subject:(Prodrug)

University of Colorado

1. Rudnicki, Daniel Lee. Targeted Prodrugs of a Novel Platform Anthracycline: Doxazolidine.

Degree: PhD, Chemistry & Biochemistry, 2012, University of Colorado

URL: https://scholar.colorado.edu/chem_gradetds/61

► Doxorubicin (Dox) is an antitumor drug that has been used as a chemotherapeutic agent in the clinic for over 30 years. Dox treatments have… (more)

Subjects/Keywords: Anthracycline; Cancer; Prodrug; Chemistry

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Rudnicki, D. L. (2012). Targeted Prodrugs of a Novel Platform Anthracycline: Doxazolidine. (Doctoral Dissertation). University of Colorado. Retrieved from https://scholar.colorado.edu/chem_gradetds/61

Chicago Manual of Style (16^th Edition):

Rudnicki, Daniel Lee. “Targeted Prodrugs of a Novel Platform Anthracycline: Doxazolidine.” 2012. Doctoral Dissertation, University of Colorado. Accessed April 11, 2021. https://scholar.colorado.edu/chem_gradetds/61.

MLA Handbook (7^th Edition):

Rudnicki, Daniel Lee. “Targeted Prodrugs of a Novel Platform Anthracycline: Doxazolidine.” 2012. Web. 11 Apr 2021.

Vancouver:

Rudnicki DL. Targeted Prodrugs of a Novel Platform Anthracycline: Doxazolidine. [Internet] [Doctoral dissertation]. University of Colorado; 2012. [cited 2021 Apr 11]. Available from: https://scholar.colorado.edu/chem_gradetds/61.

Council of Science Editors:

Rudnicki DL. Targeted Prodrugs of a Novel Platform Anthracycline: Doxazolidine. [Doctoral Dissertation]. University of Colorado; 2012. Available from: https://scholar.colorado.edu/chem_gradetds/61

Victoria University of Wellington

2. Li, Ye. Design and Synthesis of Antiviral Iminoribitol C-Nucleosides.

Degree: 2017, Victoria University of Wellington

URL: http://hdl.handle.net/10063/9098

► Infections caused by RNA viruses, such as Ebola and Zika, continue to exist worldwide as significant public health problems. In response to the urgent need… (more)

▼ Infections caused by RNA viruses, such as Ebola and Zika, continue to exist worldwide as significant public health problems. In response to the urgent need for safer and more efficacious treatment options to treat infections caused by RNA viruses, the pharmaceutical and biotechnology industries have devoted significant efforts over the last two decades to discovering and developing new antiviral agents. One such antiviral, Sofosbuvir®, was approved by the US Federal Drug Administration (FDA) in 2014 and has revolutionized the treatment of Hepatitis-C. Sofosbuvir® was the second largest selling drug in the world in 2016 and in just twenty-one months Gilead reported sales worth $26.6 billion USD.The strategy of using nucleoside analogues to inhibit viral RNA dependent RNA polymerase(RdRp)has been pursued since the 1970s, and exemplified bythe discovery and development of ribavirin. The natural substrates of RNA polymerases are nucleoside triphosphates and often the efficacy of nucleoside analogues as antivirals are dependent on their ability to be converted by the host or virus to mono-, di-, and ultimately tri-phosphate analogues which block the active site of RNA polymerase as an analogue of the substrate causing chain termination. Recently Biocryst Pharmaceuticals (Biocryst) described the anti-viral properties of Immucillin-A (Galidesivir), an iminoribitol based nucleoside analogue, which was found to have broad spectrum antiviral activity especially against RNA viruses including Ebola. Researchers at the Ferrier Research Institute (Ferrier) have synthesizedan analogue of Immucillin-A, 8-aza-Immucillin-A (AIA) which shows comparable activityto Immucillin-A, in anti-viral screens against Ebola, and this antiviral activity forms part of a US patent application. The Ferrier is keen to further exemplify this compound class through the synthesis of analogues of both Immucillin-A and AIA as well as improve the overall synthesis of the lead compound AIA.Included as part of this study is the synthesis of pro-drugs of these iminoribitol based nucleoside analogues. Prodrugs are metabolized inside the body and are often converted to the corresponding pharmacologically active form. In general, prodrug strategies have improved the bioavailability and efficacy of many drugs. In particular, prodrugs strategies involving nucleoside analogue antivirals, which target RNA polymerase, have been particularly effective as they ensure conversion to the monophosphate in vivo. Conversion to the 5’-monophosphate form of a nucleoside analogue is the rate limiting step to the inhibition of the RNA polymerase –prior to its conversion to the triphosphateanalogue. The prodrug is effectively a protected monophosphate, and is then readily converted to monophosphate by the host and then onto the di-and tri-phosphate by kinases in both the host and virus. ProTide prodrugs, such as Sofosbuvir® provide a verified strategy for improving anti-viral activity and hence our desire to synthesize pro-drugs of all our iminoribitol based nucleoside… Advisors/Committee Members: Evans, Gary, Tyler, Peter.

Subjects/Keywords: Iminoribitol; Immucillins; Prodrug; ProTides

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Li, Y. (2017). Design and Synthesis of Antiviral Iminoribitol C-Nucleosides. (Masters Thesis). Victoria University of Wellington. Retrieved from http://hdl.handle.net/10063/9098

Chicago Manual of Style (16^th Edition):

Li, Ye. “Design and Synthesis of Antiviral Iminoribitol C-Nucleosides.” 2017. Masters Thesis, Victoria University of Wellington. Accessed April 11, 2021. http://hdl.handle.net/10063/9098.

MLA Handbook (7^th Edition):

Li, Ye. “Design and Synthesis of Antiviral Iminoribitol C-Nucleosides.” 2017. Web. 11 Apr 2021.

Vancouver:

Li Y. Design and Synthesis of Antiviral Iminoribitol C-Nucleosides. [Internet] [Masters thesis]. Victoria University of Wellington; 2017. [cited 2021 Apr 11]. Available from: http://hdl.handle.net/10063/9098.

Council of Science Editors:

Li Y. Design and Synthesis of Antiviral Iminoribitol C-Nucleosides. [Masters Thesis]. Victoria University of Wellington; 2017. Available from: http://hdl.handle.net/10063/9098

University of Sydney

3. Tondl, Elisabeth Michelle. Modulating prodrug selectivity for prostate cancer: Design, synthesis, and testing of a modified peptide vehicle .

Degree: 2020, University of Sydney

URL: http://hdl.handle.net/2123/24553

► Precision oncology approaches in prostate cancer treatment offer a complementary approach to genomics by targeting molecular phenotypes of an individual’s cancer, such as membrane transporter… (more)

Subjects/Keywords: prostate cancer; prodrug; peptide; selectivity

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Tondl, E. M. (2020). Modulating prodrug selectivity for prostate cancer: Design, synthesis, and testing of a modified peptide vehicle . (Thesis). University of Sydney. Retrieved from http://hdl.handle.net/2123/24553

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Tondl, Elisabeth Michelle. “Modulating prodrug selectivity for prostate cancer: Design, synthesis, and testing of a modified peptide vehicle .” 2020. Thesis, University of Sydney. Accessed April 11, 2021. http://hdl.handle.net/2123/24553.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Tondl, Elisabeth Michelle. “Modulating prodrug selectivity for prostate cancer: Design, synthesis, and testing of a modified peptide vehicle .” 2020. Web. 11 Apr 2021.

Vancouver:

Tondl EM. Modulating prodrug selectivity for prostate cancer: Design, synthesis, and testing of a modified peptide vehicle . [Internet] [Thesis]. University of Sydney; 2020. [cited 2021 Apr 11]. Available from: http://hdl.handle.net/2123/24553.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Tondl EM. Modulating prodrug selectivity for prostate cancer: Design, synthesis, and testing of a modified peptide vehicle . [Thesis]. University of Sydney; 2020. Available from: http://hdl.handle.net/2123/24553

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

4. Soraya da Silva Santos. Antichagásicos e leishmanicidas potenciais: estudo das condições de síntese de pró-fármacos dendriméricos de 3-hidroxiflavona.

Degree: 2016, University of São Paulo

URL: http://www.teses.usp.br/teses/disponiveis/9/9138/tde-07122016-084358/

►

INTRODUÇÃO: A doença de Chagas e a leishmaniose são doenças tropicais supernegligenciadas, que afetam regiões de extrema pobreza. Os fármacos disponíveis para estas duas doenças… (more)

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INTRODUÇÃO: A doença de Chagas e a leishmaniose são doenças tropicais supernegligenciadas, que afetam regiões de extrema pobreza. Os fármacos disponíveis para estas duas doenças são escassos, de eficácia limitada, de alta toxicidade e suscitam casos de resistência. OBJETIVO: Considerando-se a necessidade de desenvolvimento de novos agentes antichagásicos e leishmanicidas, a importância da latenciação no aprimoramento de fármacos/compostos bioativos e a versatilidade de transportadores dendriméricos, o objetivo deste trabalho foi a síntese de pró-fármacos dendriméricos de primeira geração de 3-hidroxiflavona, composto que apresenta potencial atividade tripanomicida e leishmanicida. Desta forma, pretendeu-se obter liberação controlada, melhora da permeabilidade, toxicidade reduzida e aumento da eficácia deste agente bioativo. MATERIAL E MÉTODOS: Para a obtenção desses dendrímeros empregaram-se as abordagens divergente e convergente, compostas por várias etapas de síntese com reações de proteção, desproteção e acoplamentos. RESULTADOS E DISCUSSÃO: A abordagem convergente apresentou problemas sintéticos, devido à instabilidade dos derivados contendo 3-hidroxiflavona nas diferentes condições reacionais e de purificação testadas. No entanto, há indícios da síntese dos pró-fármacos dendriméricos de 3-hidroxiflavona, mas esses compostos apresentam-se impuros. Devido a essa instabilidade e a dificuldade de purificação na abordagem convergente, optou-se pela síntese divergente, no qual o composto bioativo é acoplado na etapa final. Os estudos sintéticos mostraram a obtenção dos intermediários puros formados pelos focos centrais propano- e hexano-diamina acoplados ao ácido málico protegido. CONCLUSÃO: Há indicativos da obtenção de pró-fármacos dendriméricos de 3-hidroxiflavona, ainda que impuros. As maiores dificuldades encontradas foram a purificação e a estabilidade dos compostos obtidos.

INTRODUCTION: Chagasd́isease and leishmaniasis are super neglected tropical diseases that affect primarily areas of extreme poverty. The drugs available for these diseases are scarce and of limited effectiveness, toxic and rouse resistance. OBJECTIVE: Considering that the development of new antichagasic and leishmanicide agents are urgently needed, the importance of prodrug design to the improvement of drugs and bioactive compounds and the versatility of dendrimers as drug carriers, the objective of this work was the synthesis of dendrimer prodrug of 3-hydroxyflavone, which shows potential antichagasic and leishmanicide activities. Thus, we intended to obtain controlled release, improvement of the permeability, reduction of the toxicity and increase of efficacy of this bioactive agent. MATERIAL AND METHODS: Convergent and divergent approaches have been used to synthesize those compounds. Synthetic steps consist of protection, deprotection and coupling reactions. RESULTS AND DISCUSSION: The convergent approach presented problems due to the instability of the 3-hydroxyflavone derivatives, in different reaction and purification…

Advisors/Committee Members: Elizabeth Igne Ferreira, Reinaldo Camino Bazito, Leoberto Costa Tavares, Carlota de Oliveira Rangel Yagui.

Subjects/Keywords: Dendrímeros; Flavonóides; Latenciação; Pró-fármacos; Dendrimer; Flavonoid; Prodrug; Prodrug design

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Santos, S. d. S. (2016). Antichagásicos e leishmanicidas potenciais: estudo das condições de síntese de pró-fármacos dendriméricos de 3-hidroxiflavona. (Doctoral Dissertation). University of São Paulo. Retrieved from http://www.teses.usp.br/teses/disponiveis/9/9138/tde-07122016-084358/

Chicago Manual of Style (16^th Edition):

Santos, Soraya da Silva. “Antichagásicos e leishmanicidas potenciais: estudo das condições de síntese de pró-fármacos dendriméricos de 3-hidroxiflavona.” 2016. Doctoral Dissertation, University of São Paulo. Accessed April 11, 2021. http://www.teses.usp.br/teses/disponiveis/9/9138/tde-07122016-084358/.

MLA Handbook (7^th Edition):

Santos, Soraya da Silva. “Antichagásicos e leishmanicidas potenciais: estudo das condições de síntese de pró-fármacos dendriméricos de 3-hidroxiflavona.” 2016. Web. 11 Apr 2021.

Vancouver:

Santos SdS. Antichagásicos e leishmanicidas potenciais: estudo das condições de síntese de pró-fármacos dendriméricos de 3-hidroxiflavona. [Internet] [Doctoral dissertation]. University of São Paulo; 2016. [cited 2021 Apr 11]. Available from: http://www.teses.usp.br/teses/disponiveis/9/9138/tde-07122016-084358/.

Council of Science Editors:

Santos SdS. Antichagásicos e leishmanicidas potenciais: estudo das condições de síntese de pró-fármacos dendriméricos de 3-hidroxiflavona. [Doctoral Dissertation]. University of São Paulo; 2016. Available from: http://www.teses.usp.br/teses/disponiveis/9/9138/tde-07122016-084358/

5. Wright, Robert Clay. ADVANCES IN THE DEVELOPMENT OF HIF-1α-ACTIVATED PROTEIN SWITCHES FOR ENZYME PRODRUG THERAPY.

Degree: 2014, Johns Hopkins University

URL: http://jhir.library.jhu.edu/handle/1774.2/37975

► Prevailing approaches for developing cancer protein therapeutics focus on creating proteins that therapeutically modulate a cancer marker’s function. Such an approach limits the therapeutic mechanism… (more)

▼ Prevailing approaches for developing cancer protein therapeutics focus on creating proteins that therapeutically modulate a cancer marker’s function. Such an approach limits the therapeutic mechanism to those that naturally arise from modulation of the cancer marker and precludes the use of cancer markers for which therapeutic modulation is not feasible. Furthermore, many potential protein therapies lack the desired cancer targeting. The ability to link recognition of any cancer marker with activation of any desired therapeutic function would enormously expand the number of possible protein therapeutics. We have previously engineered a switchable prodrug-activating enzyme that selectively kills human cancer cells that accumulate the cancer marker hypoxia-inducible factor 1α (HIF-1α). This HIF-1α-activated enzyme switch (Haps59) was created by fusing the prodrug-converting enzyme yeast cytosine deaminase (yCD) and the CH1 domain of the p300 protein, which binds HIF-1α. Haps59 autonomously increases its ability to convert the prodrug 5-fluorcytosine (5FC) into the chemotherapeutic 5-fluorouracil (5FU) in a HIF-1α-dependent manner, rendering colon and breast cancer cells more susceptible to the prodrug. However, the difference in 5FC sensitivity between the presence and absence of HIF-1α was not as large as desired. Using a variety of mutagenesis methods, followed by a two-tiered genetic selection for improved switches, we have identified new HIF-1α-activated enzymes that confer E. coli with modest increases in HIF-1α-dependent 5FC toxicity. However, the current bottleneck in further translation of HIF-1α-activated protein switches is screening potential switch candidates in mammalian cells. To accommodate higher throughput, we explored the use of Flp recombinase-mediated isogenic integration. While initial results in this system are promising, these experiments also brought to light the disadvantageous promiscuous binding activity of the CH1 domain, which we further confirmed in E. coli. This promiscuous binding and subsequent off-target activation needs to be examined under normal physiological conditions to pinpoint off-target activity in these potential therapeutics. With relevant aberrant activators identified, further directed evolution can be used to improve the cancer specificity of HIF-1α-activated protein switches. Advisors/Committee Members: Townsend, Craig A (advisor).

Subjects/Keywords: Enzyme Prodrug Therapy; Protein Engineering; Cancer Therapy

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APA (6^th Edition):

Wright, R. C. (2014). ADVANCES IN THE DEVELOPMENT OF HIF-1α-ACTIVATED PROTEIN SWITCHES FOR ENZYME PRODRUG THERAPY. (Thesis). Johns Hopkins University. Retrieved from http://jhir.library.jhu.edu/handle/1774.2/37975

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Wright, Robert Clay. “ADVANCES IN THE DEVELOPMENT OF HIF-1α-ACTIVATED PROTEIN SWITCHES FOR ENZYME PRODRUG THERAPY.” 2014. Thesis, Johns Hopkins University. Accessed April 11, 2021. http://jhir.library.jhu.edu/handle/1774.2/37975.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Wright, Robert Clay. “ADVANCES IN THE DEVELOPMENT OF HIF-1α-ACTIVATED PROTEIN SWITCHES FOR ENZYME PRODRUG THERAPY.” 2014. Web. 11 Apr 2021.

Vancouver:

Wright RC. ADVANCES IN THE DEVELOPMENT OF HIF-1α-ACTIVATED PROTEIN SWITCHES FOR ENZYME PRODRUG THERAPY. [Internet] [Thesis]. Johns Hopkins University; 2014. [cited 2021 Apr 11]. Available from: http://jhir.library.jhu.edu/handle/1774.2/37975.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Wright RC. ADVANCES IN THE DEVELOPMENT OF HIF-1α-ACTIVATED PROTEIN SWITCHES FOR ENZYME PRODRUG THERAPY. [Thesis]. Johns Hopkins University; 2014. Available from: http://jhir.library.jhu.edu/handle/1774.2/37975

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of Iowa

6. Shippy, Rebekah Ruth. Synthesis of phosphoantigens and chiral trisphosphonates.

Degree: PhD, Chemistry, 2016, University of Iowa

URL: https://ir.uiowa.edu/etd/5632

► Phosphorus is an element that is essential for life, and is used in the synthesis of many proteins, carbohydrates and deoxyribonucleic acids. Phosphorus often… (more)

▼ Phosphorus is an element that is essential for life, and is used in the synthesis of many proteins, carbohydrates and deoxyribonucleic acids. Phosphorus often exists in the form of phosphate when found in the biological systems. Clinical development of possible pharmaceutical agents have used phosphorus in the form of phosphonates to increase the metabolic stability of the potential drug. Some of these phosphonates target the isoprenoid biosynthetic pathway (IBP). The IBP plays an important role in the synthesis of cholesterol and in other aspects of cellular metabolism. The enzymes of the IBP have been the target of possible therapeutic agents for treatment of multiple diseases, including cancer. Often these phosphonic acids are masked by an enzymatically cleavable group in order to increase their bioavailability and activity. Phosphoantigens are small organo-phosphorus molecules that stimulate the expansion of Vγ9Vδ2 T-cells which detect and eliminate infected cells. Both natural and non-natural phosphoantigens have exhibited a wide range of effective concentrations (EC50) for γδ T-cells. The most potent phosphoantigen is E-4-hydroxy-3-methylbut-2-enyl pyrophosphate (HMBPP), which is an intermediate in the bacterial IBP. Nanomolar concentration of this compound stimulate T-cell proliferation. While HMBPP is highly potent, it undergoes rapid decomposition when injected into the blood stream. Synthesis of more stable phosphonate analogues can show better activity for expansion of the γδ T-cell population. Increased activity was observed in T-cell assays after masking the phosphonic acids to increase the bioavailability of the active phosphoantigen. Because some phosphoantigen showed strong activity with masked phosphonic acids, families of phosphonate analogues now have been prepared. Most use selenium dioxide mediated oxidation to incorporate the terminal alcohol and ester exchange to provide prodrugs to study the structure-activity-relationships. The biological activity of these compounds has been investigated and new phosphoantigens were shown to be strong activators of γδ T-cells. Furthermore, the phosphoantigens have been shown to bind to the protein butyrophilin 3A1 (BTN3A1) at an intracellular domain. A second family of phosphoantigen derivatives, masked by a new pH fluorescent cell-cleavable ester, were prepared and tested by our collaborators to explore the compounds’ activity and to investigate the mechanism of action. Finally, a new class of phosphorus compounds alkyl 1, 1, 1-trisphosphonates has been studied to obtain salts that might be biologically active. Trisphosphonates contain a unique arrangement of phosphonate groups on a single carbon and could provide charge states unseen in the more traditional bisphosphonates. A general route to asymmetric trisphosphonates through a step-wise phosphorylation of each phosphonate has been developed. Selective phosphonate ester cleavage would allow for the ability to obtain a multitude of charge states and possible biological activity.… Advisors/Committee Members: Wiemer, David F. (supervisor).

Subjects/Keywords: Fluorescent; Phosphoanitgens; Phosphonates; Prodrug; Trisphosphonates; Chemistry

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Shippy, R. R. (2016). Synthesis of phosphoantigens and chiral trisphosphonates. (Doctoral Dissertation). University of Iowa. Retrieved from https://ir.uiowa.edu/etd/5632

Chicago Manual of Style (16^th Edition):

Shippy, Rebekah Ruth. “Synthesis of phosphoantigens and chiral trisphosphonates.” 2016. Doctoral Dissertation, University of Iowa. Accessed April 11, 2021. https://ir.uiowa.edu/etd/5632.

MLA Handbook (7^th Edition):

Shippy, Rebekah Ruth. “Synthesis of phosphoantigens and chiral trisphosphonates.” 2016. Web. 11 Apr 2021.

Vancouver:

Shippy RR. Synthesis of phosphoantigens and chiral trisphosphonates. [Internet] [Doctoral dissertation]. University of Iowa; 2016. [cited 2021 Apr 11]. Available from: https://ir.uiowa.edu/etd/5632.

Council of Science Editors:

Shippy RR. Synthesis of phosphoantigens and chiral trisphosphonates. [Doctoral Dissertation]. University of Iowa; 2016. Available from: https://ir.uiowa.edu/etd/5632

University of Manitoba

7. Liang, Dinghua. Progress towards hypoxia-activated SN-38: the potential to target hypoxic tumors.

Degree: Pharmacy, 2015, University of Manitoba

URL: http://hdl.handle.net/1993/31591

► Solid tumors are commonly subject to hypoxia. Hypoxic cancer cells have undesirable properties such as a high tendency to metastasize and resistance to chemotherapy and… (more)

Subjects/Keywords: Hypoxia; Prodrug; Targeted chemotherapy; Bioreductive; Antineoplastic agents

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Liang, D. (2015). Progress towards hypoxia-activated SN-38: the potential to target hypoxic tumors. (Masters Thesis). University of Manitoba. Retrieved from http://hdl.handle.net/1993/31591

Chicago Manual of Style (16^th Edition):

Liang, Dinghua. “Progress towards hypoxia-activated SN-38: the potential to target hypoxic tumors.” 2015. Masters Thesis, University of Manitoba. Accessed April 11, 2021. http://hdl.handle.net/1993/31591.

MLA Handbook (7^th Edition):

Liang, Dinghua. “Progress towards hypoxia-activated SN-38: the potential to target hypoxic tumors.” 2015. Web. 11 Apr 2021.

Vancouver:

Liang D. Progress towards hypoxia-activated SN-38: the potential to target hypoxic tumors. [Internet] [Masters thesis]. University of Manitoba; 2015. [cited 2021 Apr 11]. Available from: http://hdl.handle.net/1993/31591.

Council of Science Editors:

Liang D. Progress towards hypoxia-activated SN-38: the potential to target hypoxic tumors. [Masters Thesis]. University of Manitoba; 2015. Available from: http://hdl.handle.net/1993/31591

University of Minnesota

8. Rautiola, Davin. Two-Part Reactive Formulations for Intranasal Delivery of Benzodiazepines.

Degree: PhD, Pharmaceutics, 2019, University of Minnesota

URL: http://hdl.handle.net/11299/208986

► A seizure emergency occurs when an individual experiences a seizure that lasts for more than five minutes (status epilepticus) or multiple distinct seizures with incomplete… (more)

▼ A seizure emergency occurs when an individual experiences a seizure that lasts for more than five minutes (status epilepticus) or multiple distinct seizures with incomplete recovery between them (acute repetitive seizures). A patient experiencing a seizure emergency must be treated as quickly as possible to avoid lasting neurological damage and other life-threatening complications. Benzodiazepines are the primary rescue medications used to treat seizure emergencies, the most commonly used being intravenous lorazepam or rectal diazepam. Despite the effectiveness of these drugs, the delivery routes are not ideal for first-line, outpatient treatments. A skilled caregiver must be present to administer drugs intravenously, and the social stigma associated with rectal administration results in low compliance. Intranasal delivery is an attractive alternative because it requires little training, is easily performed by non-medical personnel, carries a low risk of injury to the patient, and can provide a rapid therapeutic effect. However, formulating a benzodiazepine nasal spray is challenging because these drugs have very low aqueous solubilities. One strategy to circumvent solubility issues relies on in situ production of drug from co-administration of soluble reactants. Herein, we describe how a prodrug/enzyme reaction or an acid/base reaction can be used to deliver a benzodiazepine in an aqueous vehicle with a volume and pH appropriate for intranasal administration. When the soluble components of these two-part reactive formulations are mixed at the time of administration, a metastable supersaturated solution of the benzodiazepine is produced. The supersaturated state of the benzodiazepine provides a large chemical activity gradient for rapid absorption across the nasal mucosa and into systemic circulation. In vitro characterization of the reaction kinetics and supersaturation behaviors for diazepam prodrug/enzyme reactions, midazolam prodrug/enzyme reactions, and midazolam acid/base reactions demonstrated that these two-part formulations generate predictable levels of supersaturated drug. An in vivo pharmacokinetic study in rats showed that rapid absorption and high bioavailability of diazepam results from intranasal administration of a diazepam prodrug/enzyme formulation. Furthermore, a dual chamber nasal spray device capable of mixing and atomizing the components of a two-part formulation was designed, prototyped, and tested. These two-part reactive formulations, coupled with the specialized nasal spray device, exemplify a new intranasal drug delivery strategy that may be applicable to a variety of other drugs with poor stability or low solubility.

Subjects/Keywords: benzodiazepines; intranasal; metastable; prodrug; solubility; supersaturated

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Rautiola, D. (2019). Two-Part Reactive Formulations for Intranasal Delivery of Benzodiazepines. (Doctoral Dissertation). University of Minnesota. Retrieved from http://hdl.handle.net/11299/208986

Chicago Manual of Style (16^th Edition):

Rautiola, Davin. “Two-Part Reactive Formulations for Intranasal Delivery of Benzodiazepines.” 2019. Doctoral Dissertation, University of Minnesota. Accessed April 11, 2021. http://hdl.handle.net/11299/208986.

MLA Handbook (7^th Edition):

Rautiola, Davin. “Two-Part Reactive Formulations for Intranasal Delivery of Benzodiazepines.” 2019. Web. 11 Apr 2021.

Vancouver:

Rautiola D. Two-Part Reactive Formulations for Intranasal Delivery of Benzodiazepines. [Internet] [Doctoral dissertation]. University of Minnesota; 2019. [cited 2021 Apr 11]. Available from: http://hdl.handle.net/11299/208986.

Council of Science Editors:

Rautiola D. Two-Part Reactive Formulations for Intranasal Delivery of Benzodiazepines. [Doctoral Dissertation]. University of Minnesota; 2019. Available from: http://hdl.handle.net/11299/208986

Louisiana State University

9. Batton, Chyree Shantel. Synthetic Routes to Therapeutic Agents Via Masked Functionalities: From Orthogonal Peptide Crosslink to Photothermal Cancer Prodrug.

Degree: PhD, Chemistry, 2014, Louisiana State University

URL: etd-11172014-152711 ; https://digitalcommons.lsu.edu/gradschool_dissertations/1176

► The theonellamides are a family of compounds distinguished by their crosslinking ô-histidinoalanine (ô-HAL) residue. Part one of this dissertation details the synthesis of an orthogonally… (more)

▼ The theonellamides are a family of compounds distinguished by their crosslinking ô-histidinoalanine (ô-HAL) residue. Part one of this dissertation details the synthesis of an orthogonally protected ô-HAL building block that will be incorporated into a total synthesis of theonellamide C. Selective deprotection of each amine and acid of this orthogonally protected building block is also demonstrated. Various reaction partners for the assembly of ô-histidinoalanine were explored. One approach involved the coupling of N-Fmoc-â-iodoalanine benzyl ester and (Nðim)-blocked histidine nucleophiles including a fused bicyclic urea and a Boc-His(Nð-Pac)-OMe. While the imidazolium salts were identified by mass spectrometry, elimination of the iodide group was a major side reaction. Successful nucleophilic opening of a five-membered ring sulfamidate (derived from Fmoc-D-Ser-OH) by Boc-L-His-OTCE led to preparation of a regiochemically and stereochemically pure ô-HAL derivative. Thus, a new set of orthogonal protecting groups have been identified: Fluorenylmethyloxycarbonyl (Fmoc), 2,2,2-trichloroethylester (TCE), tert-butyl carbamate (Boc), and benzyl (Bn) ester. Part two of this dissertation outlines the synthesis of a trimethyl lock-based prodrug model system, wherein photothermal activation of a salt containing a cationic near-IR dye and an anionic prodrug, releases a paclitaxel side-chain fragment via a tandem aryl Claisen rearrangement and lactonization. The prodrug model system was prepared via coupling of the paclitaxel sidechain alcohol to an acid with a pendant substrate for the rearrangement-lactonization. Claisen rearrangement studies in various solvent systems on the release of the paclitaxel fragment demonstrated that aqueous alcoholic solutions of allyl aryl ethers accelerated the rearrangement relative to hydrocarbon solvents, temperatures achieved were still too high to be feasible in biological systems. The 1,1-dimethylallyl group was identified for its rate-accelerating properties. Studies of the Claisen rearrangement in aqueous methanol demonstrated that the aryl dimethylallyl ether derivatives rearranged significantly faster than the unsubstituted allyl ethers. Moreover, electron donating groups facilitated the reaction. A salt was formed from a cationic near-IR laser dye (IR-780) and 1-(1,1-dimethylallyl ether)-4-benzoic acid, then suspended as nanoparticles in water. Photothermal studies of these aggregated species are underway.

Subjects/Keywords: Histidinoalanine; GUMBOS; nanoparticles; photothermal; prodrug; orthogonal

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Batton, C. S. (2014). Synthetic Routes to Therapeutic Agents Via Masked Functionalities: From Orthogonal Peptide Crosslink to Photothermal Cancer Prodrug. (Doctoral Dissertation). Louisiana State University. Retrieved from etd-11172014-152711 ; https://digitalcommons.lsu.edu/gradschool_dissertations/1176

Chicago Manual of Style (16^th Edition):

Batton, Chyree Shantel. “Synthetic Routes to Therapeutic Agents Via Masked Functionalities: From Orthogonal Peptide Crosslink to Photothermal Cancer Prodrug.” 2014. Doctoral Dissertation, Louisiana State University. Accessed April 11, 2021. etd-11172014-152711 ; https://digitalcommons.lsu.edu/gradschool_dissertations/1176.

MLA Handbook (7^th Edition):

Batton, Chyree Shantel. “Synthetic Routes to Therapeutic Agents Via Masked Functionalities: From Orthogonal Peptide Crosslink to Photothermal Cancer Prodrug.” 2014. Web. 11 Apr 2021.

Vancouver:

Batton CS. Synthetic Routes to Therapeutic Agents Via Masked Functionalities: From Orthogonal Peptide Crosslink to Photothermal Cancer Prodrug. [Internet] [Doctoral dissertation]. Louisiana State University; 2014. [cited 2021 Apr 11]. Available from: etd-11172014-152711 ; https://digitalcommons.lsu.edu/gradschool_dissertations/1176.

Council of Science Editors:

Batton CS. Synthetic Routes to Therapeutic Agents Via Masked Functionalities: From Orthogonal Peptide Crosslink to Photothermal Cancer Prodrug. [Doctoral Dissertation]. Louisiana State University; 2014. Available from: etd-11172014-152711 ; https://digitalcommons.lsu.edu/gradschool_dissertations/1176

University of Georgia

10. Israel, Bridg'ette Beatrice. Topical formulations for disease treatment.

Degree: 2014, University of Georgia

URL: http://hdl.handle.net/10724/26359

► Purpose: Develop a bioadhesive formulation for the treatment of aquatic life with skin lesions or abrasions. The purpose of the second research project is to… (more)

▼ Purpose: Develop a bioadhesive formulation for the treatment of aquatic life with skin lesions or abrasions. The purpose of the second research project is to develop novel mutual prodrugs (MP) which couple n-acetyl-glucosamine with NSAID, either ketoprofen or ibuprofen. These mutual prodrugs are designed to aid in the treatment of osteoarthritis. Lastly, the transdermal permeability of N-Acetyl-D-Glucosamine is evaluated for the development of the mutual prodrug. Methods: For research project one, oleaginous gels were prepared and their viscosity measurements were taken with a rheometer to gain information pertaining to the bioadhesive forces present in each formulation. The mutual prodrugs are synthesized for project two. One mutual prodrug links n-acetyl-glucosamine to ketoprofen and the other links n-acetyl-glucosamine to ibuprofen. N-Acetyl-D-Glucosamine solutions were prepared at different concentrations for the third project. Enhancing agents were also incorporated to evaluate their influence on permeability of N-Acetyl-D-Glucosamine. The Franz cell apparatus and High Performance Liquid Chromatography were utilized to collect and analyze samples, respectively. Results: The findings of project one are as follows, gels prepared with safflower oil and wheat germ oil demonstrated the greatest viscosity and perceived bioadhesion when compared to the other gels and all controls. The gel prepared with both safflower oil and wheat germ oil provided the largest inhibition zone. The structure of the oil may be important since both safflower oil and wheat germ oil contain linoleic and linolenic acids, whereas olive oil contains mostly oleic acid. Permeability studies, of project two, show that the ketoprofen mutual prodrug permeates shed snakeskin more than three times greater than either ibuprofen derivative, while ethanol markedly increases the permeation for all three. It was determined, for project three, that the permeability coefficients of the phosphate buffer/ethanol solutions at 5%, 10%, and 25% were about threefold larger in value as those for saturated DMSO solution, whereas the 2% and 50% solution values were lower. Conclusion: The bioadhesive gel prepared with safflower oil showed greatest stickiness to chicken breast, greatest viscosity, and best antimicrobial release (for project one). It was concluded, from the results of project two, that the ketoprofen mutual prodrug appears the most likely candidate for transdermal administration; the ibuprofen mutual prodrugs for oral delivery; all three mutual prodrugs may be candidates for oral delivery or subcutaneous injection. The permeability coefficients calculated, during project three, supports the idea that phosphate buffer/ethanol solutions at 5%, 10%, and 25% are the optimal candidates for formulation while phosphate buffer/ethanol solutions at 2%, 50% contains too little ethanol and saturation has been reached, respectively.

Subjects/Keywords: Bioadhesion; Oleaginous; Transdermal Permeation; Mutual Prodrug; NSAID

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Israel, B. B. (2014). Topical formulations for disease treatment. (Thesis). University of Georgia. Retrieved from http://hdl.handle.net/10724/26359

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Israel, Bridg'ette Beatrice. “Topical formulations for disease treatment.” 2014. Thesis, University of Georgia. Accessed April 11, 2021. http://hdl.handle.net/10724/26359.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Israel, Bridg'ette Beatrice. “Topical formulations for disease treatment.” 2014. Web. 11 Apr 2021.

Vancouver:

Israel BB. Topical formulations for disease treatment. [Internet] [Thesis]. University of Georgia; 2014. [cited 2021 Apr 11]. Available from: http://hdl.handle.net/10724/26359.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Israel BB. Topical formulations for disease treatment. [Thesis]. University of Georgia; 2014. Available from: http://hdl.handle.net/10724/26359

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

11. Ball, Patrick. Identification and testing of enzymes and prodrugs for use in directed enzyme prodrug therapy strategies for the treatment of cancer.

Degree: PhD, 2019, Bangor University

URL: https://research.bangor.ac.uk/portal/en/theses/identification-and-testing-of-enzymes-and-prodrugs-for-use-in-directed-enzyme-prodrug-therapy-strategies-for-the-treatment-of-cancer(c07f9470-fc01-4ef9-8e23-426f320c3abd).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.793161

► Cancer is one of the leading causes of death worldwide and improving the efficacy of cancer chemotherapy treatments is one of the most pressing issues… (more)

▼ Cancer is one of the leading causes of death worldwide and improving the efficacy of cancer chemotherapy treatments is one of the most pressing issues of the day. Prodrugs hold great promise in that regard as they can be activated selectively, allowing for a more focused treatment strategy than with conventional chemotherapy drugs. Directed enzyme prodrug therapy (DEPT) is a form of cancer chemotherapy that is being developed to utilise prodrugs in combination with prodrug-activating enzymes which would be selectively delivered to a tumour site prior to prodrug administration to allow prodrug activation to occur only at the cancer site. Current DEPT strategies have their own inherent flaws based on the biological methods being used to deliver the prodrug-activating enzymes to the tumour site. Magnetic nanoparticle directed enzyme prodrug therapy (MNDEPT) is a novel approach that is being developed within our research group that seeks to overcome these problems by using gold-coated magnetic nanoparticles as the enzyme delivery system. In this study, the suitability of several enzymes and prodrugs for use in future MNDEPT treatments were tested. The study assessed a range of enzymes including two novel nitroreductases from Bacillus cereus, two Xenobiotic reductases from Pseudomonas putida and two genetically modified nitroreductases previously developed within our research group. The prodrug candidates tested were the heavily investigated nitroreductase prodrug, CB1954, and two forefront dinitrobenzamide mustard prodrugs, PR-104A and SN27686. Several enzyme/prodrug combinations tested were identified as being promising for use in future DEPT treatments, including 1619-his with CB1954, XenB-cys with CB1954 and YfkO-cys with PR-104A. The YfkO-cys/PR-104A combination was of particular promise as it displayed a Michaelis-Menten kinetic efficiency that is nearly three times greater than that shown by the heavily investigated NfnB/CB1954 combination, which displayed limited clinical performance because of the low turnover rate of CB1954 by NfnB. Furthermore, a new method of assessing the ratio of the hydroxylamine products formed from the enzymatic reduction of CB1954 using HPLC has been identified and is reported within this body of work. Building on this, new revelations about how the product ratio changes over time have come to light and this has proven that kinetics-driven changes to the product ratio can occur as the reaction proceeds over time and this is reported here.

Subjects/Keywords: 500; Nitroreductase; Prodrug; Cancer; Dept; HPCC

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Ball, P. (2019). Identification and testing of enzymes and prodrugs for use in directed enzyme prodrug therapy strategies for the treatment of cancer. (Doctoral Dissertation). Bangor University. Retrieved from https://research.bangor.ac.uk/portal/en/theses/identification-and-testing-of-enzymes-and-prodrugs-for-use-in-directed-enzyme-prodrug-therapy-strategies-for-the-treatment-of-cancer(c07f9470-fc01-4ef9-8e23-426f320c3abd).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.793161

Chicago Manual of Style (16^th Edition):

Ball, Patrick. “Identification and testing of enzymes and prodrugs for use in directed enzyme prodrug therapy strategies for the treatment of cancer.” 2019. Doctoral Dissertation, Bangor University. Accessed April 11, 2021. https://research.bangor.ac.uk/portal/en/theses/identification-and-testing-of-enzymes-and-prodrugs-for-use-in-directed-enzyme-prodrug-therapy-strategies-for-the-treatment-of-cancer(c07f9470-fc01-4ef9-8e23-426f320c3abd).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.793161.

MLA Handbook (7^th Edition):

Ball, Patrick. “Identification and testing of enzymes and prodrugs for use in directed enzyme prodrug therapy strategies for the treatment of cancer.” 2019. Web. 11 Apr 2021.

Vancouver:

Ball P. Identification and testing of enzymes and prodrugs for use in directed enzyme prodrug therapy strategies for the treatment of cancer. [Internet] [Doctoral dissertation]. Bangor University; 2019. [cited 2021 Apr 11]. Available from: https://research.bangor.ac.uk/portal/en/theses/identification-and-testing-of-enzymes-and-prodrugs-for-use-in-directed-enzyme-prodrug-therapy-strategies-for-the-treatment-of-cancer(c07f9470-fc01-4ef9-8e23-426f320c3abd).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.793161.

Council of Science Editors:

Ball P. Identification and testing of enzymes and prodrugs for use in directed enzyme prodrug therapy strategies for the treatment of cancer. [Doctoral Dissertation]. Bangor University; 2019. Available from: https://research.bangor.ac.uk/portal/en/theses/identification-and-testing-of-enzymes-and-prodrugs-for-use-in-directed-enzyme-prodrug-therapy-strategies-for-the-treatment-of-cancer(c07f9470-fc01-4ef9-8e23-426f320c3abd).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.793161

University of Sydney

12. Chen, Catherine. The Design and Synthesis of Stabilised Cis- and Trans-Platinum (IV) Complexes for Targeted Drug Delivery .

Degree: 2016, University of Sydney

URL: http://hdl.handle.net/2123/16513

► Platinum(IV) complexes are a promising class of pro-drugs which may bypass the problems associated with their platinum(II) counterparts, such as cisplatin and oxaliplatin. However, any… (more)

▼ Platinum(IV) complexes are a promising class of pro-drugs which may bypass the problems associated with their platinum(II) counterparts, such as cisplatin and oxaliplatin. However, any pharmacokinetic advantages conferred by the platinum(IV) oxidation state are often lost due to the rapid reduction of these complexes en route to the tumour site. Despite several platinum(IV) complexes, such as satraplain, undergoing extensive clinical trials, no platinum(IV) complexes have been approved for clinical use to date. Recently, platinum(IV) complexes with a cis-diamminetetracarboxylato coordination sphere were shown to exhibit unusual resistance to reduction by L-ascorbate that did not correlate with their electrochemical reduction potential. In this study, we further investigated the influence of the overall coordination and geometry of platinum(IV) complexes on their resistance to reduction in a range of endogenous and biological reductants and biological environments using various spectroscopic and biological techniques such as XANES, SXFM, XRF μCT, 1D and 2D NMR and GF-AAS. We report the resistance to reduction exhibited by cis and trans-diamminetetracarboxylato platinum(IV) complexes, using 1H NMR and XANES spectroscopy. Interestingly, this class of platinum(IV) complex appears to be usually resistant to reduction in the presence of excess endogenous reductants, but are rapidly reduced within DLD-1 human colon cancer cells. A series of 13C labelled platinum(IV) complexes with various coordination spheres and geometries were synthesised. The reduction of these complexes by aqueous cellular extracts of DLD-1 cells were observed to undergo several reduction pathways. Finally, we report several design and synthetic strategies for the development of targeted drug delivery for classical and non-classical platinum(IV) pro-drugs that can potentially bypass uptake and reduction by red blood cells and selectively deliver platinum(IV) complexes to specific tumour environments.

Subjects/Keywords: platinum; drug design; cancer; tumour; prodrug; chemotherapy

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APA (6^th Edition):

Chen, C. (2016). The Design and Synthesis of Stabilised Cis- and Trans-Platinum (IV) Complexes for Targeted Drug Delivery . (Thesis). University of Sydney. Retrieved from http://hdl.handle.net/2123/16513

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Chen, Catherine. “The Design and Synthesis of Stabilised Cis- and Trans-Platinum (IV) Complexes for Targeted Drug Delivery .” 2016. Thesis, University of Sydney. Accessed April 11, 2021. http://hdl.handle.net/2123/16513.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Chen, Catherine. “The Design and Synthesis of Stabilised Cis- and Trans-Platinum (IV) Complexes for Targeted Drug Delivery .” 2016. Web. 11 Apr 2021.

Vancouver:

Chen C. The Design and Synthesis of Stabilised Cis- and Trans-Platinum (IV) Complexes for Targeted Drug Delivery . [Internet] [Thesis]. University of Sydney; 2016. [cited 2021 Apr 11]. Available from: http://hdl.handle.net/2123/16513.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Chen C. The Design and Synthesis of Stabilised Cis- and Trans-Platinum (IV) Complexes for Targeted Drug Delivery . [Thesis]. University of Sydney; 2016. Available from: http://hdl.handle.net/2123/16513

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of Vienna

13. Bielec, Björn. Entwicklung neuer Prodrug-Strategien für die Krebstherapie.

Degree: 2015, University of Vienna

URL: http://othes.univie.ac.at/39218/

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Trotz großer Fortschritte in der Entwicklung von Krebstherapeutika in den letzten Jahrzehnten, leiden viele Patienten nach wie vor unter drastischen Nebenwirkungen. Eine Möglichkeit die Nebenwirkungen… (more)

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Trotz großer Fortschritte in der Entwicklung von Krebstherapeutika in den letzten Jahrzehnten, leiden viele Patienten nach wie vor unter drastischen Nebenwirkungen. Eine Möglichkeit die Nebenwirkungen eines Wirkstoffs zu mindern, bietet das sogenannte Prodrug-Konzept. Dabei wird ein Therapeutikum chemisch deaktiviert und erst selektiv im Tumorgewebe wieder aktiviert. Eine solche Prodrug besteht normalerweise aus drei Einheiten: dem Trigger, der die spezifische Aktivierung des Wirkstoffs ermöglicht, einem Linker und dem Wirkstoff selbst. Diese Masterarbeit beschäftigt sich mit zwei Themen. Ersteres ist die Entwicklung eines neuen Konzepts für cathepsin-selektive Triggereinheiten. Cathepsine sind proteolytische Enzyme, welche in diversen Tumorarten überexprimiert werden. Trotz der großen Vielfalt von Cathepsinen existieren derzeit allerdings nur Triggereinheiten für Cathepsin B. Das neue Konzept umfasst den Einbau hochspezifischer Inhibitorfragmente in die Triggereinheiten, welche dann über selbstzerstörende Linker an einen Wirkstoff gebunden werden. Dieses Konzept wurde in dieser Masterarbeit für Cathepsin K umgesetzt, ein Enzym, das in Metastasen von Brust- und Darmkrebspatieten exprimiert wird. Dazu wurde in 11 Stufen eine modifizierte Inhibitoreinheit über einen selbstzerstörenden para-Aminobenzylalkohol-Linker an einen Fluorophor gebunden. Die synthetisierte Prodrug wurde mittels NMR-Spektroskopie und Massenspektrometrie charakterisiert und die Freisetzung des Fluorophors mittels Fluoreszenzspektroskopie untersucht. Das zweite Thema dieser Masterarbeit beschäftigt sich mit der Entwicklung einer Prodrug des anablastic lymphoma kinase (ALK)-Inhibitors Crizotinib. Diese Verbindung ist bereits klinisch zur Behandlung von nichtkleinzelligen Bronchialkarzinomen zugelassen, zeigt jedoch stark leberschädigende und gastrointestinale Nebenwirkungen. Daher wurde an der entscheidenden Stelle für die Bindung zwischen Wirkstoff und Enzym eine Trigger-Einheit implementiert. Die Freisetzung des Wirkstoffs aus der synthetisierten Prodrug wurde mittels HPLC-Messungen untersucht.

Despite the great progress in cancer treatment over the last decades, most patients still suffer from severe side effects during cancer therapy. One approach to decrease these side effects is the design of so-called tumor activatable prodrugs. Thus, a deactivated drug species is applied and specifically activated inside the tumor tissue. This type of prodrugs usually consists of three different moieties: a trigger unit which enables the selective release of the drug, a linker unit and the anti-cancer drug. This master thesis focused on two topics. The first topic is the development of a novel trigger system specific for cathepsin activation. Cathepsins are proteolytic enzymes which are known to be overexpressed in various types of cancer. Interestingly, despite the high number of different cathepsins, prodrug systems are currently only known for cathepsin B. The new concept comprises the use of highly specific fragments of cathepsin inhibitors as…

Subjects/Keywords: 35.79 Biochemie: Sonstiges; 35.50 Organische Chemie: Allgemeines; 35.62 Aminosäuren, Peptide, Eiweiße; 35.52 Präparative Organische Chemie; Prodrug-Design / Prodrug / Cathepsin / Cathepsin K / Trigger / selektive Triggereinheit / Crizotinib / Crizotinib-Prodrug; prodrug design / prodrug / cathepsin / cathepsin K / trigger / selective trigger moiety / crizotinib / crizotinib prodrug

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Bielec, B. (2015). Entwicklung neuer Prodrug-Strategien für die Krebstherapie. (Thesis). University of Vienna. Retrieved from http://othes.univie.ac.at/39218/

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Bielec, Björn. “Entwicklung neuer Prodrug-Strategien für die Krebstherapie.” 2015. Thesis, University of Vienna. Accessed April 11, 2021. http://othes.univie.ac.at/39218/.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Bielec, Björn. “Entwicklung neuer Prodrug-Strategien für die Krebstherapie.” 2015. Web. 11 Apr 2021.

Vancouver:

Bielec B. Entwicklung neuer Prodrug-Strategien für die Krebstherapie. [Internet] [Thesis]. University of Vienna; 2015. [cited 2021 Apr 11]. Available from: http://othes.univie.ac.at/39218/.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Bielec B. Entwicklung neuer Prodrug-Strategien für die Krebstherapie. [Thesis]. University of Vienna; 2015. Available from: http://othes.univie.ac.at/39218/

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of New Mexico

14. Cao, Yanting. Development of Novel Small Molecules for Imaging and Drug Release.

Degree: Department of Chemistry and Chemical Biology, 2014, University of New Mexico

URL: https://digitalrepository.unm.edu/chem_etds/36

► Small organic molecules, including small molecule based fluorescent probes, small molecule based drugs or prodrugs, and smart multifunctional fluorescent drug delivery systems play important roles… (more)

▼ Small organic molecules, including small molecule based fluorescent probes, small molecule based drugs or prodrugs, and smart multifunctional fluorescent drug delivery systems play important roles in biological research, drug discovery, and clinical practices. Despite the significant progress made in these fields, the development of novel and diverse small molecules is needed to meet various demands for research and clinical applications. My Ph.D study focuses on the development of novel functional molecules for recognition, imaging and drug release. In the first part, a turn-on fluorescent probe is developed for the detection of intracellular adenosine-5'-triphosphate (ATP) levels based on multiplexing recognitions. Considering the unique and complicated structure of ATP molecules, a fluorescent probe has been implemented with improved sensitivity and selectivity due to two synergistic binding recognitions by incorporating of 2, 2'-dipicolylamine (Dpa)-Zn(II) for targeting of phospho anions and phenylboronic acid group for cis-diol moiety. The novel probe is able to detect intracellular ATP levels in SH-SY5Y cells. Meanwhile, the advantages of multiplexing recognition design concept have been demonstrated using two control molecules. In the second part, a prodrug system is developed to deliver multiple drugs within one small molecule entity. The prodrug is designed by using 1-(2-nitrophenyl)ethyl (NPE) as phototrigger, and biphenol biquaternary ammonium as the prodrug. With controlled photo activation, both DNA cross-linking agents mechlorethamine and o-quinone methide are delivered and released at the preferred site, leading to efficient DNA cross-links formation and cell death. The prodrug shows negligible cytotoxicity towards normal skin cells (Hekn cells) with and without UV activation, but displays potent activity towards cancer cells (HeLa cells) upon UV activation. The multiple drug release system may hold a great potential for practical application. In the last part, a new photo-initiated fluorescent anticancer prodrug for DNA alkylating agent mechlorethamine releasing and monitoring has been developed. The theranostic prodrug consists a photolabile NPE group, an inactive form of mechlorethamine and a nonfluorescent coumarin in one small molecule. It is demonstrated that the prodrug shows negligible cytotoxicity towards normal skin cells (Hekn cells) with and without UV activation, while the original parent drug mechlorethamine can be photocontrol-released and induces effective DNA cross-linking activity. Importantly, the drug release progress can be conveniently monitored by the 'off-on' fluorescence enhancement in cells. Moreover, the selective prodrug is not only cell permeable but also nuclear permeable. Therefore, the prodrug serves as a promising drug delivery system for spatiotemporal control release and monitoring of an anticancer drug to obtain the optimal treatment efficacy. Advisors/Committee Members: Wang, Wei, Wang, Wei, Qin, Yang, Melancon, Charles, Feng, Changjian.

Subjects/Keywords: anticancer prodrug; DNA cross-linking; drug delivery system; drug release; fluorescent imaging; fluorescent probe; mechlorethamine; multiple drugs delivery; multiplexing recognitions; photo-activated prodrug; prodrug

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Cao, Y. (2014). Development of Novel Small Molecules for Imaging and Drug Release. (Doctoral Dissertation). University of New Mexico. Retrieved from https://digitalrepository.unm.edu/chem_etds/36

Chicago Manual of Style (16^th Edition):

Cao, Yanting. “Development of Novel Small Molecules for Imaging and Drug Release.” 2014. Doctoral Dissertation, University of New Mexico. Accessed April 11, 2021. https://digitalrepository.unm.edu/chem_etds/36.

MLA Handbook (7^th Edition):

Cao, Yanting. “Development of Novel Small Molecules for Imaging and Drug Release.” 2014. Web. 11 Apr 2021.

Vancouver:

Cao Y. Development of Novel Small Molecules for Imaging and Drug Release. [Internet] [Doctoral dissertation]. University of New Mexico; 2014. [cited 2021 Apr 11]. Available from: https://digitalrepository.unm.edu/chem_etds/36.

Council of Science Editors:

Cao Y. Development of Novel Small Molecules for Imaging and Drug Release. [Doctoral Dissertation]. University of New Mexico; 2014. Available from: https://digitalrepository.unm.edu/chem_etds/36

15. Aribi, Fallia. Development and biological evaluation of novel fluorinated ingredients for modern crop protection : Développement et évaluation biologique de nouveaux ingrédients fluorés pour une protection moderne des cultures.

Degree: Docteur es, Chimie organique, 2017, Université de Strasbourg

URL: http://www.theses.fr/2017STRAF020

►

Ce doctorat a permis la conception de nouvelles molécules destinées aux développements de futurs produits phytosanitaires. Tout d’abord, la synthèse d’alpha,alpha-difluoro-beta-hydroxy cétones a été réalisée.… (more)

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Ce doctorat a permis la conception de nouvelles molécules destinées aux développements de futurs produits phytosanitaires. Tout d’abord, la synthèse d’alpha,alpha-difluoro-beta-hydroxy cétones a été réalisée. Motif déjà reconnu dans le domaine pharmaceutique, nous voulions étendre son champ d’application à l’agrochimie. Une série de composés possédant une activité biologique en tant qu’agonistes des récepteurs GABA a été synthétisée. Ils ont été obtenus à l’issu d’une synthèse convergente nécessitant une réaction de couplage entre un aldéhyde aromatique et un intermédiaire alpha,alpha-difluoro-beta-trifluoromethyldihydroxy cétone. L’analyse biologique de nos produits a fait ressortir un type de famille spécifique. Une approche prodrug a débuté afin d’en affiner la structure et d’en faire ressortir un hit. Dans un second temps, le développement d’une série de quinoléines substituées par des groupements fluorés en position 2 et 4 a été conduit. Ces molécules peu décrites dans la littérature fûrent synthétisées dans des conditions douces avec de bons rendements et une complète régiosélectivité, inspirée par les réactions de Combes et de Meth-Cohn utilisant un Réactif Fluoroalkyl Amine (FARs). La post-fonctionnalisation en position 3 et 8 a permis l’exemplification de ces composés. Une étude physico-chimique réalisée sur une série homogène a apporté des informations complémentaires sur leurs propriétés électroniques. Bien qu’aucune molécule n’ait montré d’activité biologique, nous avons pu lors de ce projet réaliser la synthèse de nouvelles quinoléines et évaluer des FARs dans la synthèse de molécules inconnues de la littérature jusqu’à ce jour.

This PhD thesis allowed the conception of new molecules for the development of novel phytosanitary ingredients. First, the synthesis of alpha,alpha-difluoro-betahydroxy ketones was performed. Since this motif is already known in the pharmaceutical field, we decided to extend their application to the agrochemical field. A series of compounds with biological activities as GABA agonist receptors was synthesized. They were obtained by a convergent method after a coupling reaction between benzaldehydes and alpha,alpha-difluoro-beta-trifluoromethyldihydroxy ketone intermediates. Biological analysis highlighted a specific family of compounds. A prodrug approach was applied to tune the structure and allowed the discovery of a hit. Second, the development of a series of 2,4-(fluoroalkyl)-substituted quinoline derivatives was conducted. Scarcely described in literature, these molecules were obtained under smooth conditions, with good yields and a complete regioselectivity, inspired by Combes and Meth- Cohn reactions using Fluoroalkyl Amino Reagents (FARs). Post-functionalization in position 3 and 8 allowed us to increase the scope of the reaction. A physico-chemical study gave complementary informations on their electronical properties. Although none of these molecules have shown biological activity, we have during this project realized the synthesis of new quinolines and evaluated the…

Advisors/Committee Members: Leroux, Frédéric (thesis director).

Subjects/Keywords: GABA; Agonistes; Prodrug; Quinoléines; FAR; Fluor; Hétérocyles; Synthèse; GABA; Agonists; Prodrug; Quinolines; FAR; Fluor; Heterocycles; Synthesis; 547.2

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Aribi, F. (2017). Development and biological evaluation of novel fluorinated ingredients for modern crop protection : Développement et évaluation biologique de nouveaux ingrédients fluorés pour une protection moderne des cultures. (Doctoral Dissertation). Université de Strasbourg. Retrieved from http://www.theses.fr/2017STRAF020

Chicago Manual of Style (16^th Edition):

Aribi, Fallia. “Development and biological evaluation of novel fluorinated ingredients for modern crop protection : Développement et évaluation biologique de nouveaux ingrédients fluorés pour une protection moderne des cultures.” 2017. Doctoral Dissertation, Université de Strasbourg. Accessed April 11, 2021. http://www.theses.fr/2017STRAF020.

MLA Handbook (7^th Edition):

Aribi, Fallia. “Development and biological evaluation of novel fluorinated ingredients for modern crop protection : Développement et évaluation biologique de nouveaux ingrédients fluorés pour une protection moderne des cultures.” 2017. Web. 11 Apr 2021.

Vancouver:

Aribi F. Development and biological evaluation of novel fluorinated ingredients for modern crop protection : Développement et évaluation biologique de nouveaux ingrédients fluorés pour une protection moderne des cultures. [Internet] [Doctoral dissertation]. Université de Strasbourg; 2017. [cited 2021 Apr 11]. Available from: http://www.theses.fr/2017STRAF020.

Council of Science Editors:

Aribi F. Development and biological evaluation of novel fluorinated ingredients for modern crop protection : Développement et évaluation biologique de nouveaux ingrédients fluorés pour une protection moderne des cultures. [Doctoral Dissertation]. Université de Strasbourg; 2017. Available from: http://www.theses.fr/2017STRAF020

16. 古澤, 美麗. 細胞内生命現象の制御を指向した刺激応答性核酸の合成と応用.

Degree: Japan Advanced Institute of Science and Technology / 北陸先端科学技術大学院大学

URL: http://hdl.handle.net/10119/12723

Supervisor:藤本健造

マテリアルサイエンス研究科

修士

Subjects/Keywords: 5-Fluorouracil; Prodrug; Photoirradiation; Oligonucleotide

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APA (6^th Edition):

古澤, �. (n.d.). 細胞内生命現象の制御を指向した刺激応答性核酸の合成と応用. (Thesis). Japan Advanced Institute of Science and Technology / 北陸先端科学技術大学院大学. Retrieved from http://hdl.handle.net/10119/12723

Note: this citation may be lacking information needed for this citation format:
No year of publication.
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

古澤, 美麗. “細胞内生命現象の制御を指向した刺激応答性核酸の合成と応用.” Thesis, Japan Advanced Institute of Science and Technology / 北陸先端科学技術大学院大学. Accessed April 11, 2021. http://hdl.handle.net/10119/12723.

Note: this citation may be lacking information needed for this citation format:
No year of publication.
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

古澤, 美麗. “細胞内生命現象の制御を指向した刺激応答性核酸の合成と応用.” Web. 11 Apr 2021.

Note: this citation may be lacking information needed for this citation format:
No year of publication.

Vancouver:

古澤 �. 細胞内生命現象の制御を指向した刺激応答性核酸の合成と応用. [Internet] [Thesis]. Japan Advanced Institute of Science and Technology / 北陸先端科学技術大学院大学; [cited 2021 Apr 11]. Available from: http://hdl.handle.net/10119/12723.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
No year of publication.

Council of Science Editors:

古澤 �. 細胞内生命現象の制御を指向した刺激応答性核酸の合成と応用. [Thesis]. Japan Advanced Institute of Science and Technology / 北陸先端科学技術大学院大学; Available from: http://hdl.handle.net/10119/12723

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
No year of publication.

University of California – San Diego

17. Perez, Christian. Esterase and reactive-oxygen species (ROS)-activated prodrug strategies.

Degree: Chemistry, 2015, University of California – San Diego

URL: http://www.escholarship.org/uc/item/8rh8n8sb

► Prodrugs are derivatives of bioactive molecules that can become activated in vivo by a chemical or enzymatic stimulus. They serve as tools to help improve… (more)

Subjects/Keywords: Chemistry; Esterase; Metalloenzyme; Prodrug; Reactive Oxygen Species; ROS; Thiazolidinone

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APA (6^th Edition):

Perez, C. (2015). Esterase and reactive-oxygen species (ROS)-activated prodrug strategies. (Thesis). University of California – San Diego. Retrieved from http://www.escholarship.org/uc/item/8rh8n8sb

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Perez, Christian. “Esterase and reactive-oxygen species (ROS)-activated prodrug strategies.” 2015. Thesis, University of California – San Diego. Accessed April 11, 2021. http://www.escholarship.org/uc/item/8rh8n8sb.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Perez, Christian. “Esterase and reactive-oxygen species (ROS)-activated prodrug strategies.” 2015. Web. 11 Apr 2021.

Vancouver:

Perez C. Esterase and reactive-oxygen species (ROS)-activated prodrug strategies. [Internet] [Thesis]. University of California – San Diego; 2015. [cited 2021 Apr 11]. Available from: http://www.escholarship.org/uc/item/8rh8n8sb.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Perez C. Esterase and reactive-oxygen species (ROS)-activated prodrug strategies. [Thesis]. University of California – San Diego; 2015. Available from: http://www.escholarship.org/uc/item/8rh8n8sb

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of Minnesota

18. Li, Shui. Evaluation of Eukaryotic Initiation Factor 4E (eIF4E) antagonist 4Ei-1 in mammalian breast cancer and lung cancer cells : chemosensitizaiton with low cytotoxicity.

Degree: 2012, University of Minnesota

URL: http://purl.umn.edu/140071

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University of Minnesota M.S. thesis. August 2012. Major: Medicinal Chemistry. Advisors:Dr. Patrick Hanna, Dr. Carston Wagner. 1 computer file (PDF); vi, 95 pages.

The development… (more)

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University of Minnesota M.S. thesis. August 2012. Major: Medicinal Chemistry. Advisors:Dr. Patrick Hanna, Dr. Carston Wagner. 1 computer file (PDF); vi, 95 pages.

The development of cancer and fibrotic diseases has been shown to be highly dependent on disregulation of cap-dependent translation. Binding protein eIF4E to N7-methylated guanosine capped mRNA has been found to be the rate-limiting step governing translation initiation; and therefore represents an attractive target for drug discovery. Our group has found that 7-benzyl guanosine monophosphate (7Bn-GMP) is a potent antagonist of eIF4E cap binding (Kd = 0.8 uM). Recent X-ray crystallographic studies have revealed that the cap-dependent pocket undergoes a unique structural change in order to accommodate the benzyl group. Unfortunately, 7Bn-GMP is not cell permeable. Recently, we have prepared a tryptamine phosphoramidate prodrug of 7Bn-GMP, 4ei1, and shown that it is a substrate for human histidine triad nucleotide binding protein (hHINT1) and is inhibit eIF4E initiated epithelial-mesenchymal transition (EMT) by Zebra fish embryo cells. To assess the intracellular uptake of 4ei1 and conversion to 7Bn-GMP by cancer cells, we developed a sensitive assay using LC-ESI-MS/MS for the intracellular quantitation of 4ei1 and 7Bn-GMP. When incubated with the breast cancer cell line MDA-231; or lung cancer cell lines H460, H383 and H2009, 4ei1 was found to be rapidly internalized and converted to 7Bn-GMP. Since oncogenic mRNAs are predicted to have the highest eIF4E requirement for translation, we carried out chemosensitization studies with 4ei1. The prodrug was found to chemosensitize both breast and lung cancer cells to non-toxic levels of gemcitabine. Further mechanistic studies revealed that the expressed levels of eIF4E were substantially reduced in cells treated with 4ei1 in a dose dependent manner. The levels of eI4E could be restored by treatment with the proteasome inhibitor MG-132. Taken together, our results demonstrate that 4ei1 is likely to inhibit translation initiation by eIF4E cap binding by both antagonizing eIF4E cap binding and initiating eIF4E proteasomal degradation.

Subjects/Keywords: Chemosensitization; eIF4E; Eukaryotic translation initiation; Intracellular detection; Phosphoramidate; Prodrug

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APA (6^th Edition):

Li, S. (2012). Evaluation of Eukaryotic Initiation Factor 4E (eIF4E) antagonist 4Ei-1 in mammalian breast cancer and lung cancer cells : chemosensitizaiton with low cytotoxicity. (Masters Thesis). University of Minnesota. Retrieved from http://purl.umn.edu/140071

Chicago Manual of Style (16^th Edition):

Li, Shui. “Evaluation of Eukaryotic Initiation Factor 4E (eIF4E) antagonist 4Ei-1 in mammalian breast cancer and lung cancer cells : chemosensitizaiton with low cytotoxicity.” 2012. Masters Thesis, University of Minnesota. Accessed April 11, 2021. http://purl.umn.edu/140071.

MLA Handbook (7^th Edition):

Li, Shui. “Evaluation of Eukaryotic Initiation Factor 4E (eIF4E) antagonist 4Ei-1 in mammalian breast cancer and lung cancer cells : chemosensitizaiton with low cytotoxicity.” 2012. Web. 11 Apr 2021.

Vancouver:

Li S. Evaluation of Eukaryotic Initiation Factor 4E (eIF4E) antagonist 4Ei-1 in mammalian breast cancer and lung cancer cells : chemosensitizaiton with low cytotoxicity. [Internet] [Masters thesis]. University of Minnesota; 2012. [cited 2021 Apr 11]. Available from: http://purl.umn.edu/140071.

Council of Science Editors:

Li S. Evaluation of Eukaryotic Initiation Factor 4E (eIF4E) antagonist 4Ei-1 in mammalian breast cancer and lung cancer cells : chemosensitizaiton with low cytotoxicity. [Masters Thesis]. University of Minnesota; 2012. Available from: http://purl.umn.edu/140071

19. Nemdeo, Kamta Prasad. Synthesis of some new derivatives: a Redox delivery prodrug approach for brain specific sustained release; -.

Degree: Chemistry, 2013, Bundelkhand University

URL: http://shodhganga.inflibnet.ac.in/handle/10603/10814

None

Summary p. 206-213, References 214p.

Advisors/Committee Members: Shrivastava, S K, Chandra, Ramesh.

Subjects/Keywords: Chemistry; Redox delivery prodrug

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Nemdeo, K. P. (2013). Synthesis of some new derivatives: a Redox delivery prodrug approach for brain specific sustained release; -. (Thesis). Bundelkhand University. Retrieved from http://shodhganga.inflibnet.ac.in/handle/10603/10814

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Nemdeo, Kamta Prasad. “Synthesis of some new derivatives: a Redox delivery prodrug approach for brain specific sustained release; -.” 2013. Thesis, Bundelkhand University. Accessed April 11, 2021. http://shodhganga.inflibnet.ac.in/handle/10603/10814.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Nemdeo, Kamta Prasad. “Synthesis of some new derivatives: a Redox delivery prodrug approach for brain specific sustained release; -.” 2013. Web. 11 Apr 2021.

Vancouver:

Nemdeo KP. Synthesis of some new derivatives: a Redox delivery prodrug approach for brain specific sustained release; -. [Internet] [Thesis]. Bundelkhand University; 2013. [cited 2021 Apr 11]. Available from: http://shodhganga.inflibnet.ac.in/handle/10603/10814.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Nemdeo KP. Synthesis of some new derivatives: a Redox delivery prodrug approach for brain specific sustained release; -. [Thesis]. Bundelkhand University; 2013. Available from: http://shodhganga.inflibnet.ac.in/handle/10603/10814

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

20. Bordat, Alexandre. Stratégies alternatives pour la délivrance d'anticancéreux par encapsulation physique dans des nanoparticules polymère thermosensibles ou par couplage chimique en prodrogues polymères : Alternative strategies for the delivery of anticancer drugs by physical encapsulation in thermoresponsive polymer nanoparticles or chemical coupling as polymer prodrugs.

Degree: Docteur es, Pharmacotechnie et biopharmacie, 2018, Université Paris-Saclay (ComUE)

URL: http://www.theses.fr/2018SACLS595

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Cette thèse s’articule autour de systèmes innovants de délivrance d’anticancéreux pour répondre aux limitations actuelles des systèmes de type nanoparticules. Celles-ci permettent l’encapsulation d’anticancéreux pour… (more)

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Cette thèse s’articule autour de systèmes innovants de délivrance d’anticancéreux pour répondre aux limitations actuelles des systèmes de type nanoparticules. Celles-ci permettent l’encapsulation d’anticancéreux pour prolonger leur temps de circulation dans le sang et diminuer leurs effets secondaires. Néanmoins les produits disponibles en cliniques ne permettent pas un contrôle précis de la libération de la substance active, ni un ciblage de la tumeur.Pour répondre à ces deux limitations, nous avons synthétisé un copolymère thermosensible ayant une température critique haute de solubilité (upper critical solution temperature, UCST) pour formuler des nanoparticules encapsulant physiquement la doxorubicine. Celles-ci permettent la libération contrôlée de la substance active par hyperthermie modérée à 43 °C. Nous avons étudié notre système d’un point de vue physico-chimique et évalué sa cytotoxicité in vitro sur des cellules de cancer de l’ovaire.Nous avons également opté pour une approche via couplage chimique entre une substance active, le paclitaxel, et le polymère afin de permettre l’administration par la voie sous-cutanée d’anticancéreux. En effet, cette voie d’administration est peu utilisée pour les anticancéreux car certains d’entre eux induisent une toxicité locale au site d’injection de type irritation / nécrose de la peau. Nous avons évalué si d’une part, l’approche prodrogue polymère hydrophile permet d’empêcher cette toxicité locale et si d’autre part, l’approche prodrogue polymère UCST permet d’obtenir des nanoparticules stables à température ambiante en vue d’une administration par la voie sous-cutanée. Une fois administrées, les nanoparticules deviennent hydrophiles par le changement de température, 34 °C dans le tissu sous-cutané, et peuvent donc diffuser librement jusqu’à atteindre la circulation sanguine. Nos travaux ont permis d’évaluer l’approche prodrogue polymère hydrophile in vivo chez la souris nude, ainsi que de décrire pour la première fois la synthèse de prodrogues polymères UCST.

This thesis focuses on innovative drug delivery systems of anticancer drugs to tackle the current limitations of formulations based on nanoparticles. These allow encapsulation of anticancer drugs to prolong their circulation time in the blood stream and to decrease side effects. Yet, nanoparticle formulations available in the clinic do not allow a precise control on the drug release nor targeting of the tumor.To overcome these hurdles, we have synthesized a thermoresponsive copolymer exhibiting an upper critical solution temperature (UCST) to formulate nanoparticles physically encapsulating doxorubicin. These allow controlled release of the anticancer drug by mild hyperthermia at 43 °C. We have studied our system from a physico-chemical point of view and evaluated its cytotoxicity in vitro on ovarian cancer cells.We have also tried a chemical coupling approach between the polymer and the anticancer drug, paclitaxel, to allow innocuous subcutaneous administration. In did, this route of administration is seldom…

Advisors/Committee Members: Tsapis, Nicolas (thesis director), Nicolas, Julien (thesis director).

Subjects/Keywords: Nanoparticule; Thermosensible; Anticancéreux; Prodrogue; Polymère; Nanoparticles; Thermoresponsive; Anti-Cancer; Prodrug; Polymer

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Bordat, A. (2018). Stratégies alternatives pour la délivrance d'anticancéreux par encapsulation physique dans des nanoparticules polymère thermosensibles ou par couplage chimique en prodrogues polymères : Alternative strategies for the delivery of anticancer drugs by physical encapsulation in thermoresponsive polymer nanoparticles or chemical coupling as polymer prodrugs. (Doctoral Dissertation). Université Paris-Saclay (ComUE). Retrieved from http://www.theses.fr/2018SACLS595

Chicago Manual of Style (16^th Edition):

Bordat, Alexandre. “Stratégies alternatives pour la délivrance d'anticancéreux par encapsulation physique dans des nanoparticules polymère thermosensibles ou par couplage chimique en prodrogues polymères : Alternative strategies for the delivery of anticancer drugs by physical encapsulation in thermoresponsive polymer nanoparticles or chemical coupling as polymer prodrugs.” 2018. Doctoral Dissertation, Université Paris-Saclay (ComUE). Accessed April 11, 2021. http://www.theses.fr/2018SACLS595.

MLA Handbook (7^th Edition):

Bordat, Alexandre. “Stratégies alternatives pour la délivrance d'anticancéreux par encapsulation physique dans des nanoparticules polymère thermosensibles ou par couplage chimique en prodrogues polymères : Alternative strategies for the delivery of anticancer drugs by physical encapsulation in thermoresponsive polymer nanoparticles or chemical coupling as polymer prodrugs.” 2018. Web. 11 Apr 2021.

Vancouver:

Bordat A. Stratégies alternatives pour la délivrance d'anticancéreux par encapsulation physique dans des nanoparticules polymère thermosensibles ou par couplage chimique en prodrogues polymères : Alternative strategies for the delivery of anticancer drugs by physical encapsulation in thermoresponsive polymer nanoparticles or chemical coupling as polymer prodrugs. [Internet] [Doctoral dissertation]. Université Paris-Saclay (ComUE); 2018. [cited 2021 Apr 11]. Available from: http://www.theses.fr/2018SACLS595.

Council of Science Editors:

Bordat A. Stratégies alternatives pour la délivrance d'anticancéreux par encapsulation physique dans des nanoparticules polymère thermosensibles ou par couplage chimique en prodrogues polymères : Alternative strategies for the delivery of anticancer drugs by physical encapsulation in thermoresponsive polymer nanoparticles or chemical coupling as polymer prodrugs. [Doctoral Dissertation]. Université Paris-Saclay (ComUE); 2018. Available from: http://www.theses.fr/2018SACLS595

Central Connecticut State University

21. Barboni, Paul, 1974-. Development of an enzyme linked immunosorbant assay for quantitative detection of murine anti-human antibodies / Paul Barboni.

Degree: Department of Biomolecular Sciences, 2004, Central Connecticut State University

URL: http://content.library.ccsu.edu/u?/ccsutheses,1463

► During the development of potential protein or antibody therapeutics in a pharmaceutical environment, the use of animal models as test subjects is a necessary requirement.… (more)

Subjects/Keywords: Antibody-directed enzyme prodrug therapy

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APA (6^th Edition):

Barboni, Paul, 1. (2004). Development of an enzyme linked immunosorbant assay for quantitative detection of murine anti-human antibodies / Paul Barboni. (Thesis). Central Connecticut State University. Retrieved from http://content.library.ccsu.edu/u?/ccsutheses,1463

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Barboni, Paul, 1974-. “Development of an enzyme linked immunosorbant assay for quantitative detection of murine anti-human antibodies / Paul Barboni.” 2004. Thesis, Central Connecticut State University. Accessed April 11, 2021. http://content.library.ccsu.edu/u?/ccsutheses,1463.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Barboni, Paul, 1974-. “Development of an enzyme linked immunosorbant assay for quantitative detection of murine anti-human antibodies / Paul Barboni.” 2004. Web. 11 Apr 2021.

Vancouver:

Barboni, Paul 1. Development of an enzyme linked immunosorbant assay for quantitative detection of murine anti-human antibodies / Paul Barboni. [Internet] [Thesis]. Central Connecticut State University; 2004. [cited 2021 Apr 11]. Available from: http://content.library.ccsu.edu/u?/ccsutheses,1463.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Barboni, Paul 1. Development of an enzyme linked immunosorbant assay for quantitative detection of murine anti-human antibodies / Paul Barboni. [Thesis]. Central Connecticut State University; 2004. Available from: http://content.library.ccsu.edu/u?/ccsutheses,1463

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of Manchester

22. Song, Yiwei. Synthesis and evaluation of novel alpha-oxyalkyl-alpha,beta-cyclohexenones as pro-drugs for the intracellular delivery of inhibitors of the oxidoreductase enzyme NQO1.

Degree: PhD, 2018, University of Manchester

URL: https://www.research.manchester.ac.uk/portal/en/theses/synthesis-and-evaluation-of-novel-alphaoxyalkylalphabetacyclohexenones-as-prodrugs-for-the-intracellular-delivery-of-inhibitors-of-the-oxidoreductase-enzyme-nqo1(95e9a037-1418-4015-95eb-22bd85ea2fed).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.771355

► The alpha-oxymethyl-alpha,beta-cyclohexenone moiety is embedded in several bioactive natural products, including 2-crotonyloxymethyl-(4R,5R,6R)-4,5,6-trihydroxycyclohex-2-enone (COTC) and the terpenoid, antheminone A. Both compounds exhibit cytotoxicity towards a variety… (more)

Subjects/Keywords: 540; NQO1; organic synthesis; medicinal chemistry; anticancer prodrug

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Song, Y. (2018). Synthesis and evaluation of novel alpha-oxyalkyl-alpha,beta-cyclohexenones as pro-drugs for the intracellular delivery of inhibitors of the oxidoreductase enzyme NQO1. (Doctoral Dissertation). University of Manchester. Retrieved from https://www.research.manchester.ac.uk/portal/en/theses/synthesis-and-evaluation-of-novel-alphaoxyalkylalphabetacyclohexenones-as-prodrugs-for-the-intracellular-delivery-of-inhibitors-of-the-oxidoreductase-enzyme-nqo1(95e9a037-1418-4015-95eb-22bd85ea2fed).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.771355

Chicago Manual of Style (16^th Edition):

Song, Yiwei. “Synthesis and evaluation of novel alpha-oxyalkyl-alpha,beta-cyclohexenones as pro-drugs for the intracellular delivery of inhibitors of the oxidoreductase enzyme NQO1.” 2018. Doctoral Dissertation, University of Manchester. Accessed April 11, 2021. https://www.research.manchester.ac.uk/portal/en/theses/synthesis-and-evaluation-of-novel-alphaoxyalkylalphabetacyclohexenones-as-prodrugs-for-the-intracellular-delivery-of-inhibitors-of-the-oxidoreductase-enzyme-nqo1(95e9a037-1418-4015-95eb-22bd85ea2fed).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.771355.

MLA Handbook (7^th Edition):

Song, Yiwei. “Synthesis and evaluation of novel alpha-oxyalkyl-alpha,beta-cyclohexenones as pro-drugs for the intracellular delivery of inhibitors of the oxidoreductase enzyme NQO1.” 2018. Web. 11 Apr 2021.

Vancouver:

Song Y. Synthesis and evaluation of novel alpha-oxyalkyl-alpha,beta-cyclohexenones as pro-drugs for the intracellular delivery of inhibitors of the oxidoreductase enzyme NQO1. [Internet] [Doctoral dissertation]. University of Manchester; 2018. [cited 2021 Apr 11]. Available from: https://www.research.manchester.ac.uk/portal/en/theses/synthesis-and-evaluation-of-novel-alphaoxyalkylalphabetacyclohexenones-as-prodrugs-for-the-intracellular-delivery-of-inhibitors-of-the-oxidoreductase-enzyme-nqo1(95e9a037-1418-4015-95eb-22bd85ea2fed).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.771355.

Council of Science Editors:

Song Y. Synthesis and evaluation of novel alpha-oxyalkyl-alpha,beta-cyclohexenones as pro-drugs for the intracellular delivery of inhibitors of the oxidoreductase enzyme NQO1. [Doctoral Dissertation]. University of Manchester; 2018. Available from: https://www.research.manchester.ac.uk/portal/en/theses/synthesis-and-evaluation-of-novel-alphaoxyalkylalphabetacyclohexenones-as-prodrugs-for-the-intracellular-delivery-of-inhibitors-of-the-oxidoreductase-enzyme-nqo1(95e9a037-1418-4015-95eb-22bd85ea2fed).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.771355

University of Washington

23. Kelly, Abby M. Inhalable antibiotic prodrug therapies for the treatment of intracellular pulmonary infections.

Degree: 2018, University of Washington

URL: http://hdl.handle.net/1773/40845

► One hundred years after the discovery of antimicrobials and antibiotics, lower respiratory infections remain one of the leading causes of death worldwide. Infectious agents such… (more)

▼ One hundred years after the discovery of antimicrobials and antibiotics, lower respiratory infections remain one of the leading causes of death worldwide. Infectious agents such as Francisella tularensis and Burkholderia pseudomallei contribute to this burden as the causative agents of pulmonary tularemia and melioidosis, respectively. These pathogens cause substantial morbidity and mortality and due to their aerosolizability are weaponizable pathogens for bio-warfare. As such, the Centers for Disease Control and Prevention classify them as Tier 1 threat agents. Current care of these intracellular lung infections relies solely on weeks to months of intravenous and/or oral antibiotic delivery. Yet, 10-20% of patients die following treatment and another 5-10% relapse. These clinical failures are due to poor drug biodistribution within the lungs and low bioavailability, with potential off-target side effects due to systemic delivery. Inhalable delivery platforms aim to overcome these problems through direct delivery of antibiotics to the sight of infection. Systems such as inhalable free drug dispersions and antibiotics encapsulated within liposomal formulations are under investigation, however these systems fail to control drug pharmacokinetics often delivery a burst release, and often require complex formulations hampering large scale production and regulatory approval. Previous work in the Stayton lab, including work presented in this thesis, helped lay the foundation of a macromolecular inhalable prodrug platform utilizing RAFT polymerization of a ciprofloxacin (cipro) prodrug monomer towards the treatment of pulmonary tularemia. Initial co-monomer investigations were performed with polyethylene glycol methacrylate (PEGMA), carboxybetaine methacrylate, and mannose methacrylate monomers. These co-monomers were investigated for their ability to aid in drug solubility, loading, stability, biocompatibility, and in the case of the mannose monomer, for it’s targeting capabilities to surface receptors on alveolar macrophage. This foundational work lead to PEGMA-cipro polymers capable of prolonging survival in a lethal murine F. novicida infection model in 70% of mice to the experimental endpoint at 14 days post infection over untreated mice with 0% survival at just 4 days post infection following a 3 day treatment dosing schedule. The carboxybetaine co-monomer was only ever investigated in vitro, but was shown to be nontoxic, produce excellent drug solubility and loading, and increase cellular internalization over similar PEGMA polymers. However, the mannose co-monomer unexpectedly outperformed both the PEGMA and carboxybetaine co-monomers. The Mannose-Cipro polymers were shown to increase animal survival to 90% at 16 days post infection, compared to 0% survival in untreated mice at 8-10 days post infection following a 3 day treatment dosing schedule. Additionally, the mannose monomer was shown to increase cellular uptake by alveolar macrophage via receptor-mediated endocytosis, and provide excellent drug solubility,… Advisors/Committee Members: Stayton, Patrick S (advisor).

Subjects/Keywords: Drug Delivery; Infection; Inhalable therapies; Meropenem; Prodrug; RAFT polymerization; Bioengineering; Bioengineering

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APA (6^th Edition):

Kelly, A. M. (2018). Inhalable antibiotic prodrug therapies for the treatment of intracellular pulmonary infections. (Thesis). University of Washington. Retrieved from http://hdl.handle.net/1773/40845

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Kelly, Abby M. “Inhalable antibiotic prodrug therapies for the treatment of intracellular pulmonary infections.” 2018. Thesis, University of Washington. Accessed April 11, 2021. http://hdl.handle.net/1773/40845.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Kelly, Abby M. “Inhalable antibiotic prodrug therapies for the treatment of intracellular pulmonary infections.” 2018. Web. 11 Apr 2021.

Vancouver:

Kelly AM. Inhalable antibiotic prodrug therapies for the treatment of intracellular pulmonary infections. [Internet] [Thesis]. University of Washington; 2018. [cited 2021 Apr 11]. Available from: http://hdl.handle.net/1773/40845.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Kelly AM. Inhalable antibiotic prodrug therapies for the treatment of intracellular pulmonary infections. [Thesis]. University of Washington; 2018. Available from: http://hdl.handle.net/1773/40845

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

24. Scarbrough, Emily Desiree. Synthesis of Novel CADA Analog Prodrugs and Ring-Size Variants Designed to Act as anti-HIV Agents via Down-Modulation of the CD4 Receptor.

Degree: 2015, University of Nevada – Reno

URL: http://hdl.handle.net/11714/2623

► Cyclotriazadisulfonamide (CADA) inhibits HIV replication by selectively down-modulating expression of the CD4 receptor protein on host cells. Current studies are aimed at developing a prodrug… (more)

Subjects/Keywords: 11 membered ring; anti-HIV; aziridine; CADA; CD4 Receptor; Prodrug

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APA (6^th Edition):

Scarbrough, E. D. (2015). Synthesis of Novel CADA Analog Prodrugs and Ring-Size Variants Designed to Act as anti-HIV Agents via Down-Modulation of the CD4 Receptor. (Thesis). University of Nevada – Reno. Retrieved from http://hdl.handle.net/11714/2623

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Scarbrough, Emily Desiree. “Synthesis of Novel CADA Analog Prodrugs and Ring-Size Variants Designed to Act as anti-HIV Agents via Down-Modulation of the CD4 Receptor.” 2015. Thesis, University of Nevada – Reno. Accessed April 11, 2021. http://hdl.handle.net/11714/2623.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Scarbrough, Emily Desiree. “Synthesis of Novel CADA Analog Prodrugs and Ring-Size Variants Designed to Act as anti-HIV Agents via Down-Modulation of the CD4 Receptor.” 2015. Web. 11 Apr 2021.

Vancouver:

Scarbrough ED. Synthesis of Novel CADA Analog Prodrugs and Ring-Size Variants Designed to Act as anti-HIV Agents via Down-Modulation of the CD4 Receptor. [Internet] [Thesis]. University of Nevada – Reno; 2015. [cited 2021 Apr 11]. Available from: http://hdl.handle.net/11714/2623.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Scarbrough ED. Synthesis of Novel CADA Analog Prodrugs and Ring-Size Variants Designed to Act as anti-HIV Agents via Down-Modulation of the CD4 Receptor. [Thesis]. University of Nevada – Reno; 2015. Available from: http://hdl.handle.net/11714/2623

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

East Tennessee State University

25. McGoldrick, Christopher Allen. Novel Ester Substrates for the Detection and Treatment of Prostate Cancer.

Degree: PhD, Biomedical Sciences, 2013, East Tennessee State University

URL: https://dc.etsu.edu/etd/2308

► Cancer cell esterases are often overexpressed and some have chiral specificities different from those of corresponding normal cells. Carboxylesterases in particular are known to… (more)

▼ Cancer cell esterases are often overexpressed and some have chiral specificities different from those of corresponding normal cells. Carboxylesterases in particular are known to be overexpressed in several cancers. Additionally, cancer cells often exhibit high levels of intrinsic oxidative stress that is required for survival and an aggressive phenotype. We hypothesized that these 2 characteristics of cancer cells could be exploited to aid in the detection and treatment of prostate cancer. We have developed a fluorogenic ester probe that is activated by carboxylesterase to help distinguish tumorigenic cells from nontumorigenic prostate cells. Ester prodrugs have the same activation mechanism and have been thought to be a promising approach in cancer therapy. Prodrugs are inactive drugs that can be selectively activated by a specific enzyme. We have developed a chiral ester prodrug strategy using native polyacrylamide gel electrophoresis (n-PAGE) and proteomic methods to compare and identify the esterase profiles of several tumorigenic and nontumorigenic prostate cell lines. Our results showed that cell lysates from LNCaP, DU 145, and PC3 prostate cancer cell lines exhibit differential esterase activity compared with non-tumorigenic RWPE-1 prostate cell lysates when incubated with α- naphthyl acetate or α-naphthyl N-acetyl-alaninate ester substrates and a diazonium salt. We have identified oxidized protein hydrolase (OPH), a serine esterase/protease that catalyzes the removal of N-acylated residues from proteins, to be differentially expressed between some tumorigenic and nontumorigenic prostate cell lines. OPH was found to have high hydrolytic activity towards the S-isomer of α-naphthyl N-acetylalaninate (S-ANAA) chiral ester. LNCaP lysates incubated with N-acetyl-alanyl-p-nitroanilide, a known OPH substrate, had twofold higher OPH activity compared with RWPE-1 lysates. We have also developed and tested novel glutathione depleting prodrugs modeled after S-ANAA that increase oxidative stress and induced apoptosis in tumorigenic prostate cells with little effect on nontumorigenic RWPE-1 cells. These results suggest that ester molecular beacon probes and ester prodrugs may be effective in identifying and treating prostate cancer tumors that overexpress esterases with little effect on normal prostate cells.

Subjects/Keywords: oxidized protein hydrolase; prodrug; carboxylesterase; prostate cancer; molecular beacon; Biochemistry

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

McGoldrick, C. A. (2013). Novel Ester Substrates for the Detection and Treatment of Prostate Cancer. (Doctoral Dissertation). East Tennessee State University. Retrieved from https://dc.etsu.edu/etd/2308

Chicago Manual of Style (16^th Edition):

McGoldrick, Christopher Allen. “Novel Ester Substrates for the Detection and Treatment of Prostate Cancer.” 2013. Doctoral Dissertation, East Tennessee State University. Accessed April 11, 2021. https://dc.etsu.edu/etd/2308.

MLA Handbook (7^th Edition):

McGoldrick, Christopher Allen. “Novel Ester Substrates for the Detection and Treatment of Prostate Cancer.” 2013. Web. 11 Apr 2021.

Vancouver:

McGoldrick CA. Novel Ester Substrates for the Detection and Treatment of Prostate Cancer. [Internet] [Doctoral dissertation]. East Tennessee State University; 2013. [cited 2021 Apr 11]. Available from: https://dc.etsu.edu/etd/2308.

Council of Science Editors:

McGoldrick CA. Novel Ester Substrates for the Detection and Treatment of Prostate Cancer. [Doctoral Dissertation]. East Tennessee State University; 2013. Available from: https://dc.etsu.edu/etd/2308

University of Minnesota

26. Li, Shui. Evaluation of Eukaryotic Initiation Factor 4E (eIF4E) antagonist 4Ei-1 in mammalian breast cancer and lung cancer cells : chemosensitizaiton with low cytotoxicity.

Degree: MS, Medicinal Chemistry, 2012, University of Minnesota

URL: http://purl.umn.edu/140071

► The development of cancer and fibrotic diseases has been shown to be highly dependent on disregulation of cap-dependent translation. Binding protein eIF4E to N7-methylated guanosine… (more)

▼ The development of cancer and fibrotic diseases has been shown to be highly dependent on disregulation of cap-dependent translation. Binding protein eIF4E to N7-methylated guanosine capped mRNA has been found to be the rate-limiting step governing translation initiation; and therefore represents an attractive target for drug discovery. Our group has found that 7-benzyl guanosine monophosphate (7Bn-GMP) is a potent antagonist of eIF4E cap binding (Kd = 0.8 uM). Recent X-ray crystallographic studies have revealed that the cap-dependent pocket undergoes a unique structural change in order to accommodate the benzyl group. Unfortunately, 7Bn-GMP is not cell permeable. Recently, we have prepared a tryptamine phosphoramidate prodrug of 7Bn-GMP, 4ei1, and shown that it is a substrate for human histidine triad nucleotide binding protein (hHINT1) and is inhibit eIF4E initiated epithelial-mesenchymal transition (EMT) by Zebra fish embryo cells. To assess the intracellular uptake of 4ei1 and conversion to 7Bn-GMP by cancer cells, we developed a sensitive assay using LC-ESI-MS/MS for the intracellular quantitation of 4ei1 and 7Bn-GMP. When incubated with the breast cancer cell line MDA-231; or lung cancer cell lines H460, H383 and H2009, 4ei1 was found to be rapidly internalized and converted to 7Bn-GMP. Since oncogenic mRNAs are predicted to have the highest eIF4E requirement for translation, we carried out chemosensitization studies with 4ei1. The prodrug was found to chemosensitize both breast and lung cancer cells to non-toxic levels of gemcitabine. Further mechanistic studies revealed that the expressed levels of eIF4E were substantially reduced in cells treated with 4ei1 in a dose dependent manner. The levels of eI4E could be restored by treatment with the proteasome inhibitor MG-132. Taken together, our results demonstrate that 4ei1 is likely to inhibit translation initiation by eIF4E cap binding by both antagonizing eIF4E cap binding and initiating eIF4E proteasomal degradation.

Subjects/Keywords: Chemosensitization; eIF4E; Eukaryotic translation initiation; Intracellular detection; Phosphoramidate; Prodrug

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APA (6^th Edition):

Li, S. (2012). Evaluation of Eukaryotic Initiation Factor 4E (eIF4E) antagonist 4Ei-1 in mammalian breast cancer and lung cancer cells : chemosensitizaiton with low cytotoxicity. (Masters Thesis). University of Minnesota. Retrieved from http://purl.umn.edu/140071

Chicago Manual of Style (16^th Edition):

Li, Shui. “Evaluation of Eukaryotic Initiation Factor 4E (eIF4E) antagonist 4Ei-1 in mammalian breast cancer and lung cancer cells : chemosensitizaiton with low cytotoxicity.” 2012. Masters Thesis, University of Minnesota. Accessed April 11, 2021. http://purl.umn.edu/140071.

MLA Handbook (7^th Edition):

Li, Shui. “Evaluation of Eukaryotic Initiation Factor 4E (eIF4E) antagonist 4Ei-1 in mammalian breast cancer and lung cancer cells : chemosensitizaiton with low cytotoxicity.” 2012. Web. 11 Apr 2021.

Vancouver:

Li S. Evaluation of Eukaryotic Initiation Factor 4E (eIF4E) antagonist 4Ei-1 in mammalian breast cancer and lung cancer cells : chemosensitizaiton with low cytotoxicity. [Internet] [Masters thesis]. University of Minnesota; 2012. [cited 2021 Apr 11]. Available from: http://purl.umn.edu/140071.

Council of Science Editors:

Li S. Evaluation of Eukaryotic Initiation Factor 4E (eIF4E) antagonist 4Ei-1 in mammalian breast cancer and lung cancer cells : chemosensitizaiton with low cytotoxicity. [Masters Thesis]. University of Minnesota; 2012. Available from: http://purl.umn.edu/140071

University of Minnesota

27. Wohl, Adam Richard. Synthesis and characterization of silicate ester prodrugs and poly(ethylene glycol)-b-poly(lactic-co-glycolic acid) block copolymers for formulation into prodrug-loaded nanoparticles.

Degree: PhD, Chemistry, 2012, University of Minnesota

URL: http://hdl.handle.net/11299/167686

► Fine control of the physical and chemical properties of customized materials is a field that is rapidly advancing. This is especially critical in pursuits to… (more)

▼ Fine control of the physical and chemical properties of customized materials is a field that is rapidly advancing. This is especially critical in pursuits to develop and optimize novel nanoparticle drug delivery. Specifically, I aim to apply chemistry concepts to test the hypothesis "Silicate ester prodrugs of paclitaxel, customized to have the proper hydrophobicity and hydrolytic lability, can be formulated with well-defined, biocompatible, amphiphilic block copolymers into nanoparticles that are effective drugs." Chapter 1 briefly describes the context and motivation of the scientific pursuits described in this thesis. In Chapter 2, a family of model silicate esters is synthesized, the hydrolysis rate of each compound is benchmarked, and trends are established based upon the steric bulk and leaving group ability of the silicate substituents. These trends are then applied to the synthesis of labile silicate ester prodrugs in Chapter 3. The bulk of this chapter focuses on the synthesis, hydrolysis, and cytotoxicity of prodrugs based on paclitaxel, a widely used chemotherapeutic agent. In Chapter 4, a new methodology for the synthesis of narrowly dispersed, "random" poly(lactic-co-glycolic acid) polymers by a constant infusion of the glycolide monomer is detailed. Using poly(ethylene glycol) as a macroinitiator, amphiphilic block copolymers were synthesized. Co-formulating a paclitaxel silicate and an amphiphilic block copolymer via flash nanoprecipitation led to highly prodrug-loaded, kinetically trapped nanoparticles. Studies to determine the structure, morphology, behavior, and efficacy of these nanoparticles are described in Chapter 5. Efforts to develop a general strategy for the selective end-functionalization of the polyether block of these amphiphilic block copolymers are discussed in Chapter 6. Examples of this strategy include functionalization of the polyether with an azide or a maleimide. Finally, Chapter 7 provides an outlook for future development of the strategies described in this thesis and summarizes the results and conclusions of the experimental results that led to the development of the therapeutic, paclitaxel silicate-loaded, polymeric nanoparticles.

Subjects/Keywords: Block copolymer; Flash nanoprecipitation; Prodrug; Silicate ester; Chemistry

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APA (6^th Edition):

Wohl, A. R. (2012). Synthesis and characterization of silicate ester prodrugs and poly(ethylene glycol)-b-poly(lactic-co-glycolic acid) block copolymers for formulation into prodrug-loaded nanoparticles. (Doctoral Dissertation). University of Minnesota. Retrieved from http://hdl.handle.net/11299/167686

Chicago Manual of Style (16^th Edition):

Wohl, Adam Richard. “Synthesis and characterization of silicate ester prodrugs and poly(ethylene glycol)-b-poly(lactic-co-glycolic acid) block copolymers for formulation into prodrug-loaded nanoparticles.” 2012. Doctoral Dissertation, University of Minnesota. Accessed April 11, 2021. http://hdl.handle.net/11299/167686.

MLA Handbook (7^th Edition):

Wohl, Adam Richard. “Synthesis and characterization of silicate ester prodrugs and poly(ethylene glycol)-b-poly(lactic-co-glycolic acid) block copolymers for formulation into prodrug-loaded nanoparticles.” 2012. Web. 11 Apr 2021.

Vancouver:

Wohl AR. Synthesis and characterization of silicate ester prodrugs and poly(ethylene glycol)-b-poly(lactic-co-glycolic acid) block copolymers for formulation into prodrug-loaded nanoparticles. [Internet] [Doctoral dissertation]. University of Minnesota; 2012. [cited 2021 Apr 11]. Available from: http://hdl.handle.net/11299/167686.

Council of Science Editors:

Wohl AR. Synthesis and characterization of silicate ester prodrugs and poly(ethylene glycol)-b-poly(lactic-co-glycolic acid) block copolymers for formulation into prodrug-loaded nanoparticles. [Doctoral Dissertation]. University of Minnesota; 2012. Available from: http://hdl.handle.net/11299/167686

University of Minnesota

28. Maize, Kimberly. Structural Biology for Drug Design: Applications in Two Systems.

Degree: PhD, Medicinal Chemistry, 2016, University of Minnesota

URL: http://hdl.handle.net/11299/182796

► Two projects comprise this dissertation; both are focused on using the technique of protein X-ray crystallography to understand the molecular interactions that small molecules make… (more)

Subjects/Keywords: anthrax; crystallography; HINT; Lethal Factor; prodrug; Structure-based drug design

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Maize, K. (2016). Structural Biology for Drug Design: Applications in Two Systems. (Doctoral Dissertation). University of Minnesota. Retrieved from http://hdl.handle.net/11299/182796

Chicago Manual of Style (16^th Edition):

Maize, Kimberly. “Structural Biology for Drug Design: Applications in Two Systems.” 2016. Doctoral Dissertation, University of Minnesota. Accessed April 11, 2021. http://hdl.handle.net/11299/182796.

MLA Handbook (7^th Edition):

Maize, Kimberly. “Structural Biology for Drug Design: Applications in Two Systems.” 2016. Web. 11 Apr 2021.

Vancouver:

Maize K. Structural Biology for Drug Design: Applications in Two Systems. [Internet] [Doctoral dissertation]. University of Minnesota; 2016. [cited 2021 Apr 11]. Available from: http://hdl.handle.net/11299/182796.

Council of Science Editors:

Maize K. Structural Biology for Drug Design: Applications in Two Systems. [Doctoral Dissertation]. University of Minnesota; 2016. Available from: http://hdl.handle.net/11299/182796

University of Southern California

29. Wang, Yan. Proinsulin-transferrin recombinant fusion protein: mechanism of activation and potential application in diabetes treatment.

Degree: PhD, Molecular Pharmacology and Toxicology, 2013, University of Southern California

URL: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/91307/rec/5274

► Long-acting insulin (INS) analogues that exhibit prolonged time-action profiles and liver-specificity are currently in great demand for diabetes treatment. Native INS and its protein precursor… (more)

▼ Long-acting insulin (INS) analogues that exhibit prolonged time-action profiles and liver-specificity are currently in great demand for diabetes treatment. Native INS and its protein precursor proinsulin (ProINS) are both small peptides with short in vivo half-life and efficacy. Human transferrin (Tf) is a stable and large-sized plasma protein, and it has been demonstrated to prolong the half-life of small proteins. With the purposes of improving the therapeutic application of INS, a proinsulin-transferrin (ProINS-Tf) recombinant fusion protein has been designed and developed. This fusion protein is produced using recombinant fusion technology combined with his-tag purification method. ProINS-Tf exhibits a low activity in the 30 min promotion of glucose uptake in adipocytes, which corresponds with a low binding affinity to insulin receptor. Additionally, ProINS-Tf can be activated by ex vivo trypsin digestion. These results suggest that, similar to ProINS, the intrinsic potency of ProINS-Tf is low and an activation is required to achieve biological activity. On the other hand, ProINS-Tf elicits a Tf receptor (TfR) dependent enhanced activity in the 24 h inhibition of glucose production in hepatoma cells. Radioimmunoassays clearly demonstrate a TfR-mediated conversion and activation of ProINS-Tf to an immunoreactive insulin-transferrin fusion protein during the 24 h incubation with hepatoma cells. Therefore, we have proposed an intracellular ProINS-Tf activation mechanism that is mediated through TfR-mediated endocytosis and recycling pathway. Furthermore, compared to ProINS and INS, subcutaneously injected ProINS-Tf exerts an extended hypoglycemic efficacy with a prolonged half-life in fasted diabetic mice. The correlation of hypoglycemic efficacy with the suppression of liver-associated enzyme expression suggests a liver-preferential effect by ProINS-Tf. In addition, intravenously injection of trypsin-digested ProINS-Tf shows an immediate hypoglycemic response, whereas ProINS-Tf exhibits a delayed and long-lasting hypoglycemic efficacy. These observations imply that an activation of ProINS-Tf may also occur in vivo. Taken together, results from this dissertation have presented three contributions to the therapeutic protein discovery and development of. First, ProINS-Tf is a novel fusion protein and the first proprotein within the Tf-based fusion protein family. Second, a novel receptor-mediated intracellular proprotein activation mechanism is discovered. Lastly, ProINS-Tf shows great promise as a potential long-acting INS analogue for diabetes treatment. Advisors/Committee Members: Shen, Wei-Chiang (Committee Chair), Stiles, Bangyan L. (Committee Member), Wang, Clay C.C. (Committee Member), Haworth, Ian S. (Committee Member).

Subjects/Keywords: transferrin; insulin; proinsulin; prodrug activation; recombinant fusion protein; diabetes

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APA (6^th Edition):

Wang, Y. (2013). Proinsulin-transferrin recombinant fusion protein: mechanism of activation and potential application in diabetes treatment. (Doctoral Dissertation). University of Southern California. Retrieved from http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/91307/rec/5274

Chicago Manual of Style (16^th Edition):

Wang, Yan. “Proinsulin-transferrin recombinant fusion protein: mechanism of activation and potential application in diabetes treatment.” 2013. Doctoral Dissertation, University of Southern California. Accessed April 11, 2021. http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/91307/rec/5274.

MLA Handbook (7^th Edition):

Wang, Yan. “Proinsulin-transferrin recombinant fusion protein: mechanism of activation and potential application in diabetes treatment.” 2013. Web. 11 Apr 2021.

Vancouver:

Wang Y. Proinsulin-transferrin recombinant fusion protein: mechanism of activation and potential application in diabetes treatment. [Internet] [Doctoral dissertation]. University of Southern California; 2013. [cited 2021 Apr 11]. Available from: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/91307/rec/5274.

Council of Science Editors:

Wang Y. Proinsulin-transferrin recombinant fusion protein: mechanism of activation and potential application in diabetes treatment. [Doctoral Dissertation]. University of Southern California; 2013. Available from: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/91307/rec/5274

University of Minnesota

30. Okon, Aniekan. Development of chemical probes for intracellular nucleotide delivery, profiling of the metabolic fate(s) of nucleoside monoester phosphoramidates, and a nucleotide mimetic inhibitor of eIF4E.

Degree: PhD, Medicinal Chemistry, 2018, University of Minnesota

URL: http://hdl.handle.net/11299/216354

► Significant progress has been made towards the development of phosphate prodrugs for intracellular delivery of monophosphates. Such efforts led to the successful application of the… (more)

▼ Significant progress has been made towards the development of phosphate prodrugs for intracellular delivery of monophosphates. Such efforts led to the successful application of the aryloxy amino acid phosphoramidate (ProTide) strategy for development of sofosbuvir. Although widely successful, several drawbacks of the ProTide strategy limit its utility for delivery of significant levels of nucleotide analogs in tissues other than the liver. In order to broaden the utility of phosphate prodrugs, we have developed pronucleotide strategies that address the inefficiencies of the ProTide system. Chapter 2 describes the design and development of an anchimerically activated pronucleotide strategy, incorporating 2-(methylthio)ethyl and tryptamine as phosphate protecting moieties. The prodrug is activated by a sulfur mediated intramolecular cyclo-de-esterification reaction to yield a monoester phosphoramidate, which gets hydrolyzed by HINT1 to release a monophosphate. In a proof-of-concept application, we applied the pronucleotide strategy towards intracellular delivery of 7-Chlorophenoxyethyl guanosine monophosphate, as a chemical tool for translational control of protein synthesis. Furthermore, in Chapter 3 we provide another proof-of-concept application of the new pronucleotide strategy for intracellular delivery of 2´-C-β-Methyl guanosine monophosphate as an anti-Dengue virus (DENV) agent. In a related project, we sought to profile the protein interacting partners of nucleoside monoester phosphoramidates. Mapping the small molecule-protein interactome of nucleoside monoester phosphoramidates should help us decipher the mode of cellular uptake and identify other metabolizing enzymes of nucleoside monoester phosphoramidates (excluding HINT1). Chapter 4 outlines the design and synthesis of phosphoramidate-based photoaffinity probes as chemical tools for profiling the protein binding partners of nucleoside monoester phosphoramidates. The synthesized probes were utilized for in vitro proteomics studies in whole cell extracts (lysates) and in live cells. Finally, we describe the design and development of a nucleotide mimetic inhibitor of eIF4E in Chapter 5. As a proof-of-concept application, we employed a sulfamido alkyl moiety as a substitute for 5´-phosphate in the design of 5´-mRNA cap analog antagonists of eIF4E. We successfully synthesized a mimetic of 7-Chlorophenoxyethyl guanosine monophosphate and demonstrated that its binding potency to eIF4E is comparable to that of the parent nucleotide, with only a modest loss in binding potency.

Subjects/Keywords: Nucleotide mimetic; Phosphoramidate; Photoaffinity probes; Prodrug; Pronucleotide; Translational Control

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APA (6^th Edition):

Okon, A. (2018). Development of chemical probes for intracellular nucleotide delivery, profiling of the metabolic fate(s) of nucleoside monoester phosphoramidates, and a nucleotide mimetic inhibitor of eIF4E. (Doctoral Dissertation). University of Minnesota. Retrieved from http://hdl.handle.net/11299/216354

Chicago Manual of Style (16^th Edition):

Okon, Aniekan. “Development of chemical probes for intracellular nucleotide delivery, profiling of the metabolic fate(s) of nucleoside monoester phosphoramidates, and a nucleotide mimetic inhibitor of eIF4E.” 2018. Doctoral Dissertation, University of Minnesota. Accessed April 11, 2021. http://hdl.handle.net/11299/216354.

MLA Handbook (7^th Edition):

Okon, Aniekan. “Development of chemical probes for intracellular nucleotide delivery, profiling of the metabolic fate(s) of nucleoside monoester phosphoramidates, and a nucleotide mimetic inhibitor of eIF4E.” 2018. Web. 11 Apr 2021.

Vancouver:

Okon A. Development of chemical probes for intracellular nucleotide delivery, profiling of the metabolic fate(s) of nucleoside monoester phosphoramidates, and a nucleotide mimetic inhibitor of eIF4E. [Internet] [Doctoral dissertation]. University of Minnesota; 2018. [cited 2021 Apr 11]. Available from: http://hdl.handle.net/11299/216354.

Council of Science Editors:

Okon A. Development of chemical probes for intracellular nucleotide delivery, profiling of the metabolic fate(s) of nucleoside monoester phosphoramidates, and a nucleotide mimetic inhibitor of eIF4E. [Doctoral Dissertation]. University of Minnesota; 2018. Available from: http://hdl.handle.net/11299/216354

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