Dissertations / Theses: 'Pharmaceutical chemistry'

1

Raynel, Guillaume. "Application of green chemistry principles to the pharmaceutical industry." Thesis, University of Leeds, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.553778.

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Vallin, Karl S. A. "Regioselective Heck Coupling Reactions : Focus on Green Chemistry." Doctoral thesis, Uppsala University, Department of Medicinal Chemistry, 2003. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-3380.

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Carbon-carbon bond formation reactions are among the most important processes in chemistry, as they represent key steps in the synthesis of more complex molecules from simple precursors. This thesis describes mainly the development of novel regioselective applications of the mild and versatile palladium-catalyzed carbon-carbon coupling method, commonly known as the Heck reaction. In addition, this thesis will focus on environmentally friendly developments of the Heck reaction.

Novel ligand-controlled internal Heck vinylations of vinyl ethers and enamides to form branched electron-rich dienes were performed with high regioselectivity. The vinylation of 2-hydroxyethyl vinyl ether permits a chemoselective transformation of a vinylic triflate or bromide into a blocked α,β-unsaturated methyl ketone. Furthermore, a simple separation of the palladium catalyst was achieved with new fluorous-tagged bidentate ligands in combination with fluorous solid phase extraction. The reaction times could be reduced up to 1000 times with controlled microwave heating in the palladium-catalyzed reactions with, in the majority of cases, retained, high selectivity.

The development of a “green” regioselective arylation and vinylation method relying on an aqueous DMF-potassium carbonate system and excluding the toxic thallium salt has been accomplished. Ionic liquids as the versatile and environmentally friendly class of solvents have been used in rapid phosphine-free terminal Heck arylations with controlled microwave heating. Recycling of the catalytic medium was achieved after a simple product purification.

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3

Brown, Stacy D., Andy Coop, Paul Trippier, and Eric Walters. "Contemporary Approaches For Teaching Medicinal Chemistry." Digital Commons @ East Tennessee State University, 2017. https://dc.etsu.edu/etsu-works/5251.

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As the profession of pharmacy has transitioned from a chemistry-centered profession to a patient-centered profession, the role of medicinal chemistry in the curriculum has evolved. There is decreased emphasis on memorization of chemical structures, and priority placed on relating these structures to ADME, physical properties, and pharmacodynamics. Simultaneously, the delivery of this content has shifted from traditional lecture format to other styles. Here we discuss some new approaches to teaching medicinal chemistry.

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4

O'Neill, Catherine A. "Formulation of pharmaceutical gels." Thesis, Queen's University Belfast, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.317524.

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5

Mukherjee, Sreya. "Crystal Engineering of Pharmaceutical Cocrystals." Scholar Commons, 2011. http://scholarcommons.usf.edu/etd/3258.

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Pharmaceutical cocrystals use principles of crystal engineering for the design of crystalline forms of drugs and can improve their solubility, bioavailability, stability and other important properties without changing the efficacy of the drug. Herein reported are pharmaceutical cocrystals of two API's, caffeine and Pentoxifylline. Research has indicated that caffeine has the ability to reverse AB; plaque deposition in the brain (believed to be the primary cause of Alzheimer's pathogenesis) and thus revert memory and improve cognitive impairment. But owing to the fast absorption rate and short half life, a controlled release formulation of caffeine would be clinically beneficial. Thus, novel cocrystals of caffeine are presented with varying solubilities with respect to caffeine. The pharmaceutical cocrystals of caffeine used herein include: caffeine.cyanuric acid monohydrate, caffeine.syringic acid tetrahydrate, caffeine.chlorogenic acid and caffeine.catechin hydrate. Three caffeine cocrystals were prepared in our lab previously which include caffeine.ferulic acid, caffeine.ethyl gallate dihydrate and caffeine.caffeic acid. In addition, six caffeine cocrystal forms were reproduced from the literature and included in the solubility study: caffeine.quercetin, caffeine.salicylic acid, caffeine.1-hydroxy-2-napthoic acid, caffeine.gallic acid hemihydrate, caffeine.ellagic acid monohydrate and caffeine.coumaric acid. Dissolution studies were performed in aqueous media at room temperature. All of the cocrystals decreased the solubility of caffeine with the highest being a 278 fold decrease in the solubility of caffeine. Analysis of melting point, crystal packing efficiency and solubility of cocrystal former with solubility was also done to determine if they influenced the solubility. Presented herein are the results of the analyses. It was seen that solubility of the cocrystal former had no effect on the decrease in cocrystal solubility. Moreover melting point and solubility of the cocrystal could not be correlated probably due to the variability in the cocrystal formers. Crystal packing efficiency though did not show a high correlation with solubility but it was seen that highest solubility achieved by pure caffeine achieved the lowest crystal packing efficiency and vice versa suggesting its role in cocrystal solubility. Pentoxifylline is contraindicated for its use in autism. But owing to high solubility of the drug, a less soluble form of the drug would help in decreasing the half life and thereby help in forming a sustained form of the drug by modifying the inherent solubility of the API. Here, novel cocrystals of Pentoxifylline are presented with varying solubilities with respect to the API. The pharmaceutical cocrystals used herein include: pentoxifylline.benzoic acid, pentoxifylline.1-hydroxy-2-napthoic acid, pentoxifylline.salicylic acid, pentoxifylline.gallic acid, pentoxifylline. salicylamide, pentoxifylline.coumaric acid, pentoxifylline.caffeic acid and pentoxifylline.catechin hydrate. Dissolution studies were also performed in aqueous media at room temperature. All of the cocrystals decreased the solubility of Pentoxifylline with the highest being a 99 fold decrease in the solubility with pentoxifylline.coumaric acid. On analyzing melting point, crystal packing efficiency and relation of solubility of cocrystal former with solubility of cocrystal, as was done in the case of caffeine, the parameters showed no effect on solubility of the cocrystal.

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6

Thakur, Shravan Singh. "Introduction to Pharmaceutical Thermal Analysis: A Teaching Tool." Cleveland State University / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=csu1316880806.

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7

Ye, Zhu Yi Fan. "Deep learning for pharmaceutical formulation prediction." Thesis, University of Macau, 2018. http://umaclib3.umac.mo/record=b3952123.

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8

Sander, John Roy George. "Expansions of supramolecular chemistry: nanocrystals, pharmaceutical cocrystals, imaging, and decorated olefins." Diss., University of Iowa, 2012. https://ir.uiowa.edu/etd/3527.

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Crystal engineering has matured into a design-driven field based on the exploitation of reliable interactions between the functional groups of molecules so as to achieve desired properties. The utility of crystal engineering has been realized in a breadth of fields and, as a microcosm of crystal engineering, this thesis will explore the application of crystal engineering in the pharmaceutical sciences, nanotechnology, synthetic chemistry, materials science, and biomedical imaging. As the trend in drug development continues to skew towards molecules with poor aqueous solubility the ability improve the physicochemical properties of a pharmaceutical agent, especially via non-covalent means, has become crucial. One method to impart improved physiochemical properties to pharmaceutical agents is through cocrystallization. A portion of this thesis will focus on the design-driven development of pharmaceutical cocrystals so as to impart improved mechanical properties to acetaminophen. As part of our investigation, we observed unexpected intermolecular interactions between the constituents of our cocrystals, which will contribute to the continued development of crystal engineering. In addition, we are interested in developing a methodology for the reliable fabrication of organic nanocrystals based on multi-component solids. Whereas the field of inorganic nanocrystals has blossomed, organic nanocrystals have remained largely underdeveloped. To expand the field of organic nanocrystals we turned to the synthesis of pharmaceutical nano-cocrystals. Specifically, we determined a sonochemical approach combined with multiple solvents and a surfactant could effectively synthesize pharmaceutical nano-cocrystals. As part of our desire to synthesize complex, multi-component, organic nanocrystals we also investigated the ability of a sonochemical approach to synthesize host-guest nanocrystals. In particular, the results demonstrated that sonochemistry successfully fabricates nano- and micrometer sized crystals of a host-guest solid and affords rhombic-dodecahedral crystals of a hollow topology. This thesis will also examine [2+2] photodimerizations in the solid-state. Previous work has successfully established the application of a template-directed solid-state approach to the photodimerization of olefins in the solid-state. However, these studies have largely focused on the reactivity of symmetric bipyridines. Thus, we have expanded the functional group diversity associated with [2+2] photodimerizations to include the cyano moiety. We have shown the template approach successfully aligns our targeted cyano-substituted olefins to enable photodimerizations in the solid-state. In addition, we have investigated the ability to synthesize cocrystals based on iodinated contrast agents. We believe the cocrystal approach could afford contrast agents with tailored properties based on the selected cocrystal former. The results of our investigation include five cocrystals and five salts composed of iodinated contrast agents. The results help to establish a knowledge base to be exploited in the design of future contrast agent based cocrystals with tailored properties.

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9

Williams, Brett H. "Design and synthesis of 3-[N-(cyclopropylmethyl) amino]-7-(methoxy or hydroxy)-2, 2-dimethyl-1-tetralone analogs as potential opioid receptor antagonists." Scholarly Commons, 2004. https://scholarlycommons.pacific.edu/uop_etds/591.

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A series of 3-aminotetralins were synthesized as potential opioid antagonists. Each proposed target compound was based on a 3-(mono- or dialkylamino )-7 -(hydroxy or methoxy)-2, 2-dimethyl-1-tetralone parent structure. Three synthetic schemes were developed utilizing the common intermediate, ethyl3-benzylamino-2, 2-dimethyl-4-(4- methoxyphenyl)butyrate 3. In Scheme I, compound 3 was modified through a series of six steps to obtain 3-(N-methyl-N-cyclopropanecarboxamido )-7 -methoxy-2, 2-dimethyl- 1-hydroxy-1-phenyltetralin (9). To carry out further synthetic steps on the intermediate 9 required the reduction of the amide function, which proved to be problematic in terms of product isolation. Scheme II was a four-step procedure, which utilized the intermediate ethyl 3- amino-2, 2 dimethyl-4-(4-methoxyphenyl)butyrate (4), also utilized in Scheme I. Ester hydrolysis of the amino ester 4 produced the amino acid 12. Internal cyclization of 12 yielded the key intermediate, 3-amino-7 -methoxy-2, 2-dimethyl-1-tetralone (13). TheNalkylation step was carried out on 13 and this yielded the target compounds, 3-[N- ( cyclopropylmethyl)amino ]- and 3-[N, N-( dicyclopropylmethyl)amino ]-7 -methoxy-2, 2- dimethyl-1-tetralone (14, 15). Subsequently, compounds 14 and 15 were 0-demethylated to obtain the respective target compounds, 3-[N-(cyclopropylmethyl)amino]- and 3-[N, N-(dicyclopropylmethyl)amino ]-7-hydroxy-2, 2-dimethyl-1-tetralone (16, 17). Scheme III was an alternate synthetic route to obtain the target compounds 3-[Nmethyl- N-( cyclopropylmethyl)amino ]-2, 2-dimethyl-7-(hydroxy or methoxy)-1-hydroxy- 1-phenyltetralin (10, 11) without the amide reduction step required in Scheme I. The intermediate 3 was N-methylated to form the 3-N-methyl-N-benzylamino ester 18 by the Eschweiler-Clarke procedure. Compound 18 was converted through a series of four steps to obtain 3-[ N-methyl-N-( cyclopropylmethyl)amino ]-7 -methoxy-2, 2-dimethyl-1- tetralone (22), a target compound which was 0-demethylated to obtain compound 23, the 7-0H analog. The mono- and dialkylated 3-aminotetralins were synthesized and confirmed for purity and correct molecular formula by utilizing 1H NMR, 13C NMR, mass spectrometry, and elemental analysis. The target compounds 14, 15, 16, 17,22 and 23 were converted to their salts and are being analyzed for opioid-related activity in receptor binding assays.

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10

Sun, Hongzhe. "Biological chemistry of bismuth drugs." Thesis, Birkbeck (University of London), 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.244018.

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11

Brown, Stacy D. "Using Guided Inquiry to Teach Medicinal Chemistry." Digital Commons @ East Tennessee State University, 2019. https://dc.etsu.edu/etsu-works/5249.

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12

Franke, Roland Rolf. "The impact of combinatorial chemistry on the pharmaceutical drug discovery process." Thesis, Massachusetts Institute of Technology, 1995. http://hdl.handle.net/1721.1/11159.

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13

Khan, Musharraf Naveed. "Synthesis of different heterocyclic compounds of pharmaceutical relevance." Thesis, University of Huddersfield, 2013. http://eprints.hud.ac.uk/id/eprint/19503/.

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This thesis describes the synthesis of different cyclic imines and the exploration of their reactivity with cyclopropenones and 1,3-dipoles,as well as an investigation of the chemistry of the products. The synthesis of biologically and pharmaceutically important heterocyclic natural product analogues, such as the pyrroloazepines, indolizidines and pyrrolizidines has been achieved using a cycloaddition reaction between cyclic imidates and cyclopropenones. A new route to pyridines has been developed using the generation of a proposed 3-azacyclopentadienone as the key step. The 3-azacyclopentadienones are generated by using boiling toluene to induce a [2+2]-cycloreversion in a series of azabicyclo[3.2.0]hept-2-en-4- ones. Regiospecific Diels-Alder reaction of the intermediate 3-azacyclopentadienone with a styrene is followed by chelotropic extrusion of carbon monoxide and loss of hydrogen to give the pyridine. The process is similar to the well-known process by which benzenes are accessed from cyclopentadienones. The azabicyclo[3.2.0]hept-2 en-4-ones were available from the reaction of cyclopropenones with 1-azetines, where cyclopropenones behave as an all carbon 1,3- dipole equivalents. Using the same methodology 1,3-dipolar cycloaddition of nitrile oxides to 4-aryl-2-alkylthio-1-azetines afforded a series of oxadiazabicyclo[3.2.0]heptenes as single diastereoisomers. Heating these cycloadducts in toluene resulted in an overall [2+2]- cycloreversion to give 5-alkylthio-3-aryl-1,2,4 oxadiazoles. Cycloaddition reactions of a series of benzodiazepines were also studied. The benzodiazepines were formed using literature methods and converted to cyclic imines with the help of Meerwein’s reagent. Reactions between such cyclic imines and cyclopropenones and 1,3 dipoles were attempted to produce tricyclic and tetracyclic benzodiazepine analogues. Finally, some multicomponent reactions of aryl aldehydes with cyanides and 1,3-dicarbonyl compounds were investigated to produce fully substituted heterocyclic compounds like dihydropyridines and pyrans with substituents suitable for intramolecular cyclization and imine formation. The main substituent of interest was the azide group as this had been used in section 2.3.3.1.2 & 2.3.3.1.3 in this thesis.

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14

Lam, Ka Wing. "Pharmaceutical salt formation guided by phase diagrams /." View abstract or full-text, 2009. http://library.ust.hk/cgi/db/thesis.pl?CBME%202009%20LAM.

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15

Keiser, Michael James. "Relating protein pharmacology by ligand chemistry." Diss., Search in ProQuest Dissertations & Theses. UC Only, 2009. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3378494.

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16

Warisnoicharoen, Warangkana. "Pharmaceutical nonionic oil-in-water microemulsions." Thesis, King's College London (University of London), 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.286790.

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17

Khalaf, Ahmed S. "Pharmaceutical characterisation of novel microcrystalline cellulose." Thesis, University of Bath, 2000. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.288235.

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18

Miller, Mark Russell. "Preclinical evaluation of AG10 for therapeutic use against familial amyloid cardiomyopathy and its application in various other technologies." Scholarly Commons, 2017. https://scholarlycommons.pacific.edu/uop_etds/3556.

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Transthyretin (TTR) amyloidosis is a progressive, fatal disease in which deposition of amyloid derived from either mutant or wild-type TTR causes severe organ damage and dysfunction. TTR cardiomyopathy is an infiltrative, restrictive cardiomyopathy characterized by progressive left and right heart failure. Familial amyloid cardiomyopathy (FAC) is driven by pathogenic point mutations in the TTR gene that destabilize the TTR tetramer, prompting its dissociation into dimers and monomers, with subsequent misfolding, aggregation and deposition of toxic TTR amyloid aggregates in the myocardium. The most prevalent mutation that causes FAC is the V122I variant, carried by 3.4% of African Americans, that increases the risk of cardiomyopathic events several-fold in this population. AG10, a potent TTR kinetic stabilizer, prevents dissociation of V122I-TTR in serum samples obtained from patients with FAC. Further, we have described structural, biochemical, and animal studies of AG10 which reveal mechanistic and structural insights on the ability of AG10 to mimic the disease suppressing T119M variant in stabilizing TTR. The second part of the thesis discusses harnessing TTR as a platform to enhance in vivo half-life (t1/2) of therapeutic peptides. Native peptides typically display short in vivo t1/2, however conjugation of peptides to macromolecules causes steric hindrance which often harms the binding of peptides to target receptors, compromising the in vivo efficacy. Utilizing Gonadotropin Releasing Hormone (GnRH) as a model peptide, we show that t1/2 may be extended without compromising potency. Our approach involves endowing peptides with a small molecule that binds reversibly to the serum protein transthyretin. Our strategy was effective in enhancing the t1/2 of an agonist for GnRH receptor while maintaining its binding affinity, which was translated into superior in vivo efficacy. The third and final part of the thesis describes our effort on developing a fluorescent probe to quantify TTR in human serum using fluorescence polarization. TTR is used as a marker for nutritional and inflammatory status in critical patients. This assay development has the potential to minimize lab cost, effort, and time with regards to determination of TTR concentration in patients.

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19

Zhao, Taiping Nafie Laurence A. Freedman Teresa B. "Near-infrared vibrational circular dichroism of polypeptides and small pharmaceutical molecules." Related electronic resource: Current Research at SU : database of SU dissertations, recent titles available full text, 2004. http://wwwlib.umi.com/cr/syr/main.

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20

Weight, Alisha K. (Alisha Kessel). "Enhancing pharmaceutical formulations to improve efficacy and delivery of drug molecules." Thesis, Massachusetts Institute of Technology, 2013. http://hdl.handle.net/1721.1/82323.

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Thesis (Ph. D. in Biological Chemistry)--Massachusetts Institute of Technology, Dept. of Chemistry, 2013.
Cataloged from PDF version of thesis.
Includes bibliographical references.
Major impediments to the full utility of current and potential drugs include issues of resistance and delivery. To address these challenges, in this thesis two directions of research were pursued: (1) the use of multivalent polymeric inhibitors to overcome drug resistance in human and avian influenza and (2) low-viscosity, high-concentration protein suspensions for therapeutic antibody, in particular monoclonal antibody (MAb), delivery. (1) Influenza resistance to small molecule neuraminidase (NA) inhibitors is spreading. Little emphasis, however, has been placed on alternative formulations of inhibitors. We investigated the design of multivalent antivirals, wherein small molecule ligands of viral proteins are conjugated via a linker to a linear polymeric backbone. Unexpectedly, we found that a poly-L-glutamine bearing pendant zanamivir (ZA) groups is at least as potent as those containing both ZA and sialic acid (SA). By examining the structure-activity relationship of such monofunctional conjugates, we show that the most potent one has 10% ZA attached to a neutral, high molecular weight backbone through a short alkyl linker. Importantly, we also demonstrate that such a polymer conjugate entirely compensates for weakened binding in and has 2,000-fold enhanced anti-viral potency against, ZA-resistant strains. We further evaluated this optimized inhibitor in vivo and observed that it is an effective therapeutic of established infection in ferrets and reduces viral titers up to 190-fold when used as a combined prophylactic/therapeutic in mice. Additionally, we see no evidence that the conjugate stimulates an immune response in mice upon repeat administration. (2) Typically, high doses of MAb therapeutics are required for clinical effect. Ideally, these MAbs would be delivered by subcutaneous injection of a small liquid volume. Such highly concentrated MAb solutions, however, are far more viscous than the 50 centipose (cP) permitted by the FDA. We evaluated approaches to reduce formulation viscosity by forming protein suspensions. Aqueous suspensions induced by poly(ethylene glycol), precipitating salts, or ethanol actually increased viscosity. However, non-aqueous suspensions of amorphous antibody powders in organic solvents that have s 1 hydrogen atom available for hydrogen-bonding, exhibited up to a 38-fold decrease in viscosity.
by Alisha K. Weight.
Ph.D.in Biological Chemistry

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21

Jäverfalk-Hoyes, Emmy. "Development of Methods in CE, CE-MS and MS/MS : Applications in Pharmaceutical, Biomedical and Forensic sciences." Doctoral thesis, Uppsala University, Department of Medicinal Chemistry, 2001. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-1361.

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Capillary electrophoresis-mass spectrometry has been used successfully for the analysis of a wide range of analytes such as chiral local anaesthetics, sulphonated reactive dyes and endogenous neurotransmitters and neuropeptides.

The partial filling technique was used in CE-MS for chiral separation of bupivacaine and ropivacaine using the non-volatile selector β-cyclodextrin. By only partially filling the capillary with selector and using capillaries coated with polyacrylamide to suppress the electroosmotic flow, introduction of the selector into the mass spectrometer was avoided. An impurity of 0.25% of the R-enantiomer of ropivacaine in the S-form could be detected.

The partial filling technique was developed further using CE employing two different selectors in separate plugs in the capillary. This enhanced the separation efficiency and offered greater flexibility in controlling the separation.

By using transient-isotachophoresis (tITP)-CE-MS it was possible to concentrate and detect classical neurotransmitters and neuropeptides with masses ranging from 104 Da to 1642 Da. γ -Aminopropyltriethoxysilane coated capillaries were used to minimize adsorption of the peptides onto to capillary surface. Endogenous dopamine, glutamate, γ-aminobutyric acid (GABA), acetylcholine, methionine-enkephalin and substance P 1-7 were detected in the striatum of marmoset monkey.

Sulphonated dyes obtained from single textile fibres were analysed using CE-MS. Capillary electrophoresis was found to be a good way of removing the excess amounts of glucose present in the sample that would otherwise interfere with the electrospray ionisation.

Automatic function switching, originally developed for use together with liquid chromatography, was found to be a great method for acquiring MS/MS data when doing infusion experiments saving both time and sample without decreasing the quality of the MS/MS data. It was also found to be a more time efficient way than using the precursor ion scanning mode on the Q-TOF to obtain precursor ion data.

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22

Göransson, Ulf. "Macrocyclic polypeptides from plants." Doctoral thesis, Uppsala University, Department of Medicinal Chemistry, 2002. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-1956.

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The aim of this work was to explore the structural and functional diversity of polypeptides that are found in plants. Expanding knowledge of simililarities between plant use of these compound and animal use promises exceptional opportunities for finding, from plant research, new structures with biomedical and biotechnological potential.

A fractionation protocol was developed and applied to many plant species, providing fractions enriched in polypeptides, amenable to chemical and biological evaluation. From one species, the common field pansy (Viola arvensis), a 29-amino-acid residue polypeptide was isolated, named varv A, which revealed a remarkable macrocyclic structure (i.e., N- and C-termini are joined) stabilised by three knotted disulfides.

Varv A, together with an increasing number of homologous peptides, form the currently known peptide family of cyclotides. Their stable structure makes them an attractive scaffold for protein engineering. In addition, they display a wide range of biological activities (e.g., antimicrobial, cytotoxic, and insecticidal). As a part of this work, the cytotoxic effects of varv A and two other isolated cyclotides were evaluated in a human cell-line panel: all were active in the low µM range. Most likely, these effects involve pore formation through cell membranes.

Cyclotides were found to be common in the plant family Violaceae; with eleven cyclotides isolated and sequenced from V. arvensis, V. cotyledon, and Hybanthus parviflorus. For six members of the genus Viola, cyclotide expression profiles were examined by liquid chromatography-mass spectrometry (LC-MS): all expressed notably complex mixtures, with single species containing more than 50 cyclotides. These profiles reflect the evolution of the genus.

To assess these mixtures, a rational strategy for MS based amino acid sequencing of cyclotides was developed, circumventing inherent structural problems, such as low content of positively charged amino acids and the macrocyclic structure. This was achieved by aminoethylation of cysteines, which, following tryptic digestion, produced fragments of size and charge amenable to MS analysis. This method was also modified and used for mapping of disulfide bonds.

Methods for isolation and characterisation developed in this work may prove useful not only for further studies on macrocyclic polypeptides from plants, but also for other plant peptides and disulfide-rich peptides from animals.

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23

Nöteberg, Daniel. "Design and synthesis of aspartyl protease inhibitors : Targeting HIV-1 and malaria plasmepsin I and II." Doctoral thesis, Uppsala University, Department of Medicinal Chemistry, 2003. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-3288.

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Aspartyl proteases can generally be inhibited by peptide mimics containing an uncleavable peptide bond isostere at the proposed cleavage site. One such peptide bond isostere is the hydroxyethylamine moiety, which in this thesis has successfully been incorporated in potential inhibitors of the HIV-1-protease as well as the malarial proteases plasmepsin I and II.

The human immunodeficiency virus (HIV) has during the last 20 years given rise to a new fast-spread epidemic. The virus protease is one of the foremost targets for drug intervention. In an attempt to improve an earlier design, a P1'-anthranilic acid was exchanged for all four isomers of 2-aminocyclopentanecarboxylic acid, which were synthesized from racemic starting materials, the trans isomers via a novel synthetic route. None of the isomers enhanced potency as compared to the anthranilic acid.

Because of increasing development of resistance, the pharmaceutical intervention with malaria is becoming rapidly more difficult. A prominent new target for drug research is the hemoglobin degradation pathway. Two of the many proteases involved in this pathway are plasmepsin I and II. Two series of peptide mimics with the hydroxyethylamine were prepared and tested against these enzymes as well as against the similar human protease cathepsin D.

In the first series the central nitrogen of the target compounds is a secondary amine, derived from natural and unnatural amino acids, the side-chain of which was to bind in the S1'-site of the proteases. It was found that para-aryl substituted phenylalanines resulted in the most active inhibitors. While the P1- and P2-side-chains were kept constant at benzyl and isopropyl respectively, the P3 capping carboxylic acid was varied with a set of diverse carboxylic acids. It was found that many of the carboxylic acids were acceptable.

A selection of compounds was tested for inhibition of parasite growth in infected human erythrocytes and found to be active.

In the target compounds of the second series the P1'-side-chain was moved from the α-carbon of the initial amino acids to the adjacent nitrogen, thus rendering this a tertiary amine. The SAR of these compounds suggests that this side-chain cannot be larger than benzyl, which is in sharp contrast to the first series, where both isomers of phenylalanine (i.e. a benzyl group on the α-carbon) render inactive compounds.

Most of the compounds show a good degree of selectivity for the plasmepsins over cathepsin D, even though a few good inhibitors of the human enzyme could be identified also.

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24

Tavana-Roudsari, Aria. "Crystallization from supercritical fluids; application to pharmaceutical and biochemical compounds." Diss., The University of Arizona, 1990. http://hdl.handle.net/10150/185194.

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Crystallization from supercritical fluids was studied as a nontoxic, noncontaminating alternative to conventional techniques for purification and size manipulation of pharmaceutical solids. To proceed with crystallization solubilities of several pharmaceutical compounds in supercritical carbon dioxide were experimentally determined and modeled using solid-vapor phase equilibria. The compounds studied included benzoic acid, salicylic acid, aspirin, griseofulvin, and digoxin among others. A high pressure crystallizer was constructed and operated in batch and continuous modes. Supersaturation was generated by various schemes, such as optimal pressure reduction and salting-out. It was determined that, depending on the crystallization scheme, particles can be produced at submicron as well as large sizes. Particle nucleation and growth rates from saturated supercritical solutions were estimated and the product size distributions were simulated using the population balance theory. Observations were made regarding habit and morphology of particles nucleated and grown at supercritical conditions.

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25

Deadman, Benjamin Jade. "New tools for flow chemistry and the machine assisted synthesis of pharmaceuticals." Thesis, University of Cambridge, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.648306.

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26

Li, Ju-Yun. "Quantitative structure-activity relationship studies in medicinal chemistry." Case Western Reserve University School of Graduate Studies / OhioLINK, 1995. http://rave.ohiolink.edu/etdc/view?acc_num=case1062596938.

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27

Forbes, Safiyyah. "Hydrogen-bond driven supramolecular chemistry for modulating physical properties of pharmaceutical compounds." Diss., Manhattan, Kan. : Kansas State University, 2010. http://hdl.handle.net/2097/3756.

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28

Laferrière, Craig A. "Synthesis of sialic acid antigens." Thesis, University of Ottawa (Canada), 1990. http://hdl.handle.net/10393/5987.

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N-Acetylneuraminic acid (NeuAc) is a sialic acid which constitutes terminal positions in glycoproteins and glycolipids. It is part of the antigenic determinant of many forms of cancer (S. Hakomori, Chem. Phys. Lipids. 42, 209 (1986)) and hence a cancer "vaccine" could be made from an appropriate multivalent macromolecular form of NeuAc. To explore the possibility of inducing anti-NeuAc antibodies, we have synthesized polyvalent conjugates of $\alpha$NeuAc or NeuAc$\alpha$2-3Gal$\beta$1-4Glc (sialyl2-3lactose) on protein carriers. This was accomplished by reductive amination with 2-oxoethyl $\alpha$-NeuAc or with the concealed aldehyde of the reducing sugar (glucose) onto the lysine residues of the proteins Bovine Serum Albumin (BSA) and Tetanus Toxoid (TT). A new procedure involving a Michael-type addition employed the $\epsilon$-amino groups of the lysine residues in a 1,4 nucleophilic addition to the acrylamide functional group in two derivatives of NeuAc; the N-acryloylaminoethylthiopropyl glycoside, and the N-acryloylsialyl2-3lactosylamine. This technique does not require the use of reagents and was performed under mild basic conditions. Polyacrylamide copolymers were also synthesized by radical co-polymerization of acrylamide with NeuAc monomers, providing a polymer (Mw $\approx$ 100 kDa) with pendant NeuAc. Reactive monomers giving different spacer arms between the sugar and the polymer backbone were developed, including the allyl glycoside, a more reactive N-acryloylaminoethylthiopropyl glycoside and several lactose derivatives. The polymers were found to have a better shelf life than the proteins, and had the advantage of sharing only the NeuAc moiety. Some of the NeuAc/protein conjugates were used to immunize rabbits, and the antibodies formed were screened with polyacrylamide copolymers with pendant NeuAc. The polymer with spacer was found to react better with the antibodies in immunoprecipitation and enzyme-linked immunosorbent assay (ELISA). Inhibition of ELISA experiments were done using synthesized derivatives of NeuAc to determine the binding specificity of the antibodies. It was found that the antibodies recognized the glycerol side chain, acid function, spacer, and to a lesser extent, the acetamido function of NeuAc. The same methodology was used to map the binding site of the lectin from Triticum vulgaris (called Wheat germ agglutinin, WGA) which binds NeuAc. Nuclear magnetic resonance (nmr) studies were undertaken to determine the acidity constants (pK$\sb{\rm a}$) and conformation of several NeuAc derivatives. Also studied was the lactone of NeuAc$\alpha$2-3Gal$\beta$1-4Glc which is believed to be responsible for the immunogenicity of certain cancer cells (T. Dohi, G. Nores and S. Hakomori, Cancer Res. 48, 5680 (1988)). This work was complemented by molecular modelling using MM2. A model was proposed for the conformation of the lactone which is consistent with the n.m.r. evidence.

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29

Smith, Cindy Jane. "Design of sialyl Lewisx glycomimetics: A novel approach towards the synthesis of sugar-coated anti-inflammatory drugs." Thesis, University of Ottawa (Canada), 2002. http://hdl.handle.net/10393/6092.

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The tetrasaccharide sialyl Lewisx (SLex) is the smallest recognizable ligand for selectins. The binding of SLe x to the selectins triggers the inflammatory cascade and recruits leukocytes to the injured cells. Chronic and acute inflammatory diseases result from the over-recruitment of leukocytes leading to damage of normal cells. Carbohydrate-based mimetics, maintaining functionality while improving stability, binding affinity and structural simplicity, are ideal candidates for anti-inflammatory drugs. Sialyl Lewisx glycomimetics were synthesized using two different convergent approaches. Each synthesis used an enzyme-resistant alpha-carbon-linked fucosyl moiety (C-glycoside) to replace the unstable anomeric oxygen linkage of the natural ligand. One synthetic route coupled a rigid proline ring to the fucosyl carboxylic acid derivative made from L-fucose to form one branch of the mimetic. The second branch was synthesized by coupling modified amines to form functionalized peptide chains of various lengths. The second convergent approach used novel olefin metathesis chemistry in the preparation to orchestrate a stereoselective cis-alkene bond formation extending from the fucosyl branch of the synthetic pathway. (Abstract shortened by UMI.)

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30

Ibrahim, Rana Hosni. "A synthetic approach to an immunosuppressant analogue of subglutinol." Thesis, University of Ottawa (Canada), 2001. http://hdl.handle.net/10393/9370.

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A novel synthetic strategy for the potential analogue 17 of the immunosuppressive agents subglutinols A (3) and B ( 4) was investigated. Neither of these molecules, nor any analogues, have been synthesized previously. The route selected employed a cis -isopropylidene control group in the tether to facilitate the key synthetic step, an intramolecular Diels-Alder reaction. This approach afforded the tricyclic core of 18 in an efficient and direct manner. The Diels-Alder precursor 20 was constructed from D-isoascorbic acid (24), vinylmagnesium chloride (22), and 4-iodo-3-methoxymethoxymethyl-penta-1,3-diene (21). The synthesis of the lactone 19 and the attempts to remove the MOM group from 18 were also investigated. Unfortunately, however, the final target analogue 17 was not realized due to unsuccessful attempts at removing the MOM group from 18. Thus, an efficient route to the decalin core was established, though the coupling of the lactone 19 awaits further study.

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31

Serreqi, Alessio N. "Hydrolase catalyzed resolutions of enantiomers : a structural basis for the chiral preference of lipases : preparation of enantiomerically-pure phosphines, phospine oxides, sulfoxides and pipecolic acid." Thesis, McGill University, 1994. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=28918.

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Enantiomerically-pure compounds are becoming increasingly important particularly to the pharmaceutical industry. Enzymes are useful tools in the synthesis of such compounds. To better understand how lipases discriminate between enantiomers of chiral secondary alcohols we obtained x-ray crystal structures of covalent complexes of Candida rugosa lipase with the transition-state analogs (1R)-menthyl hexylphosphonate and (1S)-menthyl hexylphosphonate. These compounds are transition-state analogs for the hydrolysis of menthyl esters. We observed that the transition-state analog of the unfavored (1S)-enantiomer of menthol disrupted the hydrogen bond between N$ varepsilon$2 of histidine 449 and the menthol oxygen. His 449 is part of the catalytic triad in CRL. This may account for the slower reaction of the (1S)-enantiomer of menthol. The crystal structures also identified binding site regions for secondary alcohols in CRL. These regions are common among many lipases and esterases and account for their common enantiopreference toward secondary alcohols.
Lipases and esterases can resolve compounds with phosphorus and sulfur stereocenters by hydrolysis of a pendant acetoxy group. Both CRL and cholesterol esterase have high selectivity for (2-acetoxy-1-naphthyl)methylphenylphosphine oxide. They resolved this substrate with and E of 81 and 32 respectively. A synthetic scale resolution of this substrate with subsequent recrystallization and chemical transformation followed by stereospecific reduction gave both enantiomers of (2-methoxy-1-naphthyl)methylphenyl-phosphine with 96-97% ee. This chiral phosphine is potentially useful in asymmetric syntheses.
CE is the most selective enzyme for the sulfur substrates tested but these enantioselectivities were moderate, E's ranged from 5 to 25. From the CE resolution of the phosphorus and sulfur compounds and others we propose an empirical model that predicts which enatiomer reacts faster. The model is based on the size of the substituents and their conformational preferences.
Crude Aspergillus niger resolves esters of pipecolic acid with an E of 20 $ pm$ 4. A simple partial purification of ANL by fractional precipitation with ammonium sulfate increased the enantioselectivity to $>$100. The partially purified ANL can be used in a synthetic scale resolution of ($ pm$)-n-octyl pipecolate to give (S)-($-$)-pipecolic acid (93% ee) and (R)-(+)-pipecolic acid (97% ee).

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32

Li, Song 1957. "Liquid chromatographic separation of enantiomers and structurally-related compounds on b-cyclodextrin stationary phases." Thesis, McGill University, 1992. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=70269.

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The retention behaviour of 16 phenothiazines and structurally-related drugs on a $ beta$-cyclodextrin-bonded phase column was studied with respect to pH, mobile phase composition and column temperature. Both isocratic and gradient-elution separations of these compounds were investigated.
The enantiomers of twelve racemic dinitrophenyl amino acid derivatives were separated on a $ beta$-cyclodextrin-bonded phase column. The effects of pH, methanol and triethylammonium acetate (TEAA) buffer concentrations on the retention and resolution were investigated. The chiral recognition mechanism was studied by means of UV-visible, circular dichroism and proton nuclear magnetic resonance spectroscopic methods.
A multiple-interaction type of chiral stationary phase was developed by bonding $ beta$-cyclodextrin to silica gel and modifying the cyclodextrin cavity by flexibly capping its primary hydroxyl or small side. These modified $ beta$ cyclodextrin stationary phases contain a hydrophobic cavity, capable of inclusion complexation; aromatic groups, capable of $ pi$-$ pi$ interaction; and polar hydrogen-bonding sites, capable of forming hydrogen-bonding with the polar functional groups of the solutes. These stationary phases exhibit a high stereoselectivity toward a wide variety of chiral compounds. The preparation and properties of these modified $ beta$-cyclodextrin stationary phases are described. The enantiomeric separation of amino acids and their derivatives, of carboxylic acids, of phenothiazine drugs, and of other chiral compounds are reported. The effects of mobile phase composition on the retention and resolution are discussed.

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33

Villeneuve, Gérald Blaise. "Ligands synthesis and conformational studies for the investigation of opiate and protease receptor sites." Thesis, McGill University, 1994. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=28547.

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A topochemical model has been derived to account for the diverse selectivity of cyclic opioid peptides related to enkephalins and for narcotic alkaloids towards the $ mu$ and $ delta$ opiate subclasses. Efforts toward demonstrating its validity have later been accomplished. The model is based on a computer molecular modeling study using the opiate pharmacophore as a minimum prerequisite to align the molecules and benefit also of informations obtained from spectroscopic study in solution concerning the macrocycles conformation. The conformational properties of N$ sp alpha$Cbz-c((D)A$ sb2$Bu-Gly-Phe-Leu) were studied by nuclear Overhauser effect which provided semi-quantitative internuclear distances. One of the important elements that the model brings out is that the eventual presence of an aromatic ring on the beta carbon of Cys of the opioid peptide HTyr-(D)Pen-Gly-Phe-Cys-NH$ sb2$ should induce an increase in selectivity toward the 6 opiate subclass. Consequently, we engaged in preparing the special amino acid, P-phenylcysteine, using a method based on the addition of mercaptan to unsaturated azlactone. The diastereoisomers obtained were separated, and their relative configurations assigned by X-ray crystallography. The pure enantiomers were obtained by resolution with the enzyme carboxypeptidase A. Several difficulties were encountered during this preparation, the main concern being the S protecting group. This protecting group should be chosen with the property that it can be quantitatively removed when desired and compatible with the conditions of peptides synthesis. Moreover, the size of the protecting group should be minimized in order to be able to realize the resolution with the enzyme. We explored, by the same token, the size of the hydrophobic pocket of the exopeptidase. Using the structural information obtained from the X-Ray diffraction study of several of the $ beta$-phenycysteine, we have determined with the help of computer molecular modeling, the

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34

Corbeil, Christopher. "New virtual screening tools for molecular discovery." Thesis, McGill University, 2009. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=40786.

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In the field of molecular discovery, virtually screening large libraries of compounds proved to be often more cost-efficient than the traditional experimental approaches. In fact, it has now become common practice thanks to the virtual screening tools available to chemists in the pharmaceutical industry, specifically docking. Most docking programs do not account for the dynamics associated with protein-ligand binding whether it is protein flexibility or the inclusion of displaceable water molecules. FITTED1.0 was developed to include these specific two features and has been validated on a testing set of 33 protein-ligand complexes. Further developments were needed to increase the speed of FITTED to enable its application as virtual screening tool. This enhanced version, FITTED1.5, has been applied to the screening of the Maybridge library onto the HCV polymerase and revealed FITTED’S ability to identify active substances. With this and other successful applications of FITTED, a comparative study was performed against other docking programs, with a specific interest in the effect of the ligand and protein input conformation and the inclusion of bridging water molecules on the accuracy of docking programs. All three had major effects on accuracy and led to suggestions on how to better conduct comparative studies. In parallel, we applied our expertise in the virtual screening area to the field of asymmetric catalyst development and led to the creation of ACE1.0. When creating a tool for predicting steroselectivities, one has to describe the transition state with great accuracy although within a reasonable amount of time. To tackle this problem, ACE creates the transition states from linear combinations of reactant and product interactions. A genetic algorithm is then exploited as a conformational search engine to optimize the TS structure. ACE has been applied to the Diels-Alder cycloaddition and the proline-catalysed aldol reactions and has showed good correlatio
Dans le domaine pharmaceutique, le criblage virtuel de large bibliothèques de molécules est une alternative moins couteuse et souvent au moins aussi efficace que le criblage à haut débit. D’ailleurs, le développement de tels outils –et plus particulierement de méthodes de "docking"– a permis au criblage virtuelle de devenir pratique courante dans l’industrie pharmaceutique. Cependant, la plupart des méthodes de docking ne prennent pas en compte la dynamique des complexes protéine/ligand et plus spécifiquement la flexibilité des protéines et la présence de molécules d’eau nécessaires à une liaison optimale. Dans cette optique, FITTED1.0 a été développé et validé sur un jeu de 33 complexes protéine/ligand. Ainsi, FITTED1.0 permet de modéliser des complexes ternaires protéine/ligand/eau entièrement flexibles. D’autres développements ont ensuite été nécessaires pour en accroître la rapidité et permettre son utilisation pour le criblage de larges bibliothèques. Cette version améliorée, FITTED1.5, a été appliquée au criblage de la bibliothèque Maybridge sur la polymérase du virus de l’hépatite C et a permis la découverte de deux nouveaux inhibiteurs. Après ces résultats très encourageants, une étude comparative a été entreprise visant spécifiquement à évaluer l’impact des données d’entrées sur le pouvoir prédictif des programmes de docking les plus couramment utilisés incluant FITTED2.6. Nous avons alors démontré que la présence d’eau, la conformation du ligand et de la protéine au départ du calcul ont un impact majeur. En parallèle, nous avons bénéficié de notre expertise pour développer un second outil de criblage virtuel ACE1.0 mais cette fois appliqué au criblage de catalyseurs asymétriques. Dans le domaine de la catalyse asymétrique, il nous fallait prédire la structure et l’énergie potentielle des états de transition et ce, dans un temps raisonnable. Pour ce faire, ACE cr

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35

Williams, Benjamin. "Design, synthesis and evaluation of selective estrogen receptor modulator/histone deacetylase inhibitor merged bifunctional ligands." Thesis, McGill University, 2014. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=123082.

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Breast cancer remains one of the most persistent threats to women's health in the Western world. The selective estrogen receptor modulator (SERM) tamoxifen is a front-line treatment for the disease, but suffers from a high rate of acquired resistance and an increased risk of endometrial cancer. As such, improved small molecule inhibitors with the ability to overcome antiestrogen resistance while limiting adverse side effects are valuable pharmaceutical targets. Histone deacetylase inhibitors (HDACi) have recently emerged as versatile anticancer agents with antiproliferative activity in breast cancer cells. Combination therapy of SERMs and HDACi has demonstrated enhanced cytotoxicity and the ability to restore tamoxifen sensitivity to antiestrogen-resistant cancer cell lines. This research project describes a novel approach to overcoming antiestrogen resistance by combining the anticancer properties and cooperative activity of SERMs and HDACi into compact, merged bifunctional ligands. Previous research by the Gleason laboratory indicated that HDACi functionality, in the form of zinc-chelating hydroxamic acids, could be integrated into the polar side chain of SERMs while maintaining antiestrogenicity at micromolar concentrations. Building from these preliminary results, a series of novel hybrid molecules was designed with zinc-binding groups incorporated into the aliphatic side chain or the triphenylethylene core structure of the active tamoxifen metabolite 4-hydroxytamoxifen (4-OHT). The resulting structures were investigated in silico using the molecular docking program FITTED. Twelve hybrid compounds were then synthesized by geminal Suzuki coupling and McMurry coupling procedures. Despite the propensity of the compounds to isomerize around the central double bond, the majority of the syntheses proceeded diastereoselectively and HPLC purification furnished the final products as a single isomer or in good diastereomeric excess. The HDAC inhibition and ER antagonism of the bifunctional molecules were evaluated in collaboration with the Mader laboratory of the Université de Montréal. Side chain-substituted hybrid compounds demonstrated good affinity for the ER binding pocket and nanomolar ER inhibitory activity. In addition, long-chain chimeric ligands possessing amide linkers exhibited significant HDAC 6 inhibition, with one compound displaying inhibitory activity at sub-micromolar concentrations. However, these side-chain substituted hybrids also exhibited substantial ER agonism in the absence of estradiol, which limited their effectiveness as antiestrogens. Conversely, a compound containing a phenyl hydroxamic acid in the aromatic core of 4-OHT acted as a full antagonist at micromolar concentrations and displayed no estrogenic behaviour. The core-substituted hybrid also exhibited modest HDAC inhibition, though it lacked the strong activity of its side chain counterparts. The synthesized SERM/HDACi molecules therefore displayed encouraging results and provided important structural insight into the future creation of bifunctional ligands.A brief side project is also described as a contribution towards the total synthesis of (R)-puraquinonic acid. The enantioselective synthesis of this natural product was previously accomplished by the Gleason group using a novel lactam auxiliary alkylation sequence to set the molecule's sole stereocenter. However, the specific rotation of the final product was opposite that expected and contradicted previous stereochemical assignments of the alkylation sequence. To address this inconsistency, a convergent stereochemical proof was completed which allowed direct comparison of alkylation products to auxiliary-based Mannich addition products that could be characterized by X-ray diffraction. The absolute stereochemistry of the sequence was thereby unambiguously assigned and strongly supported the conclusion that our group had successfully synthesized (R)-puraquinonic acid.
Le modulateur sélectif des récepteurs des œstrogènes (SERM) tamoxifène est le traitement principal pour le cancer du sein, mais souffre d'un taux élevé de résistance acquise et augmente le risque de developer un cancer de l'endomètre. Par conséquence, de nouvelles molécules antiestrogénique avec la capacité de surmonter la résistance aux antioestrogènes et de limiter les effets secondaires indésirables sont nécessaires. Les inhibiteurs d'histones déacétylase (HDACi) ont récemment emergés comme des agents possédant une activité antiproliférative contre les cellules du sein cancéreuse. La thérapie combinatoire des SERMs et HDACi démontre non seulement une cytotoxicité améliorée, mais aussi la capacité de restaurer la sensibilité envers tamoxifène dans les lignées cellulaires de cancer résistantes aux antioestrogènes. Ce projet décrit une nouvelle stratégie pour combattre la résistance antioestrogène en combinant l'activité des SERMs et des HDACi par la fusion des pharmacophores pour produire des ligands bifonctionnels.Les recherches précédentes par le laboratoire du Dr. Gleason ont indiqué que la fonctionnalité HDACi - sous la forme d'acides hydroxamiques - peut être intégrée dans la chaîne polaire des SERMs tout en conservant une antiestrogenicité modérée. Basé sur ces résultats préliminaires, une série de nouvelles molécules hybrides a été conçue avec des groupes se liant au zinc incorporés soit dans la chaîne latérale ou dans la structure centrale triphényléthylène du métabolite actif de tamoxifène, 4-hydroxytamoxifène (4 -OHT). Ces molécules ont été étudiés in silico à l'aide de FITTED, un programme de modélisation moléculaire. Douze molécules hybrides ont été synthétisées par des reactions de Suzuki et des réactions de McMurry. La majorité des synthèses ont pu être accomplies d'une manière diastéréosélective et la purification par CLHP a fourni les produits finaux sous forme d'isomère pure ou dans de bons excès diastéréoisomèriques.Les molecules bifonctionnelles ont été évaluées pour l'inhibition des HDACs et l'antagonisme envers le recepteur d'oestrogens (ER) en collaboration avec le laboratoire du Dr. Mader à l'Université de Montréal. Les hybrides possédant une acide hydroxamique sur la chaîne laterale ont démontré une bonne affinité pour ER de l'ordre nanomolaire. De plus, les ligands chimériques à longue chaîne possédant un amide ont démontré une inhibition importante envers HDAC 6 à une concentration micromolaire. Cependant, ces hybrides ont également démontré une activité agoniste substantielle de ER, qui limité leur efficacité comme antioestrogènes. Par contre, un hybride contenant un acide hydroxamique dans la structure centrale aromatique de 4-OHT a agi comme une antagoniste à des concentrations micromolaires, sans comportement oestrogénique. Les molécules ciblant SERM/HDACi offrent donc des résultats initiaux encourageants et des leçons importantes pour la création de nouveaux ligands bifonctionnels.Un bref projet contribuant à la synthèse totale de l'acide (R)-puraquinonique est aussi décrit. La synthèse énantiosélective de ce produit naturel a été accompli par le groupe Gleason avec l'aide d'une séquence d'alkylation utilisant un auxiliaire chirale bicyclique pour établir l'unique stéréocentre de la molécule. Toutefois, le pouvoir rotatoire spécifique du produit final était l'inverse de ce qui était attendu, et en contradiction avec la stéréochimie précédente de la séquence d'alkylation. Pour prouver la stéréochimie de notre processus d'alkylation, une voie de synthèse convergente a été accomplie qui a permis une comparaison directe des produits d'alkylation avec des produits d'addition de Mannich dont on était capable de caractériser par diffraction aux rayons X. La stéréochimie absolue de la séquence a été ainsi assignée sans ambiguïté et procure une confirmation que notre groupe avait réussi à synthétiser l'acide (R)-puraquinonique.

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36

Gritzalis, Demetrios. "Conformationally rigidified inhibitors of human farnesyl pyrophosphate synthase." Thesis, McGill University, 2014. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=123177.

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The mevalonate pathway is important in all eukaryotic cells. One of the key enzymes in this pathway is the human farnesyl pyrophosphate synthase (hFPPS), which has a pivotal role in cell prenylation. Nitrogen containing bisphosphonates (N-BPs) are a class of drugs that have been shown to effectively inhibit hFPPS and improve the survival of patients with various cancers, including multiple myeloma. However, the current drugs on the market (Risedronate and Zoledronate) interact with the active site of hFPPS sub-optimally and suffer from poor oral bioavailability and soft tissue exposure. A new series of inhibitors have been designed that can potentially interact with both the GPP and IPP sub-pockets of hFPPS. Based on a computational model, substituted benzimidazole- and indole-based inhibitors were designed to bind in both sub-pockets of the active site cavity of hFPPS. The benzimidazole-based inhibitors were found to be chemically unstable due to a reversible Michael reaction. Thus all efforts were subsequently turned towards the synthesis of indole-based inhibitors. These compounds were chemically stable when the bisphosphonate moiety was placed at C-3. The compounds were tested by DSF and in an inhibition enzymatic assay. The 2-substituted indoles were found to be active and provide a new structural class of hFPPS inhibitors.
La voie du mévalonate est importante pour toutes les cellules de type eucaryote. La farnésyle pyrophosphate synthase humaine (FPPSh) est une des enzymes clés pour cette voie qui possède un rôle pivot dans la prénylation cellulaire. Les molécules azotées contenant des biphosphonates (N- BPS) appartiennent à une classe de médicaments pouvant inhiber efficacement FPPSh et améliorer le taux de survie de patients atteints de plusieurs types de cancers, incluant notamment le myélome. Cependant, les médicaments en circulation sur le marché pharmaceutique (Risedronate et Zoledronate) interagissent inefficacement avec le site actif de FPPSh et offrent à la fois une mauvaise biodisponibilité orale et une exposition des tissus mous. Une nouvelle série d'inhibiteurs a donc été proposée pouvant potentiellement interagir avec les sous cavités GPP et IPP de FPPSh. Les inhibiteurs dont la structure est basée sur le motif benzimidazole substituée en position 2 et indole présentent ce critère et ont donc été désignés pour ce projet. Bien que les inhibiteurs possédant le motif benzimidazole aient été synthétisés, il a malheureusement été impossible d'isoler les produits de réactions du fait de la réversibilité de la réaction de Michael. Nos efforts se sont alors tournés vers la synthèse d'inhibiteurs possédant le motif indole. Ces composés sont bien plus stables lorsque le groupement biphosphonate est placé au C-3. Ces molécules ont été évaluées par DSF et des essais enzymatiques. A notre plus grand plaisir, les indoles substituées en positions 2 se sont révélées être des molécules meneuses pour une nouvelle classe d'inhibiteurs de FPPSh.

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37

Lan, En-Ling 1964. "Preformulation studies of melanotan-II." Thesis, The University of Arizona, 1992. http://hdl.handle.net/10150/291574.

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Melanotan-II (MT-II) is a cyclic heptapeptide analogue of α-MSH (α-melanocyte stimulating hormone) which tans the skin rapidly and is currently being evaluated for the prevention of sunlight-induced skin cancers. In these preformulation studies, the degradation of MT-II followed apparent first-order kinetics. The degradation rate increased as the temperature or phosphate buffer concentration were increased. The pH-rate profile of MT-II degradation showed that MT-II was most stable at approximately pH 5. The degradation of MT-II was not affected by ionic strength. The pKa1 and pKa2 were estimated to be 6.53 and 11.74, respectively. The partition coefficient was studied at various pH values. The Δ log PC at pH 7.35 was 1.05 which indicated that MT-II could pass the intestinal membrane relatively easily. The preformulation data presented here can be used to help develop an appropriate dosage form for MT-II.

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38

Naylor, Melissa. "Characterization of Human Glyoxalase 2-2." Miami University Honors Theses / OhioLINK, 2004. http://rave.ohiolink.edu/etdc/view?acc_num=muhonors1111685917.

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39

莊玲玲. "香港市售活絡油揮發性化學成分的氣質聯用(GC-MS)分析研究." HKBU Institutional Repository, 2011. http://repository.hkbu.edu.hk/etd_ra/1327.

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40

Mallari, Jeremy P. "Development of potent and selective trypanocides by targeting of the trypanosomal protease Tbcat B." Diss., Search in ProQuest Dissertations & Theses. UC Only, 2008. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3339197.

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Coan, Kristin Emily deWeese. "The mechanistic and physical characterization of promiscuous aggregate-based inhibitors." Diss., Search in ProQuest Dissertations & Theses. UC Only, 2008. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3339233.

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42

Agnes, Richard S. "New paradigm for drug design: Design and synthesis of novel biologically active peptides that are agonists at opioid receptors and antagonists at cholecystokinin receptors." Diss., The University of Arizona, 2003. http://hdl.handle.net/10150/280340.

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We now know from genomics that many disease states lead to changes in expressed proteins (adaptation/plasticity). Therefore, drug design and discovery based on normal states and single targets often is inadequate or even counter-indicated. Therefore, the "system changes" that have occurred must be considered in any treatment for the disease. Such "systems changes" are clearly evident in neuropathic pain where opioids can actually heighten pain. In these pain states there are increased levels of neurotransmitters such as cholecystokinin (CCK) in which both the peptides and their receptors are increased in pain states. To effectively treat diseases involving "systems changes" a new paradigm for the design of compounds was proposed. In this new approach single peptide or peptidomimetic molecules are designed to interact with multiple receptor targets. For the treatment of pain, a series of linear and cyclic peptides and peptidomimetics were designed based on the overlapping pharmacophores of opioid and CCK ligands. The CCK/opioid analogues were synthesized and evaluated for their biological activities. Several of the CCK/opioid analogues were found to simultaneously interact with opioid receptors as agonists and CCK receptors as antagonists. In addition, the lead compounds have been tested in several pain models and were found to be promising in the treatment of neuropathic pain. Further, the structure-activity relationships of these novel peptides have provided new insights into the requirements for binding and bioactivity at opioid and CCK receptors, as well as the overlapping pharmacophores of CCK and enkephalin.

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Heimbecher, Susan Klara 1954. "Mechanism of dansylation of the polyamine pentaazapentacosane 5 HCl." Diss., The University of Arizona, 1998. http://hdl.handle.net/10150/282701.

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Pentaazapentacosane pentahydrochloride (PAPC-HCl) is a synthetically produced aliphatic pentaamine that is being investigated for use as an anticancer agent. As part of this research project a rapid high-performance liquid chromatographic method for determination of the dansyl derivative of PAPC was developed. The chromatographic system uses a reverse phase C-8 column, a mobile phase of acetic acid buffer and acetonitrile and UV detection. The dansylation conditions were optimized with a pH of 11.0 and a 20 fold dansyl chloride excess. The yield of dansyl PAPC increased 10 fold as the reaction pH was changed from 9.5 to 10.5. An investigation of the products formed in the dansylation reaction revealed that, even under conditions of pH and dansyl chloride concentration most likely to produce partially dansylated products, only perdansyl PAPC is present. This unexpected finding is explained by a mechanism whereby (1) only completely unionized amine molecules will dansylate and (2) the ratio of unionized molecules to ionized molecules increases as dansylation proceeds. The proposed mechanism is verified by comparing the dansylation vs. pH profile of PAPC to that of a reference monoamine (piperidine ·HCl). After 4 hours at room temperature and pH 9.5, 100% of piperidine is dansylated while under the same conditions only 10% of PAPC is derivatized. A pH greater than 10.5 is required to completely dansylate PAPC. This difference is significantly greater than would be predicted from the pKₐ values but it is consistent with the proposed mechanism.

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Sanghvi, Tapan. "Formulation development of anticancer drug: FB642." Diss., The University of Arizona, 2004. http://hdl.handle.net/10150/289236.

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Carbendazim (methyl-2-benzimidazolecarbamate), a well known anti-fungal agent that may have significant anti-cancer activity, is a poorly water-soluble ampholyte. Unfortunately its projected oral dose up to hundred mg per day is far greater than its water solubility of 6 μg/ml. The overall aim of this research was to conduct preformulation studies and develop therapeutically viable oral and parenteral formulations. The solubility of carbendazim was altered by using both solute and solvent modification approaches. The solvent modification was carried out by investigating the solubilization of carbendazim by pH in combination with cosolvents, surfactants or complexants. At pH 7 the total drug solubility is 6.11 ± 0.45 μg/ml which increases by 1 to 7 fold with cosolvent, surfactant or complexant. However, at pH 2 the solubility increases by 400 times and at pH 1.3 over 3000 times. Both cosolvents and non-ionic surfactants have a negligible effect on the total drug solubility at pH 2, whereas the total drug solubility increases by combining pH 2 with anionic surfactants or complexants. The solute modification was accomplished by preparing different salts of carbendazim. In all six different salts, viz., hydrochloride dihydrate, phosphate, hemisulfate hydrate, mesylate, besylate, and tosylate were prepared. Their structures were determined using single crystal x-ray diffraction. The developability attributes (i.e. hygroscopicity, thermal behavior, aqueous solubility, solid state stability, and dissolution rate) of these compounds were evaluated. The dissolution studies showed that all the salts had better dissolution rate than the free base, the mesylate salt been the best. Based on the preformulation studies, two formulations were chosen for oral dosing in mice. The proposed oral formulation of 9.4 mg/ml carbendazim at pH 1 in phosphate buffer and 20% SBEβCD phosphate buffer, respectively, did not precipitate on in vitro static serial dilution with water and seven up. However, the formulation containing only phosphate buffer showed activity in mice by significantly reducing the tumor growth in B-16 melanoma injected mice. Also, it gave active blood levels, which were comparable to IV dosing.

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Medeiros, Marina dos Santos Garruti de. "Sensory analysis of extemporaneous formulations of cardiovascular drugs prepared with the vehicle âguteâ and administered to pediatric patients." Universidade Federal do CearÃ, 2014. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=12247.

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CoordenaÃÃo de AperfeÃoamento de Pessoal de NÃvel Superior
Many pediatric patients require medications that are not available in age appropriate formulations, especially those with cardiovascular diseases. Furosemide and Captopril generally are produced in solid dosage forms for adults, and need to be fractionated and transformed in suspensions for use in children. The use of a suitable vehicle is critical to the preparation of a homogeneous, stable and palatable extemporaneous formulation that can guarantee the expected effect. In this work was evaluated the acceptability of a vehicle, named Gute, developed by a research group from Universidade Federal do CearÃ, considering that palatability is essential to treatment adherence in children. We analyzed the vehicle in different flavors with respect to the ability to mask the bitter taste of Captopril and Furosemide, the acceptance and preference without actives by healthy children and their parents, and the acceptance of extemporaneous formulations of the mentioned drugs administered to pediatric patients as prescribed. In the laboratory, eight panelists evaluated the masking ability of the vehicle flavored in mint, cherry, strawberry and neutral using a linear scale. ANOVA scores for bitterness intensity for captopril and furosemide showed that the flavored samples had significantly greater capacity of masking the bitter taste than the vehicle without flavor (neutral), however, there was no different between the flavors. 62 children 4-12 years and 21 guardians participated in the evaluation of the vehicle without actives flavored in mint, strawberry and cherry, using a facial-verbal hedonic scale with seven degrees. The three flavors were accepted and equally preferred by children and guardians. In hospitalized patients who received suspensions of Captopril (34) and furosemide (36), the flavors mint, strawberry and neutral acceptance was evaluated through the guardians with the hedonic scale and compared with the observation of the researcher .Suspensions in neutral and strawberry flavors were considered acceptable for both drugs. The correlation between the results from the two methods was moderate for Captopril, and absent Furosemide. The results for the neutral flavor showed that the addition of flavoring agents did not influenced in the acceptance and can be avoided in this case, an advantage in terms of safety for infants and neonates.
Muitos medicamentos necessÃrios a pacientes pediÃtricos nÃo sÃo disponÃveis em formulaÃÃes apropriadas Ã idade, principalmente aqueles que tratam doenÃas cardiovasculares. Captopril e Furosemida, de modo geral, sÃo produzidos na forma sÃlida em doses para adultos, e necessitam ser fracionados e transformados em suspensÃes para uso em crianÃas. O uso de um veÃculo adequado Ã crÃtico para o preparo de formulaÃÃes extemporÃneas homogÃneas, palatÃveis e estÃveis, que possam garantir o efeito esperado. Neste trabalho foi avaliada a aceitabilidade de um veÃculo com nome fantasia Gute, desenvolvido por um grupo de pesquisa da Universidade Federal do CearÃ, tendo em vista que a palatabilidade Ã essencial para a adesÃo ao tratamento em crianÃas. Analisou-se o veÃculo em diferentes sabores em relaÃÃo Ã capacidade de mascarar o gosto amargo de Captopril e Furosemida, sua aceitaÃÃo e preferÃncia sem ativos por crianÃas sadias e seus responsÃveis, bem como a aceitaÃÃo de formulaÃÃes extemporÃneas dos medicamentos citados, administradas a pacientes pediÃtricos, conforme prescriÃÃo. Em laboratÃrio, oito provadores avaliaram a capacidade de mascaramento do veÃculo flavorizado nos sabores menta, cereja, morango e neutro, utilizando uma escala linear. A anova dos valores de intensidade do sabor amargo, para Captopril e Furosemida, mostrou que a capacidade dos sabores flavorizados de mascarar o sabor amargo foi significativamente maior do que a do veÃculo sem sabor, contudo, os sabores nÃo diferiram entre si. Participaram da avaliaÃÃo do veÃculo sem ativos, nos sabores menta, morango e cereja, 62 crianÃas de 4 a 12 anos e 21 responsÃveis, usando uma escala hedÃnica facial-verbal de sete graus. Os trÃs sabores foram aceitos e igualmente preferidos pelas crianÃas e pelos responsÃveis. Com os pacientes internados que receberam suspensÃes de Captopril (34) e Furosemida (36), nos sabores menta, neutro e morango, a aceitaÃÃo foi avaliada atravÃs dos responsÃveis com uso da escala hedÃnica e comparada com a observaÃÃo da pesquisadora. As suspensÃes nos sabores neutro e morango foram consideradas aceitas para ambos os medicamentos. A correlaÃÃo entre os resultados provenientes dos dois mÃtodos de avaliaÃÃo da aceitaÃÃo foi moderada para Captopril, e para Furosemida, nÃo houve correlaÃÃo. Os resultados relativos ao sabor neutro mostraram que a adiÃÃo de flavorizantes nÃo influenciou na aceitaÃÃo das suspensÃes, podendo ser evitada nesses casos, uma vantagem em termos de seguranÃa para bebÃs e neonatos.

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Brown, Stacy D. "Drug Stability Investigations: Addressing Patient Needs Through Analytical Chemistry." Digital Commons @ East Tennessee State University, 2017. https://dc.etsu.edu/etsu-works/5253.

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47

Boyce, Sarah Emily. "Model systems for molecular docking: Understanding molecular recognition in polar and charged binding sites." Diss., Search in ProQuest Dissertations & Theses. UC Only, 2009. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3390113.

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St, Denis Francine Joy. "Studies toward the total synthesis of epothilone A." Related electronic resource: Current Research at SU : database of SU dissertations, recent titles available full text, 2005. http://wwwlib.umi.com/cr/syr/main.

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Aumand, Livia M. "A Studies towards the formation of asymmetric quaternary centres via radical allylation B Applications of chiral hydrazide organocatalysts to Diels-Alder, hydride reduction, and alpha-chlorination reactions C Studies directed towards the synthesis of potential HIV-1 reverse transcriptase inhibitors: 9-Alkylaryl TIBO derivatives." Thesis, University of Ottawa (Canada), 2005. http://hdl.handle.net/10393/26843.

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In part A, the attempts at synthesizing quaternary centres via radical reactions are described. Using tartrate acetals as chiral auxiliaries, tertiary bromides were submitted to radical allylation conditions in an effort to form 1,3-dicarbonyl compounds 27 possessing an asymmetric quaternary centre at C2.* Part B describes the synthesis of chiral hydrazide 129 and its ability to catalyze the Diels-Alder reaction is examined. The application of chiral hydrazides 131 to the organocatalytic hydride reduction of alpha,beta-unsaturated aldehydes and the alpha-chlorination of aldehydes is also recounted herein.* Finally, in Part C, efforts towards the synthesis of potential broad spectrum HIV-1 reverse transcriptase inhibitors are described. Compounds 161 are based on the TIBO family of compounds and possess a novel alkylaryl appendage.* *Please refer to dissertation for diagrams.

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Yorke, Matthew. "Photochemistry of amido xanthonate photocages: Potential candidates for polymer-tethered photorelease of drugs." Thesis, University of Ottawa (Canada), 2010. http://hdl.handle.net/10393/28762.

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Recently, photocages capable of releasing biologically relevant molecules have been reported, which utilize the rapid and efficient photodecarboxylation of 2-xanthone acetic acid (XAA) with UVA irradiation. This thesis focuses on the development of functionalized xanthonate photocages to be used for surface-tethering applications. Firstly, the preparation of amine and acetamide functionalized xanthonate (and thioxanthonate) photocage precursors will be described. Investigation into the photochemistry of the prepared derivatives led to the discovery of a solvent composition dependence on the photodecarboxylation quantum yield of acetamide derivatives. The photodecarboxylation of these derivatives occurs cleanly in the same way as XAA, but with lower efficiency. The preparation and photochemical study of acetamide functionalized photocages will then be described. Photorelease of acetate and phenylalanine demonstrated the capability of amide functionalized photocages to release biologically relevant molecules. Lastly, initial investigations into polymer tethering will be described. Attempted amide coupling through the aromatic amine led to the attachment of a short chain carboxylic acid terminated linker to modify the linking site.

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Dissertations / Theses on the topic 'Pharmaceutical chemistry'

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