative to normal cells compared to its parent Thiosemicarbazone. It also effectively depleted cellular Fe, resulting in transferrin receptor-1 up-regulation, ferritin down-regulation, and increased expression of the potent metastasis suppressor, N-myc downstream regulated gene-1. Significantly, Ap44mSe limited deleterious methemoglobin formation, highlighting its usefulness in overcoming toxicities of clinically relevant Thiosemicarbazones. Furthermore, Cu-Ap44mSe mediated intracellular reactive oxygen species generation, which was attenuated by the antioxidant, N-acetyl-l-cysteine, or Cu sequestration. Notably, Ap44mSe forms redox active Cu complexes that target the lysosome to induce lysosomal membrane permeabilization. This investigation highlights novel structure–activity relationships for future chemotherapeutic design and underlines the potential of Ap44mSe as a selective anticancer/antimetastatic agent
Darius J. R. Lane - One of the best experts on this subject based on the ideXlab platform.
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the metastasis suppressor n myc downstream regulated gene 1 ndrg1 down regulates the erbb family of receptors to inhibit downstream oncogenic signaling pathways
Journal of Biological Chemistry, 2016Co-Authors: Zaklina Kovacevic, Darius J. R. Lane, Donghun Bae, Danuta S Kalinowski, Sumit Sahni, Sharleen V Menezes, Des R RichardsonAbstract:N-MYC downstream-regulated gene-1 (NDRG1) is a potent growth and metastasis suppressor that acts through its inhibitory effects on a wide variety of cellular signaling pathways, including the TGF-β pathway, protein kinase B (AKT)/PI3K pathway, RAS, etc. To investigate the hypothesis that its multiple effects could be regulated by a common upstream effector, the role of NDRG1 on the epidermal growth factor receptor (EGFR) and other members of the ErbB family, namely human epidermal growth factor receptor 2 (HER2) and human epidermal growth factor receptor 3 (HER3), was examined. We demonstrate that NDRG1 markedly decreased the expression and activation of EGFR, HER2, and HER3 in response to the epidermal growth factor (EGF) ligand, while also inhibiting formation of the EGFR/HER2 and HER2/HER3 heterodimers. In addition, NDRG1 also decreased activation of the downstream MAPKK in response to EGF. Moreover, novel anti-tumor agents of the di-2-pyridylketone class of Thiosemicarbazones, namely di-2-pyridylketone 4,4-dimethyl-3-Thiosemicarbazone and di-2-pyridylketone 4-cyclohexyl-4-methyl-3-Thiosemicarbazone, which markedly up-regulate NDRG1, were found to inhibit EGFR, HER2, and HER3 expression and phosphorylation in cancer cells. However, the mechanism involved appeared dependent on NDRG1 for di-2-pyridylketone 4,4-dimethyl-3-Thiosemicarbazone, but was independent of this metastasis suppressor for di-2-pyridylketone 4-cyclohexyl-4-methyl-3-Thiosemicarbazone. This observation demonstrates that small structural changes in Thiosemicarbazones result in marked alterations in molecular targeting. Collectively, these results reveal a mechanism for the extensive downstream effects on cellular signaling attributed to NDRG1. Furthermore, this study identifies a novel approach for the treatment of tumors resistant to traditional EGFR inhibitors.
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Novel Mechanism of Cytotoxicity for the Selective Selenosemicarbazone, 2‑Acetylpyridine 4,4-Dimethyl-3-selenosemicarbazone (Ap44mSe): Lysosomal Membrane Permeabilization
2016Co-Authors: Zaynab Al-eisawi, Christian Stefani, Patric J. Jansson, Akanksha Arvind, Philip C. Sharpe, Maram T. Basha, George M. Iskander, Naresh Kumar, Zaklina Kovacevic, Darius J. R. LaneAbstract:Selenosemicarbazones show marked antitumor activity. However, their mechanism of action remains unknown. We examined the medicinal chemistry of the selenosemicarbazone, 2-acetylpyridine 4,4-dimethyl-3-selenosemicarbazone (Ap44mSe), and its iron and copper complexes to elucidate its mechanisms of action. Ap44mSe demonstrated a pronounced improvement in selectivity toward neoplastic relative to normal cells compared to its parent Thiosemicarbazone. It also effectively depleted cellular Fe, resulting in transferrin receptor-1 up-regulation, ferritin down-regulation, and increased expression of the potent metastasis suppressor, N-myc downstream regulated gene-1. Significantly, Ap44mSe limited deleterious methemoglobin formation, highlighting its usefulness in overcoming toxicities of clinically relevant Thiosemicarbazones. Furthermore, Cu-Ap44mSe mediated intracellular reactive oxygen species generation, which was attenuated by the antioxidant, N-acetyl-l-cysteine, or Cu sequestration. Notably, Ap44mSe forms redox active Cu complexes that target the lysosome to induce lysosomal membrane permeabilization. This investigation highlights novel structure–activity relationships for future chemotherapeutic design and underlines the potential of Ap44mSe as a selective anticancer/antimetastatic agent
Des R Richardson - One of the best experts on this subject based on the ideXlab platform.
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targeting the metastasis suppressor n myc downstream regulated gene 1 with novel di 2 pyridylketone Thiosemicarbazones suppression of tumor cell migration and cell collagen adhesion by inhibiting focal adhesion kinase paxillin signaling
Molecular Pharmacology, 2016Co-Authors: Xiongzhi Wangpu, Zaklina Kovacevic, Sumit Sahni, Sharleen V Menezes, Fei Yue, Kyung Chan Park, Michael L H Huang, Minhua Zheng, Des R RichardsonAbstract:Metastasis is a complex process that is regulated by multiple signaling pathways, with the focal adhesion kinase (FAK)/paxillin pathway playing a major role in the formation of focal adhesions and cell motility. N-myc downstream regulated gene-1 (NDRG1) is a potent metastasis suppressor in many solid tumor types, including prostate and colon cancer. Considering the antimetastatic effect of NDRG1 and the crucial involvement of the FAK/paxillin pathway in cellular migration and cell-matrix adhesion, we assessed the effects of NDRG1 on this important oncogenic pathway. In the present study, NDRG1 overexpression and silencing models of HT29 colon cancer and DU145 prostate cancer cells were used to examine the activation of FAK/paxillin signaling and the formation of focal adhesions. The expression of NDRG1 resulted in a marked and significant decrease in the activating phosphorylation of FAK and paxillin, whereas silencing of NDRG1 resulted in an opposite effect. The expression of NDRG1 also inhibited the formation of focal adhesions as well as cell migration and cell-collagen adhesion. Incubation of cells with novel Thiosemicarbazones, namely di-2-pyridylketone 4,4-dimethyl-3-Thiosemicarbazone and di-2-pyridylketone 4-cyclohexyl-4-methyl-3-Thiosemicarbazone, that upregulate NDRG1 also resulted in decreased phosphorylation of FAK and paxillin. The ability of these Thiosemicarbazones to inhibit cell migration and metastasis could be mediated, at least in part, through the FAK/paxillin pathway.
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the metastasis suppressor n myc downstream regulated gene 1 ndrg1 down regulates the erbb family of receptors to inhibit downstream oncogenic signaling pathways
Journal of Biological Chemistry, 2016Co-Authors: Zaklina Kovacevic, Darius J. R. Lane, Donghun Bae, Danuta S Kalinowski, Sumit Sahni, Sharleen V Menezes, Des R RichardsonAbstract:N-MYC downstream-regulated gene-1 (NDRG1) is a potent growth and metastasis suppressor that acts through its inhibitory effects on a wide variety of cellular signaling pathways, including the TGF-β pathway, protein kinase B (AKT)/PI3K pathway, RAS, etc. To investigate the hypothesis that its multiple effects could be regulated by a common upstream effector, the role of NDRG1 on the epidermal growth factor receptor (EGFR) and other members of the ErbB family, namely human epidermal growth factor receptor 2 (HER2) and human epidermal growth factor receptor 3 (HER3), was examined. We demonstrate that NDRG1 markedly decreased the expression and activation of EGFR, HER2, and HER3 in response to the epidermal growth factor (EGF) ligand, while also inhibiting formation of the EGFR/HER2 and HER2/HER3 heterodimers. In addition, NDRG1 also decreased activation of the downstream MAPKK in response to EGF. Moreover, novel anti-tumor agents of the di-2-pyridylketone class of Thiosemicarbazones, namely di-2-pyridylketone 4,4-dimethyl-3-Thiosemicarbazone and di-2-pyridylketone 4-cyclohexyl-4-methyl-3-Thiosemicarbazone, which markedly up-regulate NDRG1, were found to inhibit EGFR, HER2, and HER3 expression and phosphorylation in cancer cells. However, the mechanism involved appeared dependent on NDRG1 for di-2-pyridylketone 4,4-dimethyl-3-Thiosemicarbazone, but was independent of this metastasis suppressor for di-2-pyridylketone 4-cyclohexyl-4-methyl-3-Thiosemicarbazone. This observation demonstrates that small structural changes in Thiosemicarbazones result in marked alterations in molecular targeting. Collectively, these results reveal a mechanism for the extensive downstream effects on cellular signaling attributed to NDRG1. Furthermore, this study identifies a novel approach for the treatment of tumors resistant to traditional EGFR inhibitors.
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Zinc(II)–Thiosemicarbazone Complexes Are Localized to the Lysosomal Compartment Where They Transmetallate with Copper Ions to Induce Cytotoxicity
2016Co-Authors: Alexandra E. Stacy, Paul V Bernhardt, Danuta S Kalinowski, Patric J Jansson, Duraippandi Palanimuthu, Des R RichardsonAbstract:As the di-2-pyridylketone Thiosemicarbazone (DpT) and 2-acetylpyridine Thiosemicarbazone (ApT) series show potent antitumor activity in vitro and in vivo, we synthesized their fluorescent zinc(II) complexes to assess their intracellular distribution. The Zn(II) complexes generally showed significantly greater cytotoxicity than the Thiosemicarbazones alone in several tumor cell-types. Notably, specific structure–activity relationships demonstrated the importance of the di-2-pyridyl pharmacophore in their activity. Confocal fluorescence imaging and live cell microscopy showed that the Zn(II) complex of our lead compound, di-2-pyridylketone 4-cyclohexyl-4-methyl-3-Thiosemicarbazone (DpC), which is scheduled to enter clinical trials, was localized to lysosomes. Under lysosomal conditions, the Zn(II) complexes were shown to transmetallate with copper ions, leading to redox-active copper complexes that induced lysosomal membrane permeabilization (LMP) and cytotoxicity. This is the first study to demonstrate direct lysosomal targeting of our novel Zn(II)–Thiosemicarbazone complexes that mediate their activity via transmetalation with copper ions and LMP
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identification of differential anti neoplastic activity of copper bis Thiosemicarbazones that is mediated by intracellular reactive oxygen species generation and lysosomal membrane permeabilization
Journal of Inorganic Biochemistry, 2015Co-Authors: Christian Stefani, Danuta S Kalinowski, Zaynab Aleisawi, Patric J Jansson, Des R RichardsonAbstract:Bis(Thiosemicarbazones) and their copper (Cu) complexes possess unique anti-neoplastic properties. However, their mechanism of action remains unclear. We examined the structure-activity relationships of twelve bis(Thiosemicarbazones) to elucidate factors regarding their anti-cancer efficacy. Importantly, the alkyl substitutions at the diimine position of the ligand backbone resulted in two distinct groups, namely, unsubstituted/monosubstituted and disubstituted bis(Thiosemicarbazones). This alkyl substitution pattern governed their: (1) Cu(II/I) redox potentials; (2) ability to induce cellular (64)Cu release; (3) lipophilicity; and (4) anti-proliferative activity. The potent anti-cancer Cu complex of the unsubstituted bis(Thiosemicarbazone) analog, glyoxal bis(4-methyl-3-Thiosemicarbazone) (GTSM), generated intracellular reactive oxygen species (ROS), which was attenuated by Cu sequestration by a non-toxic Cu chelator, tetrathiomolybdate, and the anti-oxidant, N-acetyl-l-cysteine. Fluorescence microscopy suggested that the anti-cancer activity of Cu(GTSM) was due, in part, to lysosomal membrane permeabilization (LMP). For the first time, this investigation highlights the role of ROS and LMP in the anti-cancer activity of bis(Thiosemicarbazones).
