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Christopher R. Chitambar - One of the best experts on this subject based on the ideXlab platform.
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the therapeutic potential of iron targeting Gallium Compounds in human disease from basic research to clinical application
Pharmacological Research, 2017Co-Authors: Christopher R. ChitambarAbstract:Gallium, group IIIa metal, shares certain chemical characteristics with iron which enable it to function as an iron mimetic that can disrupt iron-dependent tumor cell growth. Gallium may also display antimicrobial activity by disrupting iron homeostasis in certain bacteria and fungi. Gallium's action on iron homeostasis leads to inhibition of ribonucleotide reductase, mitochondrial function, and changes in proteins of iron transport and storage. In addition, Gallium induces an increase in mitochondrial reactive oxygen species in cells which triggers downstream upregulation of metallothionein and hemoxygenase-1. Early clinical trials evaluated the efficacy of the simple Gallium salts, Gallium nitrate and Gallium chloride. However, newer Gallium-ligands such as Tris(8-quinolinolato)Gallium(III) (KP46) and Gallium maltolate have been developed and are undergoing clinical evaluation. Additional Gallium-ligands that demonstrate antitumor activity in preclinical studies have emerged. Their mechanisms of action and their spectrum of antitumor activity may extend beyond the earlier generations of Gallium Compounds and warrant further investigation. This review will focus on the evolution and potential of Gallium-based therapeutics.
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iron targeting antitumor activity of Gallium Compounds and novel insights into triapine metal complexes
Antioxidants & Redox Signaling, 2013Co-Authors: Christopher R. Chitambar, William E AntholineAbstract:Significance: Despite advances made in the treatment of cancer, a significant number of patients succumb to this disease every year. Hence, there is a great need to develop new anticancer agents. Recent Advances: Emerging data show that malignant cells have a greater requirement for iron than normal cells do and that proteins involved in iron import, export, and storage may be altered in cancer cells. Therefore, strategies to perturb these iron-dependent steps in malignant cells hold promise for the treatment of cancer. Recent studies show that Gallium Compounds and metal-thiosemicarbazone complexes inhibit tumor cell growth by targeting iron homeostasis, including iron-dependent ribonucleotide reductase. Chemical similarities of Gallium(III) with iron(III) enable the former to mimic the latter and interpose itself in critical iron-dependent steps in cellular proliferation. Newer Gallium Compounds have emerged with additional mechanisms of action. In clinical trials, the first-generation-compound Gallium nitrate has exhibited activity against bladder cancer and non-Hodgkin's lymphoma, while the thiosemicarbazone Triapine® has demonstrated activity against other tumors. Critical Issues: Novel Gallium Compounds with greater cytotoxicity and a broader spectrum of antineoplastic activity than Gallium nitrate should continue to be developed. Future Directions: The antineoplastic activity and toxicity of the existing novel Gallium Compounds and thiosemicarbazone-metal complexes should be tested in animal tumor models and advanced to Phase I and II clinical trials. Future research should identify biologic markers that predict tumor sensitivity to Gallium Compounds. This will help direct Gallium-based therapy to cancer patients who are most likely to benefit from it. Antioxid. Redox Signal. 00, 000–000.
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Gallium containing anticancer Compounds
Future Medicinal Chemistry, 2012Co-Authors: Christopher R. ChitambarAbstract:There is an ever pressing need to develop new drugs for the treatment of cancer. Gallium nitrate, a group IIIa metal salt, inhibits the proliferation of tumor cells in vitro and in vivo and has shown activity against non-Hodgkin's lymphoma and bladder cancer in clinical trials. Gallium can function as an iron mimetic and perturb iron-dependent proliferation and other iron-related processes in tumor cells. Gallium nitrate lacks crossresistance with conventional chemotherapeutic drugs and is not myelosuppressive; it can be used when other drugs have failed or when the blood count is low. Given the therapeutic potential of Gallium, newer generations of Gallium Compounds are now in various phases of preclinical and clinical development. These Compounds hold the promise of greater anti-tumor activity against a broader spectrum of cancers. The development of Gallium Compounds for cancer treatment and their mechanisms of action will be discussed.
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medical applications and toxicities of Gallium Compounds
International Journal of Environmental Research and Public Health, 2010Co-Authors: Christopher R. ChitambarAbstract:Over the past two to three decades, Gallium Compounds have gained importance in the fields of medicine and electronics. In clinical medicine, radioactive Gallium and stable Gallium nitrate are used as diagnostic and therapeutic agents in cancer and disorders of calcium and bone metabolism. In addition, Gallium Compounds have displayed anti-inflammatory and immunosuppressive activity in animal models of human disease while more recent studies have shown that Gallium Compounds may function as antimicrobial agents against certain pathogens. In a totally different realm, the chemical properties of Gallium arsenide have led to its use in the semiconductor industry. Gallium Compounds, whether used medically or in the electronics field, have toxicities. Patients receiving Gallium nitrate for the treatment of various diseases may benefit from such therapy, but knowledge of the therapeutic index of this drug is necessary to avoid clinical toxicities. Animals exposed to Gallium arsenide display toxicities in certain organ systems suggesting that environmental risks may exist for individuals exposed to this compound in the workplace. Although the arsenic moiety of Gallium arsenide appears to be mainly responsible for its pulmonary toxicity, Gallium may contribute to some of the detrimental effects in other organs. The use of older and newer Gallium Compounds in clinical medicine may be advanced by a better understanding of their mechanisms of action, drug resistance, pharmacology, and side-effects. This review will discuss the medical applications of Gallium and its mechanisms of action, the newer Gallium Compounds and future directions for development, and the toxicities of Gallium Compounds in current use.
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Development of Gallium Compounds for Treatment of Lymphoma: Gallium Maltolate, a Novel Hydroxypyrone Gallium Compound, Induces Apoptosis and Circumvents Lymphoma Cell Resistance to Gallium Nitrate
The Journal of pharmacology and experimental therapeutics, 2007Co-Authors: Christopher R. Chitambar, David P. Purpi, Jeffrey Woodliff, Meiying Yang, Janine P WereleyAbstract:Clinical studies have shown Gallium nitrate to have significant antitumor activity against non-Hodgkin's lymphoma and bladder cancer, thus indicating that Gallium-based drugs have potential for further development as antineoplastic agents. In this study, we compared the cytotoxicity of Gallium maltolate, a novel Gallium compound, with Gallium nitrate in lymphoma cell lines, including p53 variant and unique Gallium nitrate-resistant cells. We found that Gallium maltolate inhibited cell proliferation and induced apoptosis through the mitochondrial pathway at lower concentrations and more rapidly than Gallium nitrate. Gallium maltolate produced an increase in intracellular reactive oxygen species (ROS) within 2 h of incubation with cells; this effect could be blocked by mitoquinone, a mitochondria-targeted antioxidant. The role of the transferrin receptor (TfR) in Gallium maltolate's action was examined using monoclonal antibody (MoAb) 42/6 to block TfR function. However, although MoAb 42/6 reduced Gallium maltolate-induced caspase-3 activity, it had only a minor effect on cell growth inhibition. Importantly, Gallium maltolate induced apoptosis in cells resistant to Gallium nitrate, and, unlike Gallium nitrate, its cytotoxicity was not affected by cellular p53 status. Cellular Gallium uptake was greater with Gallium maltolate than with Gallium nitrate. We conclude that Gallium maltolate inhibits cell proliferation and induces apoptosis more efficiently than Gallium nitrate. Gallium maltolate is incorporated into lymphoma cells to a greater extent than Gallium nitrate via both TfR-independent and -dependent pathways; it has significant activity against Gallium nitrate-resistant cells and acts independently of p53. Further studies to evaluate its antineoplastic activity in vivo are warranted.
Rudolf J Wehmschulte - One of the best experts on this subject based on the ideXlab platform.
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catalytic reduction of carbon dioxide using cationic organoaluminum and Gallium Compounds
Organometallics, 2017Co-Authors: Mahmoud A Saleh, Douglas R Powell, Rudolf J WehmschulteAbstract:Ethide abstraction from Et3M (M = Al and Ga), (2,6-Ph2C6H3)AlEt2, 1, and (2,6-Dipp2C6H3)GaEt2, 2 (Dipp = 2,6-iPr2C6H3), using the silylium ion [Et3Si][CHB11Cl11] afforded crystalline ion-like Compounds [Et2M][CHB11Cl11] (M = Al, 3; Ga, 5) and [(2,6-Ph2C6H3)AlEt][CHB11Cl11], 4, and the likely solvent-separated ion pair [(2,6-Dipp2C6H3)GaEt][CHB11Cl11], 6. Crystalline Compounds 3–5 feature cation···anion contacts in the solid state, and their solubility in low polarity benzene indicates that these contacts are maintained in solution. All Compounds catalyze the reduction of CO2 with Et3SiH, but the activity of the Gallium compound 5 is significantly lower due to its polymeric structure and the lower Lewis acidity of Gallium. Whereas the reduction products from the reactions catalyzed by Compounds 3–5 are mostly methane and toluene (from Friedel–Crafts alkylation of the benzene solvent), catalysis by 6 led mostly to Et3SiOCH3.
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Catalytic Reduction of Carbon Dioxide Using Cationic Organoaluminum and -Gallium Compounds
2017Co-Authors: Mahmoud Saleh, Douglas R Powell, Rudolf J WehmschulteAbstract:Ethide abstraction from Et3M (M = Al and Ga), (2,6-Ph2C6H3)AlEt2, 1, and (2,6-Dipp2C6H3)GaEt2, 2 (Dipp = 2,6-iPr2C6H3), using the silylium ion [Et3Si][CHB11Cl11] afforded crystalline ion-like Compounds [Et2M][CHB11Cl11] (M = Al, 3; Ga, 5) and [(2,6-Ph2C6H3)AlEt][CHB11Cl11], 4, and the likely solvent-separated ion pair [(2,6-Dipp2C6H3)GaEt][CHB11Cl11], 6. Crystalline Compounds 3–5 feature cation···anion contacts in the solid state, and their solubility in low polarity benzene indicates that these contacts are maintained in solution. All Compounds catalyze the reduction of CO2 with Et3SiH, but the activity of the Gallium compound 5 is significantly lower due to its polymeric structure and the lower Lewis acidity of Gallium. Whereas the reduction products from the reactions catalyzed by Compounds 3–5 are mostly methane and toluene (from Friedel–Crafts alkylation of the benzene solvent), catalysis by 6 led mostly to Et3SiOCH3
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m terphenylaluminum and Gallium Compounds synthesis and conversion into low coordinate organoGallium cations
European Journal of Inorganic Chemistry, 2007Co-Authors: Jackie D Young, Masood A Khan, Douglas R Powell, Rudolf J WehmschulteAbstract:The reaction of two or 3 equiv. of m-terphenyllithium with MCl 3 or AlH 3 ·NMe 3 (M = Al, Ga) affords the bis(terphenyl)-aluminum and -Gallium chloride Compounds [{2,6-(4-tBuC 6 H 4 ) 2 C 6 H 3 } 2 GaCl] (1), [{2,6-(3,5-Me 2 C 6 H 3 ) 2 C 6 H 3 } 2 GaCl] (2), [{2,6-(4-tBuC 6 H 4 ) 2 C 6 H 3 } 3 Ga] (3), [(2,6-Mes 2 C 6 H 3 } 2 AlCl] (5), and [(2,6-Mes 2 C 6 H 3 ) 2 AlH] (7; Mes = 2,4,6-Me 3 C 6 H 2 ). While the Gallium Compounds can be obtained at room temperature, heating is required for the aluminum derivatives. The dibutyl Compounds [(2,6-Mes 2 C 6 H 3 )GaBu 2 ] (8) and [(2,6-Dipp 2 C 6 H 3 )GaBu2] (9; Dipp = 2,6-iPr 2 C 6 H 3 ) have also been synthesized by the reaction of m-terphenyllithium with ClGaBu 2 . A metathesis reaction of 2 with Li[Al{OCH(CF 3 ) 2 } 4 ] gives the ionic species [(2,6-Mes2C6H3)2Ga]+[Li{Al-[OCH(CF 3 ) 2 ] 4 } 2 ] - (11). The cationic butyl(terphenyl)Gallium Compounds [(2,6-Mes2C6H3)GaBu]+ ([13) + ) and [(2,6-Dipp 2 C 6 H 3 )GaBu]+ ([14] + ) have been prepared by butanide ion with the trityl salts of the weakly coordinating anions [B(C 6 F 5 ) 4 ] - , [CHB 11 Br 6 Me 5 ] - , and [CHB 11 Cl 11 ] - . These ionic species are stable at room temperature for days or weeks, although their combinations with the borate anion [B-(C 6 F 5 ) 4 ] - suffer from C 6 F 5 migration, which is slow at room temperature and faster at elevated temperatures. The compound [14] + [CHB 11 Cl 11 ] - is stable at 70 °C for at least 23 h. Addition of 1-octene to a solution of [14] + [CHB 11 Cl 11 ] - in C 6 D 6 results in olefin exchange and formation of the octyl species [(2,6-Dipp 2 C 6 H 3 )Ga(octyl)]+ ([17] + ), and a slow alkylation of the solvent to afford various octylbenzenes. Hydrolysis of 8 and [13] + [CHB 11 Br 6 Me 5 ] - gives the Compounds [[(2,6-Mes2C6H3)GaBu(μ-OH)} 2 ] (10) and [(BuGa) 4 (μ-OH) 6 ] 2+ [CHB 11 Br 6 Me 5 ] - 2 (16). All Compounds have been characterized by 1 H and 13 C{ 1 H} NMR spectroscopy and mass spectrometry, and Compounds 3, 5, 7, 10, and 16·4.5C 6 H 6 have also been characterized by single-crystal X-ray crystallography.
Vera Susanne Rotter - One of the best experts on this subject based on the ideXlab platform.
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challenges for critical raw material recovery from weee the case study of Gallium
Waste Management, 2017Co-Authors: Maximilian Ueberschaar, Sarah Julie Otto, Vera Susanne RotterAbstract:Abstract Gallium and Gallium Compounds are more frequently used in future oriented technologies such as photovoltaics, light diodes and semiconductor technology. In the long term the supply risk is estimated to be critical. Germany is one of the major primary Gallium producer, recycler of Gallium from new scrap and GaAs wafer producer. Therefore, new concepts for a resource saving handling of Gallium and appropriate recycling strategies have to be designed. This study focus on options for a possible recycling of Gallium from waste electric and electronic equipment. To identify first starting points, a substance flow analysis was carried out for Gallium applied in integrated circuits applied on printed circuit boards and for LEDs used for background lighting in Germany in 2012. Moreover, integrated circuits (radio amplifier chips) were investigated in detail to deduce first approaches for a recycling of such components. An analysis of recycling barriers was carried out in order to investigate general opportunities and risks for the recycling of Gallium from chips and LEDs. Results show, that significant Gallium losses arose in primary production and in waste management. 93 ± 11%, equivalent to 43,000 ± 4700 kg of the total Gallium potential was lost over the whole primary production process until applied in electronic goods. The largest share of 14,000 ± 2300 kg Gallium was lost in the production process of primary raw materials. The subsequent refining process was related to additional 6900 ± 3700 kg and the chip and wafer production to 21,700 ± 3200 kg lost Gallium. Results for the waste management revealed only low collection rates for related end-of-life devices. Not collected devices held 300 ± 200 kg Gallium. Due to the fact, that current waste management processes do not recover Gallium, further 80 ± 10 kg Gallium were lost. A thermal pre-treatment of the chips, followed by a manual separation allowed an isolation of Gallium rich fractions, with Gallium mass fractions up to 35%. Here, Gallium loads per chip were between 0.9 and 1.3 mg. Copper, gold and arsenic were determined as well. Further treatment options for this Gallium rich fraction were assessed. The conventional pyrometallurgical copper route might be feasible. A recovery of gold and Gallium in combination with copper is possible due to a compatibility with this base-metal. But, a selective separation prior to this process is necessary. Diluted with other materials, the Gallium content would be too low. The recycling of Gallium from chips applied on printed circuit boards and LEDs used for background lighting is technically complex. Recycling barriers exist over the whole recycling chain. A forthcoming commercial implementation is not expected in nearer future. This applies in particular for chips carrying Gallium.
Moses O Oyewumi - One of the best experts on this subject based on the ideXlab platform.
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antitumor efficacy and tolerability of systemically administered Gallium acetylacetonate loaded gelucire stabilized nanoparticles
Journal of Biomedical Nanotechnology, 2013Co-Authors: Daniel Wehrung, Werner J Geldenhuys, Moses O OyewumiAbstract:The widespread clinical success with most Gallium Compounds in cancer therapy is markedly hampered by lack of tumor specific accumulation, poor tumor permeability and undesirable toxicity to healthy tissues. The aim of this work was to investigate for the first time antitumor mechanism of a new Gallium compound (Gallium acetylacetonate; GaAcAc) while assessing effectiveness of gelucire-stabilized nanoparticles (NPs) for potential application in Gallium-based lung cancer therapy. NPs loaded with GaAcAc (Ga-NPs) were prepared using mixtures of cetyl alcohol with Gelucire 44/14 (Ga-NP-1) or Gelucire 53/13 (Ga-NP-2) as matrix materials. Of special note from this work is the direct evidence of involvement of microtubule disruption in antitumor effects of GaAcAc on human lung adenocarcinoma (A549). In-vivo tolerability studies were based on plasma ALT, creatinine levels and histopathological examination of tissues. The superior in-vivo antitumor efficacy of Ga-NPs over GaAcAc was depicted in marked reduction of tumor weight and tumor volume as well as histological assessment of excised tumors. Compared to free GaAcAc, Ga-NPs showed a 3-fold increase in tumor-to-blood Gallium concentrations with minimized overall exposure to healthy tissues. Overall, enhancement of antitumor effects of GaAcAc by gelucire-stabilized NPs coupled with reduced exposure of healthy tissues to Gallium would likely ensure desired therapeutic outcomes and safety of Gallium-based cancer treatment.
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antitumor effect of novel Gallium Compounds and efficacy of nanoparticle mediated Gallium delivery in lung cancer
Journal of Biomedical Nanotechnology, 2012Co-Authors: Daniel Wehrung, Moses O OyewumiAbstract:The widespread application of Gallium (Ga) in cancer therapy has been greatly hampered by lack of specificity resulting in poor tumor accumulation and retention. To address the challenge, two lipophilic Gallium (III) Compounds (Gallium hexanedione; GaH and Gallium acetylacetonate; GaAcAc) were synthesized and antitumor studies were conducted in human lung adenocarcinoma (A549) cells. Nanoparticles (NPs) containing various concentrations of the Ga Compounds were prepared using a binary mixture of Gelucire 44/14 and cetyl alcohol as matrix materials. NPs were characterized based on size, morphology, stability and biocompatibility. Antitumor effects of free or NP-loaded Ga Compounds were investigated based on cell viability, production of reactive oxygen species and reduction of mitochondrial potential. Compared to free Ga Compounds, cytotoxicity of NP-loaded Ga (5-150 microg/ml) was less dependent on concentration and incubation time (exposure) with A549 cells. NP-mediated delivery (5-150 microg Ga/ml) enhanced antitumor effects of Ga Compounds and the effect was pronounced at: (i) shorter incubation times; and (ii) at low concentrations of Gallium (approximately 50 microg/ml) (p 0.13) suggesting the potential in overcoming Gallium resistance in some tumors. In general, preparation of stable and biocompatible NPs that facilitated Ga tumor uptake and antitumor effects could be effective in Gallium-based cancer therapy.
H Schnockel - One of the best experts on this subject based on the ideXlab platform.
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low valent aluminum and Gallium Compounds structural variety and coordination modes to transition metal fragments
Coordination Chemistry Reviews, 2000Co-Authors: G Linti, H SchnockelAbstract:Abstract The chemistry of low valent aluminum and Gallium Compounds is a very topical area of research. Accompanying the preparative challenge in synthesizing novel types of main group cluster Compounds and transition metal complexes with aluminum and Gallium ligands, an area of chemistry is being exploited, which requires new insight on the description of chemical bonds. Therefore, not only are routes to these Compounds and their structures described here, but thoughts on the description of bonding are presented as well.
