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You searched for subject:(codrugs). Showing records 1 – 2 of 2 total matches.

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University of Wollongong

1. Kirk, Nicholas. Synthetic and biological investigations into hypoxia-activated anti-tumour codrugs.

Degree: PhD, 2015, University of Wollongong

Tumour-selective, non-cytotoxic chemotherapeutics are much sought after in oncology. Two cancer-selective drug types are angiogenesis inhibitors, drugs which halt the growth of new blood vessels in tumours, and hypoxia-activated prodrugs, which are non-toxic agents that are activated into cytotoxins selectively within tumours. It is possible to conceive a dual-action prodrug (a.k.a. codrug) which releases both an angiogenesis inhibitor and a cytotoxin selectively within a tumour after bio-reductive activation. Specifically, prodrugs designed to release nitrogen mustard cytotoxins along with SU5416 from a 2-nitrophenylacetamide precursor were of particular interest. A synthesis of the prototype hypoxia-activated anti-tumour codrug (Z)-1 was successfully achieved with an overall yield of 12% over 7 steps. A synthetically more convenient route through carboxylic acid intermediate (Z)-5 was unsuccessful, as ester/amide coupling conditions produced the cyclisation product 5,7-dimethyl-2-(2- nitrophenyl)-3H-pyrrolizin-3-one 14 in high yield. Instead, it was necessary to optimise a step-wise synthesis through N-(4-(bis(O-tert-butyldimethylsilyl-2- hydoxyethyl)amino)phenyl)-2-(2-nitrophenyl)acetamide 8, then perform a Knoevenagel condensation with N-protected pyrrole aldehyde 9 to form (Z)-7. After deprotection and chlorination of (Z)-7, prototype codrug (Z)-1 was obtained as an air-stable solid.

Subjects/Keywords: Cancer; codrugs; hypoxia-activation; angiogenesis

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

APA (6th Edition):

Kirk, N. (2015). Synthetic and biological investigations into hypoxia-activated anti-tumour codrugs. (Doctoral Dissertation). University of Wollongong. Retrieved from 0304 MEDICINAL AND BIOMOLECULAR CHEMISTRY, 0305 ORGANIC CHEMISTRY ; https://ro.uow.edu.au/theses/4537

Chicago Manual of Style (16th Edition):

Kirk, Nicholas. “Synthetic and biological investigations into hypoxia-activated anti-tumour codrugs.” 2015. Doctoral Dissertation, University of Wollongong. Accessed November 26, 2020. 0304 MEDICINAL AND BIOMOLECULAR CHEMISTRY, 0305 ORGANIC CHEMISTRY ; https://ro.uow.edu.au/theses/4537.

MLA Handbook (7th Edition):

Kirk, Nicholas. “Synthetic and biological investigations into hypoxia-activated anti-tumour codrugs.” 2015. Web. 26 Nov 2020.

Vancouver:

Kirk N. Synthetic and biological investigations into hypoxia-activated anti-tumour codrugs. [Internet] [Doctoral dissertation]. University of Wollongong; 2015. [cited 2020 Nov 26]. Available from: 0304 MEDICINAL AND BIOMOLECULAR CHEMISTRY, 0305 ORGANIC CHEMISTRY ; https://ro.uow.edu.au/theses/4537.

Council of Science Editors:

Kirk N. Synthetic and biological investigations into hypoxia-activated anti-tumour codrugs. [Doctoral Dissertation]. University of Wollongong; 2015. Available from: 0304 MEDICINAL AND BIOMOLECULAR CHEMISTRY, 0305 ORGANIC CHEMISTRY ; https://ro.uow.edu.au/theses/4537

2. Eldridge, Joshua A. SYNTHESIS AND STABILITY STUDIES OF PRODRUGS AND CODRUGS OF NALTREXONE AND 6-β-NALTREXOL.

Degree: 2013, University of Kentucky

The present study was divided between two different drug delivery goals, each involving naltrexone (NTX) or its active metabolite, 6-β-naltrexol (NTXOL). First, amino acid esters of NTX and NTXOL were prepared in order to test their candidacy for microneedle-enhanced transdermal delivery. Second, a 3-O-(-)-cytisine-naltrexone (CYT-NTX) codrug was prepared for screening as a potential oral delivery form of NTX and (-)-cytisine (CYT). The amino acid prodrugs were intended for the treatment of alcohol abuse, while the codrug was designed as a single agent for the treatment of alcoholism and tobacco-dependency co-morbidities. One hypothesis of this work was that prodrugs of NTX or NTXOL can be designed that possess superior skin transport properties through microneedle-treated skin compared to parent NTX or NTXOL. Nine amino acid ester prodrugs were prepared, and only three 6-O amino acid ester prodrugs of NTXOL were stable enough at skin pH (pH 5.0) to move forward to studies in 50% human plasma. 6-O-β-Ala-NTXOL, the lead compound, exhibited the most rapid bioconversion to NTXOL in human plasma (t1/2 = 2.2 ± 0.1 h); however, this in vitro stability value indicates that the prodrug may require hepatic enzyme-mediated hydrolysis for sufficiently rapid bioconversion to NTXOL in vivo. A second hypothesis of this work was that a CYT-NTX codrug could be designed with appropriate stability characteristics for oral delivery. CYT-NTX was found to be stable over the time course of 24 h in buffer systems of pH 1.5, 5.0, 7.4 and 9.0, and in 80% rat plasma, 80% human plasma, simulated gastric fluid and simulated intestinal fluid. Six (3 rats/group) Sprague-Dawley male rats were dosed i.v. with 1 mg/kg CYT-NTX codrug, or 10 mg/kg, p.o. Oral administration of a 10 mg/kg dose of CYT-NTX codrug resulted in rapid absorption and distribution (5 min) of CYT-NTX codrug, and NTX was released from codrug with a peak plasma concentration of 6.8 ± 0.9 nmol/L reached within 65 minutes. Plasma CYT was not detected; however, NTX delivery was achieved with a fraction absorbed value of 13%. Thus, CYT-NTX may hold promise as a potential oral codrug for further optimization and development.

Subjects/Keywords: naltrexone; amino acid prodrugs; codrugs; (-)-cytisine; microneedles; Amino Acids, Peptides, and Proteins; Organic Chemicals; Pharmaceutical Preparations

…Prodrugs and Codrugs (What are they?) 13 1.8 Amino acid prodrugs 18 1.9 PTD prodrug… …design to treat alcoholism 80 1.10 MNTD prodrug design to treat alcoholism 85 1.11 Codrugs… …miscellaneous prodrugs of NTX 223 Chapter 5 Synthesis of Codrugs of Naltrexone with Bupropion and… …x28;Yerramreddy, Milewski et al. 2010). 86 Figure 1.27 Marketed Codrugs. Adapted from… …Figure 1.28 PTD codrugs for alcohol abuse or alcohol-tobacco co-abuse. Adapted from (… 

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

APA (6th Edition):

Eldridge, J. A. (2013). SYNTHESIS AND STABILITY STUDIES OF PRODRUGS AND CODRUGS OF NALTREXONE AND 6-β-NALTREXOL. (Doctoral Dissertation). University of Kentucky. Retrieved from https://uknowledge.uky.edu/pharmacy_etds/16

Chicago Manual of Style (16th Edition):

Eldridge, Joshua A. “SYNTHESIS AND STABILITY STUDIES OF PRODRUGS AND CODRUGS OF NALTREXONE AND 6-β-NALTREXOL.” 2013. Doctoral Dissertation, University of Kentucky. Accessed November 26, 2020. https://uknowledge.uky.edu/pharmacy_etds/16.

MLA Handbook (7th Edition):

Eldridge, Joshua A. “SYNTHESIS AND STABILITY STUDIES OF PRODRUGS AND CODRUGS OF NALTREXONE AND 6-β-NALTREXOL.” 2013. Web. 26 Nov 2020.

Vancouver:

Eldridge JA. SYNTHESIS AND STABILITY STUDIES OF PRODRUGS AND CODRUGS OF NALTREXONE AND 6-β-NALTREXOL. [Internet] [Doctoral dissertation]. University of Kentucky; 2013. [cited 2020 Nov 26]. Available from: https://uknowledge.uky.edu/pharmacy_etds/16.

Council of Science Editors:

Eldridge JA. SYNTHESIS AND STABILITY STUDIES OF PRODRUGS AND CODRUGS OF NALTREXONE AND 6-β-NALTREXOL. [Doctoral Dissertation]. University of Kentucky; 2013. Available from: https://uknowledge.uky.edu/pharmacy_etds/16

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