16 results on '"Steel TR"'
Search Results
2. Incorporation of β-Alanine in Cu(II) ATCUN Peptide Complexes Increases ROS Levels, DNA Cleavage and Antiproliferative Activity.
- Author
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Heinrich J, Bossak-Ahmad K, Riisom M, Haeri HH, Steel TR, Hergl V, Langhans A, Schattschneider C, Barrera J, Jamieson SMF, Stein M, Hinderberger D, Hartinger CG, Bal W, and Kulak N
- Subjects
- Cell Line, Tumor, Copper, Humans, Reactive Oxygen Species, Antineoplastic Agents pharmacology, Coordination Complexes pharmacology, DNA Cleavage, Peptides pharmacology, beta-Alanine pharmacology
- Abstract
Redox-active Cu(II) complexes are able to form reactive oxygen species (ROS) in the presence of oxygen and reducing agents. Recently, Faller et al. reported that ROS generation by Cu(II) ATCUN complexes is not as high as assumed for decades. High complex stability results in silencing of the Cu(II)/Cu(I) redox cycle and therefore leads to low ROS generation. In this work, we demonstrate that an exchange of the α-amino acid Gly with the β-amino acid β-Ala at position 2 (Gly2→β-Ala2) of the ATCUN motif reinstates ROS production (
• OH and H2 O2 ). Potentiometry, cyclic voltammetry, EPR spectroscopy and DFT simulations were utilized to explain the increased ROS generation of these β-Ala2-containing ATCUN complexes. We also observed enhanced oxidative cleavage activity towards plasmid DNA for β-Ala2 compared to the Gly2 complexes. Modifications with positively charged Lys residues increased the DNA affinity through electrostatic interactions as determined by UV/VIS, fluorescence, and CD spectroscopy, and consequently led to a further increase in nuclease activity. A similar trend was observed regarding the cytotoxic activity of the complexes against several human cancer cell lines where β-Ala2 peptide complexes had lower IC50 values compared to Gly2. The higher cytotoxicity could be attributed to an increased cellular uptake as determined by ICP-MS measurements., (© 2021 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)- Published
- 2021
- Full Text
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3. Synthetic Strategy Towards Heterodimetallic Half-Sandwich Complexes Based on a Symmetric Ditopic Ligand.
- Author
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Green LPM, Steel TR, Riisom M, Hanif M, Söhnel T, Jamieson SMF, Wright LJ, Crowley JD, and Hartinger CG
- Abstract
Multimetallic complexes have been shown in several examples to possess greater anticancer activity than their monometallic counterparts. The increased activity has been attributed to altered modes of action. We herein report the synthesis of a series of heterodimetallic compounds based on a ditopic ligand featuring 2-pyridylimine chelating motifs and organometallic half-sandwich moieties. The complexes were characterized by a combination of
1 H NMR spectroscopy, electrospray ionization mass spectrometry, elemental analysis and single crystal X-ray diffraction. Investigations into the stability of representative complexes in DMSO- d6 and 10% DMSO- d6 /D2 O revealed the occurrence of solvent-chlorido ligand exchange. Proliferation assays in four human cancer cell lines showed that the Os-Rh complex possessed minimal activity, while all other complexes were inactive., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Green, Steel, Riisom, Hanif, Söhnel, Jamieson, Wright, Crowley and Hartinger.)- Published
- 2021
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4. Metalloproteomics for molecular target identification of protein-binding anticancer metallodrugs.
- Author
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Steel TR and Hartinger CG
- Subjects
- Animals, Humans, Metabolic Networks and Pathways drug effects, Metals pharmacology, Protein Binding drug effects, Antineoplastic Agents pharmacology, Metalloproteins metabolism, Proteomics
- Abstract
Proteomics has played an important role in elucidating the fundamental processes occuring in living cells. Translating these methods to metallodrug research ('metalloproteomics') has provided a means for molecular target identification of metal-based anticancer agents which should signifcantly advance the research field. In combination with biological assays, these techniques have enabled the mechanisms of action of metallodrugs to be linked to their interactions with molecular targets and aid understanding of their biological properties. Such investigations have profoundly increased our knowledge of the complex and dynamic nature of metallodrug-biomolecule interactions and have provided, at least for some compound types, a more detailed picture on their specific protein-binding patterns. This perspective highlights the progression of metallodrug proteomics research for the identification of non-DNA targets from standard analytical techniques to powerful metallodrug pull-down methods.
- Published
- 2020
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- View/download PDF
5. Potent Inhibition of Thioredoxin Reductase by the Rh Derivatives of Anticancer M(arene/Cp*)(NHC)Cl 2 Complexes.
- Author
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Truong D, Sullivan MP, Tong KKH, Steel TR, Prause A, Lovett JH, Andersen JW, Jamieson SMF, Harris HH, Ott I, Weekley CM, Hummitzsch K, Söhnel T, Hanif M, Metzler-Nolte N, Goldstone DC, and Hartinger CG
- Subjects
- Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Cell Line, Tumor, Cell Proliferation drug effects, Coordination Complexes chemical synthesis, Coordination Complexes chemistry, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors chemistry, Heterocyclic Compounds chemistry, Heterocyclic Compounds pharmacology, Humans, Ligands, Metals, Heavy chemistry, Metals, Heavy pharmacology, Methane analogs & derivatives, Methane chemistry, Methane pharmacology, Molecular Conformation, Structure-Activity Relationship, Thioredoxin-Disulfide Reductase metabolism, Antineoplastic Agents pharmacology, Coordination Complexes pharmacology, Enzyme Inhibitors pharmacology, Thioredoxin-Disulfide Reductase antagonists & inhibitors
- Abstract
Metal complexes provide a versatile platform to develop novel anticancer pharmacophores, and they form stable compounds with N -heterocyclic carbene (NHC) ligands, some of which have been shown to inhibit the cancer-related selenoenzyme thioredoxin reductase (TrxR). To expand a library of isostructural NHC complexes, we report here the preparation of Rh
III - and IrIII (Cp*)(NHC)Cl2 (Cp* = η5 -pentamethylcyclopentadienyl) compounds and comparison of their properties to the RuII - and OsII (cym) analogues (cym = η6 - p -cymene). Like the RuII - and OsII (cym) complexes, the RhIII - and IrIII (Cp*) derivatives exhibit cytotoxic activity with half maximal inhibitory concentration (IC50 ) values in the low micromolar range against a set of four human cancer cell lines. In studies on the uptake and localization of the compounds in cancer cells by X-ray fluorescence microscopy, the Ru and Os derivatives were shown to accumulate in the cytoplasmic region of treated cells. In an attempt to tie the localization of the compounds to the inhibition of the tentative target TrxR, it was surprisingly found that only the Rh complexes showed significant inhibitory activity at IC50 values of ∼1 μM, independent of the substituents on the NHC ligand. This indicates that, although TrxR may be a potential target for anticancer metal complexes, it is unlikely the main target or the sole target for the Ru, Os, and Ir compounds described here, and other targets should be considered. In contrast, Rh(Cp*)(NHC)Cl2 complexes may be a scaffold for the development of TrxR inhibitors.- Published
- 2020
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- View/download PDF
6. Anticancer organorhodium and -iridium complexes with low toxicity in vivo but high potency in vitro: DNA damage, reactive oxygen species formation, and haemolytic activity.
- Author
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Parveen S, Hanif M, Leung E, Tong KKH, Yang A, Astin J, De Zoysa GH, Steel TR, Goodman D, Movassaghi S, Söhnel T, Sarojini V, Jamieson SMF, and Hartinger CG
- Subjects
- Animals, Antineoplastic Agents chemistry, Cell Line, Tumor, Cell Survival drug effects, Cisplatin pharmacology, Coordination Complexes chemistry, Drug Screening Assays, Antitumor, Hemolysis, Humans, Ligands, Mice, Oxidation-Reduction, Ruthenium chemistry, Structure-Activity Relationship, Zebrafish, Antineoplastic Agents pharmacology, Coordination Complexes pharmacology, DNA Damage drug effects, Iridium chemistry, Reactive Oxygen Species metabolism, Rhodium chemistry
- Abstract
Redox-modulating anticancer drugs allow the exploitation of altered redox biology observed in many cancer cells. We discovered dinuclear RhIII(Cp*) and IrIII(Cp*) complexes that have in vitro anticancer activity superior to cisplatin and the investigational drug IT-139, while being less toxic in haemolysis and in vivo zebrafish models. The mode of action appears to be related to DNA damage and ROS-mediated stress pathways.
- Published
- 2019
- Full Text
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7. Hydroxyquinoline-derived anticancer organometallics: Introduction of amphiphilic PTA as an ancillary ligand increases their aqueous solubility.
- Author
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Tremlett WDJ, Tong KKH, Steel TR, Movassaghi S, Hanif M, Jamieson SMF, Söhnel T, and Hartinger CG
- Subjects
- Amino Acids chemistry, Antineoplastic Agents, Cell Line, Tumor, Coordination Complexes chemical synthesis, Coordination Complexes chemistry, Humans, Molecular Dynamics Simulation, Mutagenesis, Site-Directed, Organometallic Compounds chemical synthesis, Peroxidase chemistry, Peroxidase genetics, Peroxidase metabolism, Solubility, Water chemistry, Organometallic Compounds chemistry
- Abstract
Organometallic compounds based on bioactive ligand systems have shown promising antiproliferative properties. The use of 8-hydroxyquinoline and its derivatives as bioactive ligands resulted in organometallic complexes with potent anticancer activity, but they lack aqueous solubility for further development. We report here the preparation of a series of M
II/III (cym/Cp*)Cl complexes (η6 -p-cymene (cym): M = Ru, Os; η5 -pentamethylcyclopentadienyl (Cp*): M = Rh, Ir) with hydroxyquinoline-derived co-ligands and in a subsequent step the substitution of the chlorido ligands for amphiphilic 1,3,5-triaza-7-phosphatricyclo-[3.3.1.1]decane (PTA). Solubility studies indicated that the introduced PTA ligand significantly improved the aqueous solubility of all complexes. The complexes were shown to be stable in aqueous and DMSO solution over a period of at least 3 d. As would be expected for such modification of complexes, the higher solubility resulted in significantly decreased cytotoxicity in cancer cells. The antiproliferative activity was still more pronounced than that of RAPTA-C [Ru(cym)(PTA)Cl] which, however, has been demonstrated to have antimetastatic and antiangiogenic properties in vivo., (Copyright © 2019 Elsevier Inc. All rights reserved.)- Published
- 2019
- Full Text
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8. Intraforaminal vertebral artery: a rare and risky anomaly.
- Author
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Murambi RT, White E, and Steel TR
- Published
- 2015
- Full Text
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9. Migration of lumbar disc herniation: an unusual case.
- Author
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Mobbs RJ and Steel TR
- Subjects
- Adult, Humans, Intervertebral Disc Displacement pathology, Lumbar Vertebrae, Magnetic Resonance Imaging, Male, Nerve Compression Syndromes pathology, Radiculopathy pathology, Intervertebral Disc pathology, Intervertebral Disc Displacement complications, Nerve Compression Syndromes etiology, Radiculopathy etiology
- Abstract
We illustrate a patient with a migrating lumbar disc fragment that caused a change in radicular symptoms from the L3 nerve root on one side to the L5 nerve root on the contralateral side, documented by magnetic resonance imaging (MRI). Our patient presented with 3 months of L3 pain on the right side with sensory and motor changes. Over a 24-hour time period, the right leg pain disappeared and he developed left leg pain attributable to left L5 nerve root compression. Investigation with MRI revealed an epidural mass, which was hypointense on Tl-weighted and T2-weighted images that had migrated, initially compressing the right L3 nerve root, to now compress the left L5 nerve root. The patient did not wish to pursue surgery. Disc fragment migration patterns are discussed. We conclude that extruded disc fragments may migrate distant from their initial origin.
- Published
- 2007
- Full Text
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10. Endoscopic treatment of spinal epidural hematoma.
- Author
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Steel TR, Kellogg JX, Kuether TA, Favre J, and Frank EH
- Abstract
We report the use of a spinal endoscope via a limited cervical laminotomy to evacuate a spinal epidural hematoma. The patient was a 75-year-old male with a 32-year history of ankylosing spondylitis. Following a low speed motor vehicle accident he developed a cervicothoracic epidural hematoma without an associated fracture. Despite a rapidly improving neurological state, his rapidly deteriorating cardiorespiratory state required systemic anticoagulation necessitating decompression of the hematoma. The hematoma was successfully removed via a limited C6 and C7 laminotomy using the endoscope and a malleable disposable aspirator. We conclude that epidural hematomas can be readily evacuated via endoscopic techniques without extensive laminectomy. This technique may be used for approaching intraspinal pathology in high risk patients where extensive exposure may be contraindicated.
- Published
- 1998
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11. Intradural neurotropic spread of malignant mesothelioma. Case report and review of the literature.
- Author
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Steel TR, Allibone J, Revesz T, D'Arrigo C, and Crockard HA
- Subjects
- Diagnosis, Differential, Dura Mater, Humans, Male, Middle Aged, Mesothelioma secondary, Spinal Cord Neoplasms secondary, Spinal Neoplasms pathology
- Abstract
This 54-year-old man with a history of right-sided malignant mesothelioma presented with signs of a partial spinal cord syndrome. The tumor had invaded the lower trunk of the brachial plexus and spread along the T-1 nerve root beneath the arachnoid onto the spinal cord itself. Mesothelioma, despite its known predilection for local spread, is rarely encountered within the spinal canal. Neurotropism is commonly encountered in facial malignancies; however, it has never been reported to affect the brachial plexus and spinal cord.
- Published
- 1998
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12. Paraganglioma of the cauda equina with associated syringomyelia: case report.
- Author
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Steel TR, Botterill P, and Sheehy JP
- Subjects
- Female, Humans, Middle Aged, Neck, Thorax, Cauda Equina, Paraganglioma, Extra-Adrenal complications, Spinal Cord Neoplasms complications, Syringomyelia complications
- Abstract
We present an association not previously described in which the rare entity of paraganglioma of the cauda equina was found in association with syringomyelia of the cervico-thoracic cord. The patient, a 50-year-old woman presented with a long history of lower back pain with recent onset of sciatic pain and altered sensation in the right leg. Surgical resection of the tumor with intraoperative syringostomy of the syrinx has led to eradication of all symptoms and at 5 months shows no evidence of residual pathology.
- Published
- 1994
- Full Text
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13. Vascular neurofibromatosis affecting the internal carotid artery: a case report.
- Author
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Steel TR, Bentivoglio PB, and Garrick R
- Subjects
- Adult, Carotid Artery, Internal pathology, Cavernous Sinus pathology, Cerebral Angiography, Diagnosis, Differential, Humans, Magnetic Resonance Imaging, Male, Tomography, X-Ray Computed, Carotid Artery Diseases diagnosis, Neurofibromatoses diagnosis
- Abstract
A patient with von Recklinghausen's disease presented with a right sixth nerve palsy. Investigations demonstrated unilateral dolichoectasia of the intracranial carotid artery and sphenoid wing dysplasia. This case demonstrates an association not previously documented, that of unilateral fusiform dilatation of the carotid artery with sphenoid wing dysplasia in the presence of classical neurofibromatosis.
- Published
- 1994
- Full Text
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14. Spinal epidural leiomyoma occurring in an HIV-infected man. Case report.
- Author
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Steel TR, Pell MF, Turner JJ, and Lim GH
- Subjects
- Epidural Neoplasms pathology, Humans, Leiomyoma pathology, Male, Middle Aged, Tomography, X-Ray Computed, Epidural Neoplasms complications, Epidural Neoplasms surgery, HIV Infections complications, Leiomyoma complications, Leiomyoma surgery
- Abstract
A case of spinal epidural leiomyoma is reported in a 52-year-old man infected with the human immunodeficiency virus (HIV). The tumor arose in the epidural region at the T-3 vertebral level, and the patient presented with radicular pain in the right T-3 dermatome. While soft-tissue tumors such as Kaposi's sarcoma and lymphomas have been well documented in association with HIV infection, this is the first reported case of primary spinal leiomyoma. Isolated cases of leiomyomas and leiomyosarcomas in unusual locations have been reported, notably in pediatric HIV-positive patients, perhaps indicating a causal relationship. This case may represent further evidence of such an association.
- Published
- 1993
- Full Text
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15. Paragangliomas of the sellar region: report of two cases.
- Author
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Steel TR, Dailey AT, Born D, Berger MS, and Mayberg MR
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- Adult, Cytoplasmic Granules ultrastructure, Female, Humans, Magnetic Resonance Imaging, Microscopy, Electron, Paraganglioma diagnosis, Paraganglioma pathology, Pituitary Neoplasms diagnosis, Pituitary Neoplasms pathology, Sella Turcica pathology, Paraganglioma surgery, Pituitary Neoplasms surgery
- Abstract
Two cases of paraganglioma arising from the parasellar region are presented. Both occurred in middle-aged women who sought treatment of headaches but who had no endocrinological dysfunction; one case was associated with ophthalmoplegia from cavernous sinus involvement. Diagnosis in both cases was confirmed by typical histological appearance and cytochemical demonstration of immunoreactive chromogranin in tumor cells. The pathological features and possible pathogenesis of parasellar paragangliomas are discussed.
- Published
- 1993
- Full Text
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16. Structure and mechanics of tendon.
- Author
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Evans JH, Barbenel JC, Steel TR, and Ashby AM
- Subjects
- Animals, Biomechanical Phenomena, Microscopy, Electron, Scanning, Models, Biological, Tendons ultrastructure, Tendons physiology
- Published
- 1980
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