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Dissertations / Theses on the topic 'Biological and Medical Chemistry'

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Published: 4 June 2021
Last updated: 1 February 2022

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1

Nichols, Alexander J. "Optical Molecular Sensing in Complex Biological Environments." Thesis, Harvard University, 2014. http://nrs.harvard.edu/urn-3:HUL.InstRepos:14226087.

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Although techniques in molecular imaging have advanced considerably over the past several decades, there remain numerous categories of biological molecular targets that are refractory to straightforward imaging. Among these is molecular oxygen, which is vital to a host of physiological as well as pathological processes, as well as the amorphous pigment pheomelanin, which may play a formerly unappreciated role in melanoma carcinogenesis. This thesis describes two related bodies of work that advance techniques in oxygen and pheomelanin imaging, respectively. First, inspired by a desire to understand how hypoxia affects cancer chemotherapy on a cellular level, we designed and synthesized a novel oxygen-sensitive, dendritic nanoconstruct that is capable of spontaneously penetrating through hundreds of microns of multiple cellular layers. After demonstrating our nanoconjugate's oxygen sensitivity using time-domain phosphorescence lifetime measurements, we demonstrate that it retains its oxygen sensitivity in a 3D spheroid in vitro model of ovarian cancer through the use of a custom-made, near infrared-optimized confocal phosphorescence imaging system. Drawing from this approach, we then describe the fabrication and calibration of a separate oxygen-sensing bandage platform for use in wound-healing applications, and demonstrate its use in ex vivo and in vivo animal systems. The second body of work describes the use of non-linear four-wave mixing techniques to facilitate straightforward imaging of the molecular pigment pheomelanin. Recent findings suggest that pheomelanin may play a previously unappreciated role in melanoma carcinogenesis, even in the complete absence of an ultraviolet light insult. However, due to its pale color, pheomelanin is difficult to visualize against a skin background, making its study challenging. After constructing a femtosecond-pulsed coherent anti-Stokes Raman scatter (CARS) microscopy imaging system, we use imaging and spectroscopy to provide proof-of-concept that pheomelanin can be imaged through a combination of CARS microscopy and electronically-enhanced four-wave mixing. We then use our non-linear imaging system to specifically observe pheomelanin in isolated "redhead" mouse melanocytes, and show through an siRNA gene knock-down strategy that our system can be used to observe changes in pheomelanin signal upon modification of biological pathways known to affect pheomelanin synthesis.
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2

Pokhrel, Laxman. "Design, synthesis, and biological evaluation of tricyclic pyrones and thiouridine nucleosides." Diss., Kansas State University, 2013. http://hdl.handle.net/2097/16233.

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Doctor of Philosophy
Department of Chemistry
Duy H. Hua
The first chapter in this thesis includes the design, synthesis, and evaluation of anti-Alzheimer and anti-norovirus activities of tricyclic pyrones (TPs). Alzheimer’s disease is a major cause of dementia and sixth leading cause of death; it is a growing problem all over the world. On the other hand, norovirus, a highly contagious agent is responsible for more than 90% of non-bacterial gastroenteritis causing severity mainly in the closed environments. No drugs exist to eradicate the symptoms developed by both of these disorders. Studies have shown that the development of Alzheimer’s disease and the infection of norovirus are dependent on cholesterol metabolism. More specifically, the inhibition of acyl-CoA: cholesterol acyltrasferase (ACAT) led to the reduction of plaques in Alzheimer’s disease as well as reduced the infection of norovirus. Mimicking the structure of CP2, a TP with promising anti-Alzheimer activities, a library of tricyclic pyrones containing phenyl, naphthyl, heterocyclic, and dipeptidyl moieties were synthesized and evaluated for their anti-Alzheimer and anti-norovirus efficacies. Several TPs containing phenyl and naphthyl groups showed sub-micromolar to nanomolar potencies for the protection of neuronal MC65 cells from Aβ-oligomers induced death. Similarly, the TPs containing pyrrolyl, imidazolyl, and quinolinyl moieties were effective to inhibit the norovirus replication in low micromolar range. The most effective TPs from MC65 cells protection assay were also effective in the inhibition ACAT and up-regulation ABCA1 gene. The second chapter in this thesis includes the design, synthesis, and anti-norovirus activity of thiouridine nucleosides. Many nucleosides have demonstrated effective inhibition of viral RNA polymerase, and some are progressing at different level of clinical trials for the treatment of hepatitis C virus. Some of the nucleosides, including 2’-C-methyl and 2’-amino substituted analogs, were found to effectively inhibit the norovirus replication. In the search of more potent anti-noroviral compounds, two thiouridine nucleosides were synthesized and evaluated as anti-norovirus agents. Both of these analogs were ineffective up to 50 μM for the inhibition of norovirus replication in cell based assay. Proposed work of converting these nucleosides to their phosphoramidate derivatives is also described.
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3

Njaria, Paul Magutu. "Antimycobacterial 2-aminoquinazolinones and benzoxazole-based oximes: synthesis, biological evaluation, physicochemical profiling and supramolecular derivatization." Doctoral thesis, University of Cape Town, 2017. http://hdl.handle.net/11427/26954.

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Tuberculosis (TB) is a life-threatening infectious disease caused by Mycobacterium tuberculosis (Mtb). Globally, TB is a major public health burden with an estimated 10.4 million new cases and 1.8 million deaths reported in 2015. Although TB is curable, the treatment options currently available are beset by numerous shortcomings such as lengthy and complex treatment regimens, drug-drug interactions, drug toxicities, as well as emergence of widespread multi-drug resistance. Therefore, there is an urgent and compelling need to develop new, more effective, safer drugs with novel mechanisms of action, and which are capable of shortening treatment duration. This study focused on hit-to-lead optimization of two new classes of compounds with potential anti-TB properties: 2-aminoquinazolinones (AQZs) and benzoxazole-based oximes (BZOs). A hit compound for each of these classes with low micromolar antimycobacterial activity had previously been identified through phenotypic whole-cell in vitro screening.
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4

Forsyth, Andrea N. "Synthesis and Biological Evaluation of Rigid Analogues of Methamphetamines." ScholarWorks@UNO, 2012. http://scholarworks.uno.edu/td/1436.

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A series of rigid azetidenyl-based methamphetamine analogs were synthesized from commercially available N-Boc-azetidinone. The benzylideneazetidine analogs were prepared via a Wittig olefination via the ylides generated from the corresponding triphenylphosphonium benzylhalide salts. The substituted benzylazetidine analogs were synthesized from the corresponding benzylideneazetidienes via hydrogention over palladium and platinum catalysts. The benzylideneazetidine and benzyliazetidine analogs were evaluated at monoamine transporters as a part of preliminary structure-activity study for the development of novel monoamine transporter ligands. The binding affinities of the azetidine analogs were determined at dopamine (DAT) and serotonin (SERT) transporters in rat brain tissue preparations. The preliminary in vitro binding studies revealed that the rigid scaffold of the azetidine ring system was an effective substitution for the 2-aminopropyl group of methamphetamine and led to compounds with nanomolar binding affinity at dopamine and serotonin. In general, the benzylideneazetidine analogs were more potent than the corresponding benzylazetidine analogs. In addition, the azetidine analogs were more selective for the serotonin transporter than the dopamine transporter. The 3-(3,4-dichlorobenzylidene)azetidine (24m) was the most potent analog of the series with Ki values of 139 nM for SERT and 531 nM for DAT (DAT/SERT = 3.8).
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5

Zhu, Chongyu. "Polymeric drug delivery systems for biological antimicrobial agents." Thesis, University of Warwick, 2017. http://wrap.warwick.ac.uk/91996/.

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The objective of this work was to develop suitable delivery systems for biological agents that have antimicrobial activities using biocompatible polymers, aiming to reduce their toxicity when administered. Two biological agents, colistin as an antibacterial agent and nystatin (Nys) as an antifungal agent, are the focus of this thesis as they are potent treatments for current pathogen infections, especially to the multidrug-resistant (MDR) bacteria/fungi, but have potential toxicity to human. Polymeric drug delivery systems, including prodrug, hydrogel and micelle formulations, have been developed and discussed for their potential as topical and systemic regimes. The majority of the work was focused on the effect of the covalently attachment of synthetic polymers onto the biological agents upon their antimicrobial activities and the toxicity. The conjugation between colistin and polymers was achieved successfully through either irreversible or releasable linkages. Although irreversible polymer modifications on colistin showed no antimicrobial activity (chapter 2), an acceptable antibacterial activity was observed from the polymer-colistin conjugates with a releasable linkage through either ‘grafting-to’ (chapter 3) or ‘grafting-from’ (chapter 4) approaches. On the other hand, even though the pure polymer-Nys conjugate with a releasable imine linkage cannot be obtained due to the nature of the labile imine bond, the crude conjugate showed an excellent antifungal activity and a reduced toxicity compared to the native Nys (chapter 6). Other polymeric delivery systems were also discussed in this thesis. The incorporation of colistin within a developed hydrogel delivery system as an antibacterial patch for burn infections was investigated through in vitro and in vivo studies, showing a similar antibacterial activity as the native colistin solution against MDR Gram-negative bacteria with no systemic toxicity (chapter 5). Finally, an amphiphilic polymer containing boronic acid groups on the side chains was synthesised and used to target the hydroxyl groups on Nys, expecting to build up an environmental responsive micelle through dynamic boronate ester bond (chapter 7). Although more work is still needed, this system showed a potential to improve Nys solubility.
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6

Shi, Fengjian. "LASER ELECTROSPRAY MASS SPECTROMETRY: INSTRUMENTATION AND APPLICATION FOR DIRECT ANALYSIS AND MOLECULAR IMAGING OF BIOLOGICAL TISSUE." Diss., Temple University Libraries, 2017. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/445496.

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Chemistry
Ph.D.
This dissertation elucidates the instrumentation and application of a hybrid ambient ionization source, laser electrospray mass spectrometry (LEMS), for the direct analysis and molecular imaging of biological tissue without matrix deposition. In LEMS, laser pulses from a Ti:Sapphire laser amplifier (60 fs, 800 nm, and 1 mJ) interact with surface analytes and transfer them from the condensed phase into the gas phase without the requirement of either exogenous matrix or endogenous water in the sample. The laser vaporized analytes are captured and ionized by an electrospray source, and finally detected by a mass analyzer. It was found that a turn-key, robust femtosecond fiber laser with longer wavelength, longer duration, and lower pulse energy at 1042 nm, 425 fs, and 50 µJ, respectively, provided comparable results with the Ti:Sapphire laser. Vaporization of intact, dried or aqueous cytochrome c and lysozyme samples was demonstrated by the fiber laser. A charge states distribution at lower charge states indicating folded conformation of proteins and the hemoglobin α subunit-heme complex from whole blood was observed. Endogenous anthocyanins, sugars, and other metabolites were detected and revealed the anticipated metabolite profile for the flower petal and leaf samples by the fiber laser. Phospholipids, especially phosphatidylcholine, were identified from a fresh mouse brain section sample. These lipid features were suppressed in both the fiber laser and Ti:Sapphire LEMS measurement in the presence of optimal cutting temperature compounds which are commonly used in animal tissue cryosectioning. This dissertation also details the design of an automated mass spectrometry imaging source based on the Ti:Sapphire LEMS. The laser, translation stage, and mass analyzer are synchronized and controlled using a customized user interface to enable step-by-step scanning of the area of interest on a given tissue sample. The imaging source is coupled with a high resolution accurate mass quadrupole time-of-flight (QTOF) mass analyzer with tandem mass analysis capability. A lateral resolution of 60 µm was demonstrated on a patterned ink film by LEMS imaging. Plant metabolites including sugar and anthocyanins were directly imaged from a leaf sample. Small metabolites, lipids and proteins were simultaneously imaged from a single tissue section of a pig liver sample. Biomarkers of blood-brain barrier damage and traumatic brain injury (TBI) that occurred during the injury were detected and imaged from a TBI mouse brain. The loading values from principal component analysis (PCA) were shown to be useful for identification of features of interest from the large LEMS imaging dataset.
Temple University--Theses
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7

Jaramillo, Forcada Tatiana. "Synthesis and biological evaluation of natural and synthetic ganoderic acids." Thesis, University of Nottingham, 2017. http://eprints.nottingham.ac.uk/43313/.

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Ganoderma lucidum also known as lingzhi or mushroom of immortality in East Asia countries, has been known for over 2000 years. Ganoderic acids (GA), which are important secondary metabolites of this mushroom, are highly oxygenated lanostane-type entities with extraordinary pharmacological properties. GA are biosynthesised from lanosterol by a still unknown mechanism. The synthesis of thirteen GA analogues and the biological evaluation of ten of them against prostate cell-lines is described in this thesis. Analogues with different functionalities at C-3, C-7, C-8, C-9, C-11, C-23, C-24, C-25 and C-26 of the lanostane frame have been synthesised. As functional groups, alcohols, acetates, ketones, carboxylic acids and single and conjugated double bonds have been introduced. For their preparation, aldehyde 89 was formed from commercial lanosterol in up to 47% overall yield over a 3 or 4 step sequence. Wittig olefination, Reformatsky reaction and direct oxidation of aldehyde 89 provided the precursors from which the analogues were achieved. Analogues were prepared after a total of six to eight steps in 7-44% overall yield. GA and their analogues inhibited the cell viability of prostate cell-lines. However, they were less effective in the inhibition than Taxotere® (docetaxel). Besides, by comparing their IC50 values and thus, building a structure activity relationship (SAR) analysis, the most important positions for activity were determined. Interestingly, some of the ganoderic acids, GA-H (24), and analogues 3-ketone 108 and 7,11-diketone 146, were less toxic for the normal prostate cells than for the pre-malignant ones, conferring on them prophylactic activity. It is believed that ketones at C-3, C-7 and C-11 could be responsible for this behaviour. Ganoderma lucidum is rare in nature. However, due to its great demand, it is now being farmed. For their cultivation sawdust, logs or cork is used. New substrates, otherwise disposed as waste, are being investigated to produce high quality mushrooms, among them oil palm fibres such as mesocarp or empty fruit bunch fibres. Therefore, to unveil new cultivation methods, the triterpene composition of the mushroom grown at different stages, with different substrates or conditions has been assessed and their biological activity evaluated against prostate cancer cell-lines. Cultivating the mushroom in mesocarp or empty fruit bunch fibres produced similar results to those of sawdust. However, poor ventilated conditions reduced their biological activity against prostate cancer cell-lines. Likewise, it was established that triterpene composition varied during different stages and for different target body parts, their biological activity also varied with age, increasing as the mushroom aged during the 2- to 8-week period studied.
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8

Petersson, Nina. "Optimisation of capillary gel electrophoresis method for enhanced separation of mRNA shortmers." Thesis, Uppsala universitet, Institutionen för kemi - BMC, 2018. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-351119.

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Advancements in the field of modified messenger RNA (mRNA) has led to new ventures in the pharmaceutical industry. However, new drug products demand new analytical methods to ensure the efficacy and purity of the drug. Capillary gel electrophoresis (CGE) with UV detection shows great potential for separation of mRNA samples due to the equal mass-to-charge ratio of mRNA and the flexible parameters of the CGE methods. This thesis investigates the optimal parameters of the capillary electrophoresis method, sample treatment procedure and sieving medium composition for enhanced shortmers separation of mRNA by CGE analysis. An RNA ladder with 100-1000 nucleotides and EPO mRNA with 900 nucleotides were used as model compounds. The effect of capillary dimensions and separation temperature on the resolution of the RNA peaks was established through comparative experiments. Sample treatment processes were evaluated to achieve an optimal conformation of the mRNA for CGE analysis. By heating the mRNA sample for 15 min at 80°C all multimers were seemingly eradicated. Moreover, it was found that addition of 4 M of urea to mRNA sample before heating resulted in improved peak shape. A sieving medium consisting of a mix of the two polymers polyvinylpyrrolidine (PVP) and hydroxyethyl cellulose (HEC) proved to have beneficial qualities for separation. The addition of sucrose as viscosity modifier in the sieving medium surprisingly further enhanced the resolution. Moreover, during the project a heavy wash was established which drastically improved repeatability of the analyses through more efficient regeneration of the capillary. ISSN:
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9

Verma, Abha. "Design, Synthesis and Biological Evaluation of Novel Cannabinoid Antagonist." ScholarWorks@UNO, 2012. http://scholarworks.uno.edu/td/1527.

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This study was aimed at the development of novel CB1 cannabinoid receptor antago­nists that may have clinical applications for the treatment of cannabinoid and psychostimulant addiction. The rationale for the design for our target was to incorporate a bioisosteric 1,2,3-triazole ring into the vicinal diaryl group revealed in the prototypical antagonist/inverse agonist SR141716 (Rimonabant) that was pre­sumed to interact with a unique region in the CB1 receptors. Based on our prelimi­nary results we identified a novel series of 1,2,3-triazole ester and keto deriva­tives as lead compounds for biological evaluation. Here in the design rationale, syn­thesis and CB1 receptor affinity for a series of 4,5-diaryl-1-substituted-1,2,3-triazoles of ester and ketones is described. These derivatives were synthesized via a one-pot regiospecific click/acylation reaction sequence from 1-azido-2,4-dichlorobenzene and commercially available arylacetylenes. From the structure-activity studies the 5-(4-chlorophenyl) congeners exhibited the most potent CB1 receptor affinities relative to other 5-(substituted-phenyl) moieties. The 1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-4-propylcarbonyl-1,2,3-triazole (­31a) was found to be the most potent (Ki = 4.6 nM) CB1 receptor ligand of the series and exhibited high CB1 selectivity (CB2/CB1 = 417). The triazole ester 31a was further characterized as a cannabinoid antagonist in locomotor-activity studies by blocking the locomotor-reducing effects of cannabinoid agonist WIN55,212-2. In addition, unlike the prototypical cannabinoid antagonist SR141716A (Rimonabant), the triazole ester 31a did not exhibit increased activity in locomotor activ­ity studies, thus indicating the potential for a neutral antagonist profile.
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10

Muth, Aaron. "Design, Synthesis, and Biological Evaluation of Novel Polyamine Transport System Probes and their Application to Human Cancers." Doctoral diss., University of Central Florida, 2012. http://digital.library.ucf.edu/cdm/ref/collection/ETD/id/5348.

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The mammalian polyamine transport system (PTS) has been of interest due to its roles in cancer and maintaining cellular homeostasis. Polyamines are essential growth factors which are tightly controlled via a balance of biosynthesis, metabolism, import, and export. This work focused on the development and biological testing of polyamine transport probes to help understand the molecular requirements of the PTS. This was mediated through the use of a CHO (PTS active) and CHO-MG* (PTS deficient) screen, where compounds demonstrating high toxicity in CHO and low toxicity in CHO-MG* were considered PTS selective. The first chapter focused on the development of polyamine-based drugs which are both metabolically stable to polyamine oxidase (PAO) activity and are hyperselective for targeting the PTS. This approach was optimized by combining a di-substituted aryl design with terminal N-methylation of the appended polyamine chains to generate a new class of superior PTS agonists. The metabolic stability of these compounds was demonstrated in CHO and CHO-MG* in the presence and absence of a known PAO inhibitor, aminoguanidine (AG). Highly PTS selective compounds were then tested in the NCI-60 cell line screen to demonstrate the effectiveness of polyamine-based drugs in cancer therapy. During this screen, the MALME-3M (human melanoma) cell line was identified as being very sensitive to these PTS targeting drugs. Further studies using MALME-3M and its normal counterpart, MALME-3, showed excellent targeting of the cancer line over MALME-3. For example, The MeN44Nap44NMe compound showed 59-fold higher toxicity in MALME-3M over MALME-3. The second chapter focused on the development of potential polyamine transport inhibitors (PTIs) for use in combination therapy with ?-difluoromethylornithine (DFMO). This therapy is predicated upon reducing sustained polyamine depletion within cells by inhibiting both polyamine biosynthesis with DFMO and polyamine transport with the PTI ligand. Potential PTIs were identified by blocking the uptake of spermidine in DFMO-treated CHO and L3.6pl cells. Previous work has identified a tri-substituted polyamine-based design as an effective PTI. Low toxicity and a low Ki value in a L1210 screen were good predictors for PTI efficacy. The structural requirements for a potent PTI were explored by modulating the toxicity through the introduction of amide bonds, and also by determining the number and orientation of the polyamine messages (appended to an aryl core) required for efficient inhibition of polyamine uptake. These experiments showed that a tri-substituted design and a triamine message (homospermidine) appended was optimal for PTI potency. The final chapter focused on the development of Dihydromotuporamine C derivatives as non-toxic anti-metastatic agents. Dihydromotuporamine C demonstrated good anti-invasive properties with tumor cells. Derivatives were made in an effort to reduce the cytotoxicity of the parent and improve the anti-migration potency. The motuporamine derivatives all have a polyamine message (norspermidine or homospermidine) appended to make a macrocycle core, making them prime targets to evaluate as potential PTS ligands in the CHO and CHO-MG* screen. Each compound was also tested in the highly metastatic pancreatic cancer cell line L3.6pl to determine both its IC50 value and maximum tolerated dose (MTD). The anti-migration assay was performed at the lowest MTD obtained (0.6 [micro]M) in order to compare the series at the same non-toxic dose. The results suggested that as the N1-amine center was moved further from the macrocyclic ring, an increased ability to inhibit cell migration and reduced toxicity was observed. These collective findings provide new tools for cell biologists to modulate and target polyamine transport in mammalian cells. Future applications of these technologies include new cancer therapies which are cell-selective and inhibit the spread of tumors.
Ph.D.
Doctorate
Chemistry
Sciences
Chemistry
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11

Komati, Rajesh. "Cu (II) Catalyzed Gateways In The Synthesis of Acridine Derivatives and Their Biological Evaluation as Anti-Cancer Drugs." ScholarWorks@UNO, 2014. http://scholarworks.uno.edu/td/1818.

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Telomeres are nucleoprotein complexes found at the ends of linear eukaryotic chromosomes. Telomeres consist of a short sequence of repetitive double stranded DNA, TTAGGG repeats in humans (and all mammals), and a complex of 6 proteins, termed the shelterin complex. The length of the telomeres varies greatly between species, from approximately 300 base pairs in yeast to many 10-15 kilo bases in humans, because of the end replication problem this length get shorten with each cell division and ultimately leads to cell death. However the immortal eukaryotic cells and some transformed human cells over come this incomplete end replication problem with the use of enzyme called Telomerase. Telomerase is a ribonucleoprotein enzyme that adds a specific DNA sequence repeats (TTAGGG) to the 3¢ end of DNA strands in the telomere regions. However from the telomerase activity studies, it was concluded that telomerase is active in almost 90% of human cancers but not in normal somatic tissues. Finally, the low or transient expression of telomerase in normal tissues, including normal stem cells, and the generally longer telomeres in normal cells versus tumor cells provide a degree of tumor specificity to telomerase-based drugs and reduce the probability of toxicity to normal tissue. All of these factors suggest that cancer drugs based on telomerase might have a broad therapeutic window. This dissertation focusing on the synthesis of acridine derivatives that have the capability to inhibit the enzyme telomerase. Several N-acridyl maleimide (NAM), N-acridyl succinimide (NAS) and N-acridyl phthalimide (NAP) derivatives have been synthesized and evaluated for their anti cancer activity against various cancer cell lines. While synthesizing acridine derivatives it was required to form the C-N bonds at various stages. Developed a copper-nicotinic acid complex, which catalyzes the coupling of aryl halides with N-formyl amines and cyclic imides to form C-N bond. Explored Cu (II) catalyzed formation of C-N bond by coupling aryl halides with various N-nucleophiles such as formamide, N,N-dimethyl formamide, N-formyl amines and various cyclic imides.
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12

Jagu, Elodie. "Design, synthesis and biological evaluation of new polyamine derivatives as antikinetoplastid agents." Thesis, Université Paris-Saclay (ComUE), 2016. http://www.theses.fr/2016SACLS589/document.

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Ce projet d’interface Chimie/Biologie repose sur les expertises complémentaires de deux équipes. Il concerne la conception et le développement d’inhibiteurs dirigés contre les Kinétoplastidés (trypanosomes, leishmanies). Il est en effet urgent de développer de nouvelles stratégies thérapeutiques pour répondre à la chimiorésistance et à la toxicité des médicaments actuellement utilisés contre ces parasites. Le métabolisme et le transport des polyamines étant essentiel chez les parasites, ils constituent des cibles thérapeutiques d’intérêt contre les Kinétoplastidés. Le projet intègre la synthèse de nouveaux dérivés polyamines spécifiques des parasites, l’évaluation sur des modèles in vitro de leishmaniose et de trypanosomose africaine, ainsi qu’une évaluation sur trypanothione réductase. La mise au point d’une méthode de quantification du transport de polyamine a également été initiée. Cinquante-quatre composés, répartis en trois séries chimiques, ont été synthétisés et évalués. Un grand nombre d’entre eux présentent des activités antiparasitaires de l’ordre du micromolaire et des évaluations in vivo sont actuellement en cours avec le composé le plus prometteur
This project is at the interface of chemistry and biology and relies on the expertise of two different teams. This thesis involves the design and development of inhibitors directed against Kinetoplastids. It is urgent to develop new therapeutic strategies to respond to drug resistance and toxicity of currently used drugs against these parasites. Polyamine metabolism and transporter have been demonstrated as essential for parasite growth. Therefore, these systems are potential drug targets for development of antikinetoplastid compounds. We chose to synthesize polyamine derivatives and evaluate their biological activity against Kinetoplatids. Fifty-four compounds, divided into three chemical series, have been synthesized and evaluated. Many have shown a micromolar biological activity in vitro against parasite. In vivo evaluation is foreseen for the most promising derivative
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Akin, Myles. "Site specific thermodynamic study of OH radical addition to DNA bases." Thesis, Georgia Institute of Technology, 2010. http://hdl.handle.net/1853/33919.

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In medical and health physics, we are interested in the effects of ionizing radiation on biological systems, in particular, human biology. The main process by which ionizing radiations causes damage to biological systems, is through the creation of radicals close to DNA strands. The radicals are very reactive and those created within close proximity to DNA will react with the DNA causing damage, in particular single strand or double strand breaks. This damage to the DNA can cause mutations that can kill the cell, either mitotically or apoptotically, or possibly lead to a cancerous formation. Therefore it is important to study how these radicals interact with DNA strands for a correlation between the resultant products of radical reactions and DNA strand breaks. For this study, we look at the most important radical, the OH radical and it's addition to DNA bases. We will study, through quantum chemistry, the thermodynamics of OH radical addition to the four bases, Adenine, Guanine, Cytosine and Thymine. The Jaguar program developed by Schrodinger was used for DFT calculations of the Gibbs free energy of the addition. In addition, calculations for the partial charge, HOMO's and Fukui indices were calculated and compared to experiment.
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14

Singh, Shilpa. "SYNTHESIS AND BIOLOGICAL EVALUATION OF SECOND GENERATION ANIBAMINE ANALOGUES AS NOVEL ANTI-PROSTATE CANCER AGENTS." VCU Scholars Compass, 2012. http://scholarscompass.vcu.edu/etd/359.

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Prostate cancer is the most prevalent non-cutaneous cancer among men. Since the 19th century when Virchow first introduced the concept of inflammation in cancer, chemokines and their receptors have garnered a lot of interest. Chemokine receptor CCR5 has been especially implicated in many disease states and recently found to be over expressed in prostate cancer cell lines. Anibamine, a natural CCR5 antagonist discovered in 2004, has been found to have significant anti-prostate cancer activity at micromolar level. To optimize this compound and also discover a novel pharmacophore, exploration of the original structure was carried out. Significant modifications were made to the side chain in the original structure and ten different analogues were prepared by altering the original synthetic route. While cytotoxicity assay proved the compounds to be non toxic to normal cells, anti-proliferation assay displayed that having a bulky, hydrophobic group in the side chain of the parent compound is essential for the activity. Looking at this data, the third generation of analogues can be prepared that might generate a better lead compound for the treatment of prostate cancer.
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15

Wazeerud-Din, Idris. "Synthetic Approaches towards Novel Isoform Selective PI3K Inhibitors and Their Biological Activities against Prostate Cancer Cells." DigitalCommons@Robert W. Woodruff Library, Atlanta University Center, 2018. http://digitalcommons.auctr.edu/cauetds/143.

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The development of novel imidazopyridines, which includes both tetrahydroimidazo[1,5-a]pyridine (rIMP) and imidazo[1,5-a]pyridine (IMP) was investigated using conventional and microwave induced procedures that afforded compounds at high yield of 88-96%. rIMP was synthesized using a two-step procedure that involved the microwave synthesis of IMP, then the reduction of the pyridine moiety of the fused imidazopyridine rings using 10% Pd/C and hydrazine monohydrate. The microwave synthesis of imidazopyridines involved the one pot reaction of 2-benzoylpyridine, substituted benzaldehyde and ammonium formate in acetic acid under open vessel microwave conditions, which resulted in products within 40 minutes. Novel PEG-IMP development, involved the synthesis of ethylene glycol tethered benzaldehydes and IMPs using traditional Williamson etherification synthesis, which afforded products at a high yield of 92-95%. We have then shown IMP and rIMP roles in its antiproliferative property towards PCa cells, specificity in inhibiting PI3K isoforms, and structural motif’s interaction with different residues in the kinase binding domain of the class I PI3K isoforms. The antiproliferative property towards PC3 cells shows increased activity with compounds containing pyridyl group on carbon 3 of the imidazo[1,5-a]pyridine parent moiety with signs of toxicity to PC3 within 24 hours of incubation and at 1 μM of the parent compound. Furthermore, the IMPs were tested against five prostate cellular lines: PC3, RWPE1, D145, LNCaP and LNCaP C81. IMPs showed little activity towards RWPE1 and increased activity towards PC3 cells. We determined that functionalizing the phenyl group at position 1 increased the efficacy of rIMP compared to the IMP. After showing increased toxicity to PC3 cells, it was important to investigate the mechanism in which IMP pose toxicity towards PC3 cells. The biochemical assay showed that rIMP was more effective in inhibiting PI3Kα isoform compared to both pan inhibitor wortmannin and IMP. Both IMP and rIMP inhibited more than 60% of PI3Kγ isoform activity at nanomolar concentrations. After showing IMPs affinity to PI3K isoforms, we investigated the binding interactions rIMP and IMP towards the PI3K isoforms using MOE molecular modeling software.
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16

Sherwood, Alexander M. "Design, Synthesis and Biological Evaluation of Novel Compounds with CNS-Activity Targeting Cannabinoid and Biogenic Amine Receptors." ScholarWorks@UNO, 2014. http://scholarworks.uno.edu/td/1831.

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This work seeks to contribute to the discipline of neuropharmacology by way of structure activity relationship from the standpoint of an organic chemist. More specifically, we sought to develop robust synthetic methodology able to efficiently produce an array of compounds for the purpose of systematic evaluation of their interaction with specific sights within the central nervous system (CNS) in order to better understand the mind and to develop drugs that may have beneficial effects on neurological function. The focus of these studies has been toward the development of novel molecules, using a structure-activity relationship approach, that exhibit binding affinity at specific targets within the CNS. The merit of such studies is twofold: primarily, new compounds are produced that provide valuable scientific insight about their physiological targets, and secondarily, new synthetic methodologies that may arise in order to produce these compounds, thereby contributing to the whole of organic chemistry. As a result of the research described herein, the development of one high affinity and several moderate affinity compounds at the cannabinoid receptor subtype 1 (CB1) has been accomplished. The research demonstrates that a diaryl ether molecular scaffold represents a successful motif in the cannabinoid pharmacophore. The production of the compounds in the SAR studies also introduced a novel general synthetic methodology for the synthesis of diaryl ethers around a phloroglucinol core. A second project was initiated in order to explore the synthetic methods required to develop a general process for the synthesis of rigid aminobenzocyclobutane analogs of known phenethylamines with activity at monoaminergic neurotransmitter sites. Using the synthetic approach devised here, four novel aminobenzocyclobutane isomeric analogs of a known pharmacologically active phenethylamine, (RS)-phenylpropan-amine were synthesized and are currently being evaluated for pharmacological potential.
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Apsunde, Tushar D. "Synthesis and Biological Evaluation of N-heterocycles for Activity on Monoamine Transporters and Exploration of Iridium Chemistry for Synthesis of Medicinally Important Molecules." ScholarWorks@UNO, 2014. http://scholarworks.uno.edu/td/1862.

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The focus of these studies was directed towards the synthesis of novel N-heterocyclic compounds and pharmacological evaluation of these compounds for activity at monoamine transporters. A series of novel piperidine and pyrrolidine analogues were prepared from commercially available starting material with a three and four step synthetic method, respectively. A variety of substituents on the aromatic ring were incorporated to achieve a diverse library of compounds. The preliminary binding studies of piperidine molecules showed strong affinity towards serotonin transporters and moderate affinity towards dopamine transporters. The focus of further studies was directed towards utilization of iridium catalysis for the development of new synthetic methods for biologically important molecules. This research has led to the development of a new synthetic strategy for the construction of nicotine and its analogues. In addition, the iridium catalysis was also used for alkylation of amides with primary and secondary alcohols under microwave conditions.
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18

Boff, Bastien. "Synthesis, physicochemical and biological evaluation studies of ruthenium(II) and osmium(II) anticancer organometallic complexes." Phd thesis, Université de Strasbourg, 2012. http://tel.archives-ouvertes.fr/tel-00796216.

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Since the clinical success of platinum drugs (cisplatin and its derivatives) as anticancer agent, medicinal inorganic chemistry has become a field of growing interest because it offers an alternative for the design of therapeutic agents that are not readily available to organic compounds. Although cisplatin is one of the most widely used drugs in chemotherapy, it is not effective for all types of cancer. Moreover, platinum drugs are the cause of disabling side effects (neurotoxicity, nephrotoxicity, weight loss, nausea...) and their applicability is limited by innate or induced resistance to platinum in a narrow range of tumours. Therefore, this clinical success has promoted the search for cytotoxic compounds with enhanced activities and more acceptable toxicity profiles. This has stimulated interest in complexes containing other heavy metals of the platinum group such as ruthenium because these compounds show lower toxicity than drugs based on platinum. Some ruthenium compounds have already shown promising anticancer activity and two RuIII complexes trans-[RuCl4-(DMSO)(Im)]ImH (NAMI-A and trans-[RuCl4(Ind)2]IndH (KP1019) recently enter in clinical phase for their respectively antimetastatic and cytotoxic properties.In the essential aim of increasing activity and reducing side effects of anticancer agents, the Laboratoire de Synthèses Métallo-Induites has developed for several years organometallic ruthenium compounds RDC (Ruthenium Derivative Compound) in which one of the ligand is strongly bound to the metal via a strong σ C-Ru bond and stabilized by an intramolecular N-Ru bond. This thesis presents the recent advances of the laboratory in this field and the development of a second generation RDC in which the cylometallating ligand is stabilized by two N-Ru bonds. Thus, several complexes pass the symbolic barrier of the nanomolar range for their IC50 indicating a critical improvement. At the same time, we decided to focus our studies on osmium heavier congener, not only to complete the RDC chemical library, but also to verify the impact of exchanging the metal. An extensive chemical library ODC (Osmium Derivative Compound) of forty cyclometalated osmium complexes was synthesized and evaluated in vitro. Biological studies on these ODCs showed that osmium is another metal that deserves attention for the development of new effective antitumour drugs. The measurements of physicochemical properties such as red-ox potential and lipophylicity (log(Po/w)) allowed us to tentatively correlate these parameters to the level of activity, thus approaching a possible Property-Activity Relationship (P.A.R.). More insight into the role of the red-ox potential will probably become clearer as we progress into the mechanism of action of these species.
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19

Obeng, Samuel. "Design, Synthesis, and Biological Screening of Selective Mu Opioid Receptor Ligands as Potential Treatments for Opioid Addiction." VCU Scholars Compass, 2017. http://scholarscompass.vcu.edu/etd/4771.

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Today, more Americans die each year because of drug overdoses than are killed in motor vehicle accidents. In fact, in 2015, more than 33,000 individuals died due to an overdose of heroin or prescription opioids. Sadly, 40-60 % of patients on current opioid addiction treatment medications relapse. Studies have shown that the addiction/abuse liability of opioids are abolished in mu opioid receptor (MOR) knock-out mice; this indicates that the addiction and abuse liability of opioids are mainly mediated through MOR. Utilizing the “message-address concept”, the our laboratory reported a novel non-peptide, reversible MOR selective ligand 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α (isoquinoline-3-carboxamido)morphinan (NAQ). Molecular modeling and mutagenesis studies revealed that the selectivity of NAQ for MOR is because of the π-π stacking of the isoquinoline ring of NAQ with W318. Therefore, other heterocyclic ring systems were explored to obtain a diverse library of compounds with similar or different molecular interactions and pharmacologic characteristics as NAQ. The newly designed compounds were indole analogs of 6α/β-naltrexamine. The compounds were synthesized and the affinity and selectivity for MOR determined using the radioligand binding assay while the functional activity at MOR was determined using the [35S]GTPγS binding assay. The indole analog of 6α-naltrexamine substituted at position 7 (compound 6) was found to be very potent and had the lowest efficacy in the [35S]GTPγS functional assay while the indole analog of 6β-naltrexamine substituted at position 2 (compound 10) was identified as a MOR agonist and had the greatest efficacy. In vivo studies were conducted using the warm-water immersion assay to find whether the synthesized compounds had antinociceptive effects and/or blocked the antinociceptive effects of morphine. Not surprisingly, compound 10 was identified as an opioid agonist while compound 6 almost completely blocked morphine’s antinociceptive effects. The opioid antagonist effect of compound 6 was found to be dose dependent with an AD50 of 2.39 mg/kg (0.46-12.47). An opioid withdrawal assay was conducted on compound 6 using morphine-pelleted mice. Compound 6 produced significantly less withdrawal symptoms at 50 mg/kg than naltrexone at 1 mg/kg. Therefore, compound 6 has the potential to be used in opioid addiction and withdrawal treatment.
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20

Batra, Sumit. "Innovative Purification Protocol for Heparin Binding Proteins: Relevance in Biopharmaceutical and Biomedical Applications." TopSCHOLAR®, 2011. http://digitalcommons.wku.edu/theses/1062.

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Heparin binding (HB) proteins mediates a wide range of important cellular processes, which makes this class of proteins biopharmaceutically important. Engineering HB proteins could bring many advantages, but it necessitates cost effective and efficient purification methodologies compared to the currently available methods. One of the most important classes of heparin binding protein is the fibroblast growth factors (FGFs) and its receptors (FGFRs). In this study, we report an efficient off-column purification of FGF-1 from soluble fractions and purification of the D2 domain of FGFR from insoluble inclusion bodies, using a weak amberlite cation (IRC) exchanger. This approach is an alternative to conventional affinity column chromatography, which exhibit several disadvantages, including time-consuming experimental procedures and regeneration and results in high cost for production of recombinant proteins. Authenticity of the purified proteins was verified by SDS-PAGE and MALDI mass spectrum analysis. Results of the heparin binding chromatography and steady state fluorescence experiments showed that the FGF-1 and the D2 are in a native biologically active conformation. The findings of this study will not only aid an in-depth investigation of this class of proteins but will also provide avenues for inexpensive and efficient purification of other important biological macromolecules.
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21

Loe, Ashley M. "TOWARDS AN UNDERSTANDING OF PHARMACOLOGICALLY INDUCED INTRACELLULAR CHANGES IN NICOTINIC ACETYLCHOLINE RECEPTORS: A FLUORESCENCE MICROSCOPY APPROACH." UKnowledge, 2016. http://uknowledge.uky.edu/chemistry_etds/69.

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Upregulation of nicotinic acetylcholine receptors (nAChRs) is a well-documented response to chronic nicotine exposure. Nicotinic acetylcholine receptors are pentameric ligand-gated ion channels consisting of alpha (α2-10) and beta (β2-4) subunits. Nicotine, an agonist of nAChRs, alters trafficking and assembly of some subtypes of nAChRs, leading to an increase in expression of high sensitivity receptors on the plasma membrane. These physiological changes in nAChRs are believed to contribute to nicotine addiction, although the mechanism of these processes has not been resolved. Recently, many studies have converged on the idea that nicotine induces upregulation by an intracellular mechanism. In this dissertation, expression levels of nAChRs were quantified upon exposure to nicotine and its primary metabolite, cotinine. A pH sensitive variant of GFP, super ecliptic pHluorin (SEP), was integrated with a nAChR subunit to study expression and trafficking of nAChRs by differentiating intracellular and plasma membrane inserted receptors. In this work, cotinine is shown to increase the number of α4β2 nAChRs within a cell. Cotinine also affects trafficking of α4β2, evident by a redistribution of intracellular receptors and an increase in single vesicle insertion events on the plasma membrane. This work shows both nicotine and cotinine alter the overall assembly of α4β2 to favor the high sensitivity (α4)2(β2)3 version. Since cotinine and nicotine induce similar physiological changes in nAChRs, the metabolite potentially plays a role in the mechanism of nicotine addiction. Although an intracellular mechanism for upregulation has been supported, a shift in assembly to the high sensitivity (α4)2(β2)3 version exclusively in the endoplasmic reticulum has not previously been detected. In order to study organelle specific changes in stoichiometry, a novel method was developed to isolate single nAChRs in nanovesicles derived from native cell membranes. Separation of nanovesicles originating from the endoplasmic reticulum and plasma membrane, encompassing isolated nAChRs, allows precise changes in stoichiometry to be monitored in subcellular regions. In this work, single molecule bleaching steps of green fluorescent protein (GFP) encoded in each alpha subunit of the pentamer are detected. The number of bleaching steps, or transitions to a nonfluorescent state upon continuous excitation, corresponds to the number of GFP-labeled alpha subunits present. Therefore, the stoichiometry can be deduced by detection of two bleaching steps, as in (α4)2(β2)3, or three bleaching steps, seen in (α4)3(β2)2. Using this method on isolated nAChRs, a shift to assembly of high sensitivity (α4)2(β2)3 receptors is detected definitively within the endoplasmic reticulum. In addition, an increase in (α4)2(β2)3 receptors located on the plasma membrane is shown when nicotine is present. This work provides convincing evidence that nicotine acts intracellularly, within the endoplasmic reticulum, to alter stoichiometry of nAChRs.
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22

Ngo, Huy. "SYNTHESIS AND BIOLOGICAL EVALUATION OF NOVEL DRUG CANDIDATES TO ADDRESS DRUG RESISTANCE IN TUBERCULOSIS AND FUNGAL DISEASES." UKnowledge, 2018. https://uknowledge.uky.edu/pharmacy_etds/95.

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Tuberculosis (TB) and fungal infections are two of the most lethal infectious diseases worldwide due to the emergence of drug-resistant Mycobacterium tuberculosis (Mtb) and fungal strains that can resist the most potent antimicrobial drugs currently employed. Due to the rise of these drug resistant strains, effective treatment options for these two infections are limited. This dissertation aims at exploring novel drug scaffolds to help combat drug resistance in TB and fungal infections. TB caused by the pathogenic Mtb is, alongside with human immunodeficiency virus acquired immunodeficiency virus (HIV), the deadliest infectious disease worldwide with approximately 2-3 billion people infected yearly. The situation has become increasingly intensified due to the emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mtb strains.Aminoglycoside (AG) antibiotics such as amikacin and kanamycin A (KAN) are heavily relied upon for the treatment of MDR- and XDR-Mtb strains. However, the success rate for the treatment of these MDR- and XDR-TB cases is decreasing as a result of increased KAN resistance. It was reported by the Centers for Disease Control and Prevention (CDC) that upregulation of the enhanced intracellular survival (eis) gene was the cause of resistance to KAN in a large portion of Mtb clinical isolates. Our lab previously demonstrated that Eis is an AG acetyltransferase that can inactivate AGs via chemoenzymatic modification of the AG scaffolds. As Eis has been shown to acetylate a wide variety of AG scaffolds, the development of novel AGs that can completely escape the action of Eis remains highly challenging. Therefore, we suggested an alternative therapeutic approach involving inhibiting Eis enzyme and still employing the current FDA-approved KAN. As exemplified by the clinically successful combination of penicillin and b-lactamase inhibitors, we hypothesized that an Eis inhibitor may be used as adjuvant therapy in combination with KAN to treat MDR- and XDR-tuberculosis. Using high-throughput screening, we were able to identify several small-molecule scaffolds capable of inhibiting Eis. We performed structure activity relationship (SAR) studies using purified Eis enzyme and optimized lead compounds. Additionally, we also showed that co-administration of Eis lead inhibitors with KAN led to recovery of KAN activity against a KAN-resistant Mtb cell line that overexpressed Ei Invasive fungal infections are on the rise due to an increased population of critically ill patients as a result of HIV infections, chemotherapies, and organ transplantations. Unlike antibiotics that are greatly diverse in categories and mechanisms of action, our current antifungal drug repertoire is greatly limited and insufficient in addressing the problem of drug-resistant fungal infections. Thus, there is a growing need for novel antimycotics that are safe and effective. We report a number of lead compounds with potent antifungal activitiy. The MIC values of these compounds were as low as 0.02 mg/mL against the fungal strains tested. Our compounds are derived from the ebselen core structure, which has been shown to be safe in multicenter clinical trials. Notably, fungal cells treated with our compounds showed the accumulation of ROS, which may further contribute to the growth inhibitory effect against fungi. This study provides new lead compounds for the development of antimycotic agents.
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23

Khalaf, Ali. "Design, synthesis and biological evaluation of new platelet aggregation inhibitors and novel methodologies for the preparation of CF₂R containing molecules." Phd thesis, Université Rennes 1, 2013. http://tel.archives-ouvertes.fr/tel-00861475.

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The first part of the thesis deals with the synthesis and biological evaluation of new platelets aggregation inhibitors, based on 12-HETE, 13-HODE and their analogues. In the second part we are interested in novel methodologies for the preparation of CF₂-containing molecules : First, a flexible strategy for the synthesis of gem-difluoro-bisarylic derivatives and heteroaromatic analogues was designed based on the easy synthesis and the reactivity of gem-difluoro propargylic intermediates, which by Diels-Alder cycloaddition and 1,3-dipolar cycloadditions afforded respectively the bisarylic and mixed arylic heteroarylic scaffolds. In addition, two small libraries were constructed around a bisarylic scaffold as representative examples. Second, we were interested in the synthesis of optically active functionalized molecules containing a gem-difluoro group, using asymmetric organocatalysis protocols. After preparation of the gem-difluoro enals, from their difluoropropargylic precursors, asymmetric organocalytic Diels-Alder cycloaddition and 1,4-conjugated additions were successfully performed.
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24

Boibessot, Thibaut. "Approche pluridisciplinaire de la problématique de la résistance bactérienne : conception, synthèse, évaluation de l'activité biologique et de la biodégradabilité de nouveaux agents antibactériens." Thesis, Nîmes, 2016. http://www.theses.fr/2016NIME0002/document.

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Depuis une vingtaine d’années, l’utilisation massive des antibiotiques a provoqué l’apparition de souches bactériennes résistantes contre la plupart des familles d’antibiotiques disponibles sur le marché pharmaceutique. L’apparition de souches multirésistantes voire totorésistantes notamment dans le milieu hospitalier, pose de manière croissante des difficultés thérapeutiques et constitue un grave problème de santé publique. Lors de mon doctorat, deux approches ont été abordées.La première approche consiste à inhiber les enzymes DapF et MurE impliquées dans la voie de biosynthèse du peptidoglycane, composant principal de la paroi des cellules bactériennes. Nous avons donc préparé des acides aminés comportant des groupes fonctionnels triazolyle ou alcynyle, analogues stériquement contraints de l’acide 2,6-diaminopimélique (méso-DAP).La deuxième approche développée au laboratoire repose sur le développement d’adjuvants d’antibiotiques, permettant de cibler spécifiquement les protéines responsables des mécanismes de résistances (Histidines kinases, HKs). Ce travail a permis l’obtention de trente-trois molécules dérivées du thiophène, dont huit présentent une activité biologique contre trois HKs différentes (1,63 < CI50 (μM) < 243,9). De plus, sur les huit molécules biologiquement actives, deux ont présenté une inhibition de la croissance bactérienne contre des bactéries à gram-positif et/ou à gram-négatif (B. subtilis, S. aureus, B. anthracis, E. coli…) et une restaure la sensibilité de souches bactériennes (E. coli productrice de β-lactamases à spectre large (BLSE) et S. aureus résistant à la méticilline (SARM)) à l’antibiotique approprié (céfotaxime)
Over the two past decades, the massive use of antibiotics has led to the emergence of resistant bacterial strains against most families of antibiotics available on the pharmaceutical market. The emergence of multiresistant and totoresistant bacterial strains particularly in hospitals, which create increasing problem in the development of new therapeutics and constitutes serious public health threat problems. During my PhD, two approaches were discussed.The first approach of this project consist in targeting the DapF and MurE enzymes, which are implicated in the biochemical pathway for peptidoglycan biosynthesis, a key component of the bacterial cell wall. Consequently, we prepared amino acids derivatives with triazolyl and alkynyl groups, sterically hindered analogs of 2,6-diaminopimelic acid (meso-DAP).The second approach is the development of antibiotic adjuvants, to target specific proteins implicated in the development of bacterial resistance mechanisms (Histidine kinases, HKs). This work has enabled the development of thirty-three thiophene derivatives, eight of them have biological activity against three HKs (1.63 < IC50 (μM) < 243.9). In addition, among the eight molecules with biological activity, two of them present inhibition of bacterial growth (bactericide) against both gram-positive and/or gram-negative bacteria (B. subtilis, S. aureus, B. anthracis, E. coli…) and one of them restores the sensibility of bacterial strains (E. coli producing extended spectrum of β-lactamases (ESBL) and S. aureus resistant to methicillin (MRSA)) to the appropriate antibiotic (cefotaxim)
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Avedis, Ani. "A high-throughput method for screening of protein binding behavior of multimodal anionic exchange ligands." Thesis, Uppsala universitet, Analytisk farmaceutisk kemi, 2021. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-434809.

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The biopharmaceutical industry is constantly developing biological drugs, resulting in increased levels of product related impurities having similar characteristics as the target. The aim of the ligand project was to address future challenging purifications by developing new ligands for future resins for the biopharmaceutical industry. The purpose of this study was to develop a high-throughput screening method and use it to compare 15 novel multimodal anionic exchange ligand analogues with two reference ligands, for future polishing steps in the downstream process. The protein binding behavior of the ligands were studied with alkaline phosphatase, human serum albumin, α-chymotrypsinogen A and a monoclonal antibody as model proteins, at various pH values and salt concentrations. The selection process of the model proteins was based on stability studies, a study of their adsorption to the 96 well plate, and their binding behavior on three of the ligand analogues and one reference ligand. The percent protein bound to the ligands at the various conditions was calculated and presented in plots in order to study their binding behaviors. The calculated values were also used in order to evaluate the results in principal component analysis, creating chromatographic diversity maps. The maps were used to get an overview of the differences and similarities of the ligand analogues compared to the reference resins, which can be used for selecting ligands for future research and biomanufacturing. Four analogues and one reference ligand were also studied in a column format where different gradients were used, which confirmed the obtained results in the plate experiments.
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26

Aggrawal, Manali. "Study of DNA damage on DNA G-quadruplexes and biophysical evaluation of the effects of modified bases (lesions) on their conformation and stability." Scholarly Commons, 2014. https://scholarlycommons.pacific.edu/uop_etds/134.

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Exposure of DNA to reactive oxygen species (ROS) results in the modified nucleobases (lesions) as well as strand scissions under physiological conditions. Due to its lowest oxidation potential (1.29 eV), guanine is the most easily oxidisable nucleobase. Furthermore, it has been observed that the 5'-guanine in G-tracts (e.g. GGG) has even lower oxidation potential (1.00 V vs. NHE). One of the representative G-rich examples is telomeres that consist of repeating units of 5'-d [TTAGGG]-3' found at the ends of chromosomes. Telomeres play an important role in biological functions, serving as guardians of genome stability; however, their G-rich nature implies that they can be readily oxidized. So how does nature protect these biologically important regions from oxidation? We believe the formation of a secondary structure known as G-Quadruplex in telomeric regions can partly serve as a protective role. In the first part of this work, we investigated DNA G-Quadruplex damage under various oxidation conditions and compare the damage results with single-stranded telomeric sequences. Damage to G-Quadruplex is generally less than single strands and is condition dependent. Guanines are the primary damage sites, but damage of adenine and thymine is also possible. Based on our studies, telomeric DNA can be readily oxidized to produce DNA lesions. How do DNA lesions affect the conformation and the stability of telomeric G-Quadruplex DNA? In the second part, we sought to address this question using various biophysical methods. Several native (OxodG, OxodA, and abasic site) and non-native (8-NH 2 -dA and 8-Br-dA) lesions were tested. UV thermal denaturation and circular dichroism revealed that the conformation and the stability of G-Quadruplex DNA are dependent on the location and the type of lesion in the sequence. G-Quadruplex DNA containing OxodG maintains its conformation with a decreased stability. Abasic site in the TTA loop affects the conformation of G-Quadruplex DNA but shows little effect on its stability. An unexpected stabilization of telomeric G-Quadruplex DNA was observed when deoxyadenosine (dA) in the loops was replaced with its native oxidized form OxodA. This is the first example of native DNA lesion that increases the stability of G-Quadruplex DNA. Like OxodA lesion, 8-NH 2 -dA (a non native DNA lesion) increases the stability of G-Quadruplex DNA while 8-Br-dA only affects the stability in KCl but has no significant effect in NaCl. In addition, studies of the effect of OxodA lesion on the human telomerase activity using TRAP assay will be discussed.
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27

Arikatla, Swetha. "Effect of Tumor Microenvironmental Conditions on Non Small Cell Lung Cancer." Scholarly Commons, 2017. https://scholarlycommons.pacific.edu/uop_etds/126.

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Tumor microenvironmental conditions play a vital role in promoting metastasis and tumor recurrence. Due to inefficient vasculature, cancer cells experience hypoxia, glucose deprivation and low pH even during the early stages of tumor growth. Tumor cells are proposed to adapt to these microenvironmental conditions by acquiring increased migratory and invasion potential and tumor initiating ability. Our research addresses the effect of these biochemical factors of the tumor microenvironment (TME) on motility, epithelial to mesenchymal transition (EMT) and stemness of non-small cell lung cancer (NSCLC). NCI-H292 and NCI-H1650 NSCLC cell lines were used to measure the effect of the above mentioned TME conditions. Apart from acidic pH, low glucose and hypoxia, the effect of high glucose conditions was also measured on H292 and H1650 cell lines. Acidic pH, high and low glucose conditions were observed to have no effect on the motility, EMT and stemness of H1650 cell line. Hence, use of this cell line was discontinued and no further treatment conditions were tested on this cell line. In H292 cell line, acidic pH, low glucose and tumor like conditions combined together (acidic pH + low glucose + hypoxia) [AP+LG+HYP] significantly decreased motility whereas hypoxia significantly increased the motility of H292 cells. High glucose did not affect the motility of H292 cells. Although N-cadherin, a mesenchymal marker, expression was significantly upregulated by acidic pH, high and low glucose conditions, no direct correlation was observed between N-cadherin expression and motility. E-cadherin expression was not affected by acidic pH, high and low glucose conditions. An increase in N-cadherin expression and no change in E-cadherin expression under these conditions might be an indication of partial EMT. Hypoxia and AP+LG+HYP did not alter the expression of E-cadherin and N-cadherin. Although expression of vimentin, another mesenchymal marker, and Sox2, a cancer stem cell marker (CSC), was observed at the mRNA level, no expression of vimentin and Sox2 proteins was observed in H292 cells under any of these treatment conditions. The expression of OCT4, another CSC marker, was also not observed at the protein level in H292 cells. HIF-1α expression was observed in H292 cells under normoxic conditions and was unaffected by hypoxia and AP+LG+HYP. Therefore our research indicates that the effect of these TME conditions might be different on different cancer cell lines or cancer types. Not all cancers may depend on EMT for metastasis. An increase in metastasis under hypoxia may be independent of HIF-1α.
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Marahatta, Ram Prasad. "Folding of Bovine Pancreatic Trypsin Inhibitor (BPTI) is Faster using Aromatic Thiols and their Corresponding Disulfides." FIU Digital Commons, 2017. https://digitalcommons.fiu.edu/etd/3530.

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Improvement in the in vitro oxidative folding of disulfide-containing proteins, such as extracellular and pharmaceutically important proteins, is required. Traditional folding methods using small molecule aliphatic thiol and disulfide, such as glutathione (GSH) and glutathione disulfide (GSSG) are slow and low yielding. Small molecule aromatic thiols and disulfides show great potentiality because aromatic thiols have low pKa values, close to the thiol pKa of protein disulfide isomerase (PDI), higher nucleophilicity and good leaving group ability. Our studies showed that thiols with a positively charged group, quaternary ammonium salts (QAS), are better than thiols with negatively charged groups such as phosphonic acid and sulfonic acid for the folding of bovine pancreatic trypsin inhibitor (BPTI). An enhanced folding rate of BPTI was observed when the protein was folded with a redox buffer composed of a QAS thiol and its corresponding disulfide. Quaternary ammonium salt (QAS) thiols and their corresponding disulfides with longer alkyl side chains were synthesized. These QAS thiols and their corresponding disulfides are promising small molecule thiols and disulfides to fold reduced BPTI efficiently because these thiols are more hydrophobic and can enter the core of the protein. Conformational changes of disulfide-containing proteins during oxidative folding influence the folding pathway greatly. We performed the folding of BPTI using targeted molecular dynamics (TMD) simulation and investigated conformational changes along with the folding pathway. Applying a bias force to all atoms versus to only alpha carbons and the sulfur of cysteines showed different folding pathways. The formation of kinetic traps N' and N* was not observed during our simulation applying a bias force to all atoms of the starting structure. The final native conformation was obtained once the correct antiparallel β-sheets and subsequent Cys14-Cys38 distance were decreased to a bond distance level. When bias force was applied to only alpha carbons and the sulfur of cysteines, the distance between Cys14-Cys38 increased and decreased multiple times, a structure similar to the confirmation of N*, NSH were formed and native protein was ultimately obtained. We concluded that there could be multiple pathways of conformational folding which influence oxidative folding.
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Zhang, Changfeng. "Investigation of the endoplsmic reticulum calcium stores for their potential roles in neuroprotection using the NG115-401L neuronal cell line model." Scholarly Commons, 2014. https://scholarlycommons.pacific.edu/uop_etds/142.

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There is significant interest in the field of neuroscience to gain a better understanding of how neurons die in neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. We have used the neuronal cell line NG115-401L with unique calcium signaling characteristics to test the hypothesis that improving calcium loading into the endoplasmic reticulum (ER) to increase ER calcium levels acts as a possible neuroprotective response. We approached this problem using both pharmacological and genetic approaches targeting the central mediator of calcium uptake in the ER localized sarco/endoplasmic reticulum Ca 2+ ATPase (SERCA) enzyme. The pharmacological studies involved use of the ginger root compound 6-gingerol, which to date is the best documented agent for activating SERCA enzymes in heart and skeletal muscle. However, in our experiments, gingerol did not appear to activate NG115-401L SERCA pumps; indeed, the compound produced a response more like that of a SERCA inhibitor inducing a rapid ER calcium depletion. In addition, gingerol stimulated robust calcium influx responses, an unexpected result given the NG115-401L neural cell line is uniquely deficient in calcium influx pathways. Our genetic approach involved expressing the stromal interaction molecule 1 (STIM1) protein in the NG115-401L cell, which is also an ER localized protein that serves as a pivotal calcium influx channel regulator. NG115-40lL neurons present a native deficiency of STIM1 expression in a background phenotype with well characterized perturbations in ER calcium regulation and control of calcium influx pathways. Thus, STIM1 may be predicted to increase ER calcium levels, conferring protection against neuron cell death due to ER calcium store defects. STIM1 expression reconstituted the corrupted calcium influx pathway in NG115-401L neurons, which conferred neuroprotective responses to ER calcium perturbation, mitochondrial oxidative stress and subsequent cell death. Our results argue for unique and undiscovered regulatory effects of gingerol on the ER calcium circulation system, and suggest that the expression of STIM1 in these neurons protects against ER stress and oxidative stress via reconstruction of cellular calcium homeostasis.
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30

Wang, Yu. "Mechanistic study of aryl hydrocarbon receptor nuclear translocator (ARNT)-mediated signaling." Scholarly Commons, 2013. https://scholarlycommons.pacific.edu/uop_etds/151.

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A novel aryl hydrocarbon receptor nuclear translocator (ARNT)-interacting peptide (Ainpl) was characterized from human liver cDNA library using phage display. Ainpl suppresses hypoxia inducible factor-1a (HIF-1α) signaling pathway through an ARNTdependent manner. HIF-1α is known to be overexpressed in more than 90% of solid tumors, and the inhibition of HIF-1α is proved as an effective approach to suppress tumor growth. ARNT, as the obligatory heterodimeric partner of HIF-1α for downstream gene activation, was used as a bait to screen for Ainpl. Ainpl specifically interacts with the helix-loop-helix (HLH) subdomain of ARNT, but not with HIF-1α. GFP-Ainpl is localized in both cytoplasm and nucleus, and suppresses HIF-1α signaling by two mechanisms: (1) cytoplasmic GFP-Ainp 1 retains ARNT in the cell cytoplasm and (2) nuclear GFP-Ainpl inhibits HIF-1α/ARNT heterodimerization. The suppression of Ainpl on HIF-1α signaling was reversed by introducing ARNT into the cells using transient transfection. We further utilized HIV TAT protein transduction domain to deliver 6His-TAT-Ainpl into three different cancer cell lines (Hep3B, HeLa, MCF-7), and found that 6His-TAT-Ainpl co-localizes with ARNT in the cell nucleus. 6His-TATAinpl can be detected inside the cells after 30 min of transduction, and can reach the maximum level at 2 h. 6His-TAT-Ainp 1 remained detectable in the cells up to 96 h and had a half life of 24 h after transduction. In addition, 6His-TAT-Ainp 1 suppresses HIF-1α downstream genes at both message and protein levels in a dose-dependent manner. Taken together, molecules that target the HIF-1α and ARNT interface can be developed as viable drugs to suppress HIF-1α signaling.
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31

Silva, Amauri Francisco da. "Cálculo de potenciais de redução em meio aprótico (dmf) de adutos da reação de Morita-Baylis-Hillman com potencialidades biológicas anti-leishmania." Universidade Federal da Paraíba, 2015. http://tede.biblioteca.ufpb.br:8080/handle/tede/9221.

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Nitroaromatic compounds derived from Morita-Baylis-Hillman reaction (RMBH) have been tested in the treatment of most neglected diseases such as malaria, Chagas disease and leishmaniasis. An important experimental observation is the relation between biological activity (measured by IC50) and reduction potential of these compounds (estimated by the cathodic and anodic peak potentials determined by electroanalytical techniques), the latter directly connected to the reduction of the nitro group (-NO2 ). For this reason, electrochemical methods have been used in order to mimic the enzymatic bioreduction of these compounds, as reported by Vasconcellos et al. (J. Braz. Chem. Soc. 23:894, 2012). The objective of this work was to develop a computational protocol to predict the reduction potential in aprotic media to support the molecular modeling of new compounds with desired pharmacological activity. The developed direct protocol (for aprotic solvents) consists of performing DFT calculations with B98, PBE1PBE or M06-2X functionals with 6-31+G(d,p) basis set and C-PCM solvation method (with standard cavitation method UFF/VdW). The results show that it is possible to predict the experimental variation of the reduction potential of at least 70 % of confidence (in a range of experimental data of only 140 mV) with absolute average errors less than 45 mV (much less than the experimental uncertainty of the absolute reaction potential of hydrogen electrode, approximately 400 mV) and standard deviation of about 35 mV (inferior to 1,0 kcal/mol). The application of direct protocol for a series of 65 uncorrelated molecules, whose reduction potentials vary in a range of more than 6 V, provided a model with more than 99% of predictive power. From the application of the protocol to a series of 40 molecules, for which experimental results are not available, it was possible to predict that some of these structures may have more favorable potentials to bioreduction process than the systems used in the calibration step, which makes them candidates for new drugs.
Compostos nitroaromáticos derivados da reação de Morita-Baylis-Hillman (RMBH) vêm sendo testados no tratamento de doenças extremamente negligenciadas, tais como malária, doença de Chagas e leishmanioses. Uma importante observação experimental consiste na relação entre a atividade biológica (medida pelo IC50) e o potencial de redução (estimado pelos potencias de pico anódico e catódico determinados por técnicas eletroanalíticas) destes compostos, este último diretamente ligado à redução do grupo nitro (-NO2). Por esta razão, métodos eletroquímicos têm sido utilizados com o intuito de simular a biorredução enzimática destes compostos, como reportado por Vasconcellos e colaboradores (J. Braz. Chem. Soc. 23:894, 2012). O objetivo deste trabalho foi o de desenvolver um protocolo computacional para a predição de potenciais de redução em meio aprótico para auxiliar a modelagem molecular de novos compostos com a atividade farmacológica desejada. O protocolo direto desenvolvido (para solventes apróticos) consiste na realização de cálculos DFT com os funcionais B98, PBE1PBE ou M06-2X, com o conjunto de funções de base 6-31+G(d,p) e método de solvatação C-PCM (com o método de cavitação padrão UFF/VdW). Os resultados mostram que é possível prever a variação experimental do potencial de redução com pelo menos 70 % de confiança (em uma faixa de valores experimentais de apenas 140 mV) e erros médios absolutos inferiores a 45 mV (muito inferior à incerteza experimental do potencial de redução absoluto do eletrodo de hidrogênio, que é de cerca de 400 mV) e desvio-padrão de cerca de 35 mV (inferior a 1,0 kcal/mol). A aplicação do protocolo direto a uma série de 65 moléculas não-correlacionadas, cujos potenciais de redução variam em uma faixa de mais de 6 V, forneceu um modelo com mais de 99 % de poder preditivo. A partir da aplicação do protocolo a uma série de 40 moléculas, para as quais ainda não estão disponíveis resultados experimentais, foi possível prever que algumas destas estruturas podem possuir potenciais mais favoráveis ao processo de biorredução que os estudados na etapa de calibração, o que as tornam candidatos à novos fármacos.
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32

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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33

Fraga, Keith Jeffrey. "Explorations into protein structure with the knob-socket model." Scholarly Commons, 2016. https://scholarlycommons.pacific.edu/uop_etds/264.

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Protein sequences contain the information in order for a protein to fold to a unique compact, three-dimensional native structure. The forces that drive protein structures to form compact folds are largely dominated by burial of hydrophobic amino acids, which results in non-specific packing of amino acid side-chains. The knob-socket model attempts to organize side-chain packing into tetrahedral packing motifs. This tetrahedral motif is characterized with a three residues on the same secondary structure forming the base of the tetrahedron packing with a side-chain from a separate secondary structure. The base of the motif is termed the socket, and the other side-chain is called the knob. Here, we focus on extending the knob-socket model to understand tertiary and quaternary structure. First, single knobs sometimes pack into more than one socket in real structures. We focus on understanding the topology and amino acid preferences of these tertiary packing surfaces. The main results from the study of tertiary packing surfaces is that they have a preferred handedness, some interactions are ancillary to the packing interaction, there are specific amino preferences for specific positions in packing surfaces, and there is no relationship between side-chain rotamer of the knob packing into the tertiary packing surface. Next, we examine the application of the knob-socket to irregular and mixed packing in protein structure. The main conclusions from these efforts show canonical packing modes between secondary structures and highlight the important of coil secondary structure in providing many of the knobs for packing. Third, we investigate protein quaternary structure with a clique analysis of side-chain interactions. We identify a possible pseudo knob-socket interaction, and compare knob-socket interactions between tertiary and quaternary structure. Lastly, we discuss the workflow used in CASP12 to predict side-chain contacts and atomic coordinates of proteins.
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34

Cox, Kaleb Woodrow. "Synthesis and Biological Activity of Indolinones." Wright State University / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=wright1421165680.

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35

Viscardi, Ariel. "Avaliação da atividade antiproliferativa de extratos hidroalcoólicos de plantas em linhagens celulares humanas de câncer de mama, fígado e próstata." Universidade de São Paulo, 2018. http://www.teses.usp.br/teses/disponiveis/82/82131/tde-29082018-140818/.

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O câncer é uma das doenças que mais acometem a população no mundo. Dessa forma, estudar suas terapêuticas é importante para o entendimento dos mecanismos e alvos biológicos por detrás da doença. Apesar dos tratamentos convencionais apresentarem uma boa eficácia, eles também provocam respostas indesejadas, como danos moleculares, resistência de células neoplásicas e efeitos colaterais fortes, colaborando para uma maior taxa de reincidência de neoplasias e mortalidade de pacientes. Sendo assim, a busca por alternativas é um importante desafio da Ciência Moderna para aprimorar e/ou substituir esses tratamentos. As plantas medicinais, como alternativa, são o foco de muitos estudos voltados ao câncer. O objetivo do presente trabalho foi avaliar o efeito citotóxico de 59 extratos em linhagens celulares humanas de câncer de mama (MDA-MB-231 e MCF7), próstata (PC-3 e DU 145) e fígado (HepG2). Foi realizada, inicialmente, uma triagem dos extratos por MTT em duas diluições 100x e 1000x para análise da viabilidade celular desses extratos. No total, 35 extratos obtiveram uma resposta para, pelo menos, uma das linhagens de câncer. A próxima etapa envolveu estudar os extratos pré-seletivos na triagem através de curvas-resposta quantificando a seletividade desses extratos para cada linhagem testada. Para essa etapa, foram selecionados 31 extratos. No câncer de mama, para a linhagem MDA-MB-231 nove extratos foram seletivos, e para MCF7 foram seis extratos. No câncer de próstata, para a linhagem PC-3, quinze extratos foram seletivos, e para DU 145 dezesseis extratos foram seletivos, mostrando uma maior sensibilidade do câncer de próstata comparado ao câncer de mama e fígado (HepG2 - sete extratos seletivos) em relação aos extratos testados. De todos os resultados apresentados, algodão de seda (Calotropis procera), camomila (Matricaria chamomilla), casca de anta (Drimys winteri), erva de São Caetano (Momordica charantia L.), estigmas de milho (Zea mays), graviola (Annona muricata), ipê roxo (Tabebuia sp.), malva - folhas (Malva sylvestris) e unha de gato (Uncaria tomentosa) foram os extratos mais amplamente significativos atingindo as linhagens celulares apresentando altos índices de seletividade. Com a realização desse trabalho podemos concluir que os extratos apresentam atividade antiproliferativa e seus fitoquímicos podem ser utilizados no estudo de novos fitoterápicos. O próximo passo é elucidar os mecanismos moleculares onde eles atuam.
Cancer is one of the most common diseases overworld. Studying the therapeutics of it is important to understand the biological mechanisms and targets behind this disease. Although conventional treatments show a good outcome against some types of cancer, they also currently cause undesired responses, such as molecular damage, neoplastic cell resistance and strong side effects, increasing recurrence of neoplasms, metastasis formation, and patient mortality. Therefore, the search for new alternatives is a challenge for Modern Science to improve or replace conventional treatments. In view of their antiproliferative effects medicinal plants have become the focus of many cancer studies as an alternative. The aim of the present study was to evaluate the cytotoxic and antiproliferative effect of 59 plant extracts in human cancer cell lines as breast cancer (MDA-MB-231 and MCF7), prostate cancer (PC-3 and DU 145) and liver cancer (HepG2). Initially, the extracts were screened in two different dilutions 100x and 1000x by MTT to analyze the cellular viability and cytotoxicity effects of them. To 59 extracts analyzed, 35 were effective against at least one of the tested lineages. The next step involved studying those pre-selective extracts through response curves to quantify the selectivity of these extracts for each cell lineage tested. For this stage, 31 extracts were selected. In breast cancer, for MDA-MB-231, nine extracts were selective and for MCF7 were six extracts. In prostate cancer, for PC-3, fifteen extracts were selective and for DU 145 were sixteen extracts. For liver cancer (HepG2) only seven extracts were selective. Comparing all the cancer lineages we can see a greater sensitivity of prostate cancer lineages compared to breast cancer and liver cancer in response of these tested extracts. Of all the results presented, silk cotton (Calotropis procera), chamomile (Matricaria chamomilla), winter\'s bark (Drimys winteri), bitter melon (Momordica charantia L.), corn silk (Zea mays), graviola (Annona muricata), purple trumpet tree (Tabebuia sp.), malva - folhas (Malva sylvestris) e unha de gato (Uncaria tomentosa) silk cotton (Calotropis procera), chamomile (Matricaria chamomilla), graviola (Annona muricata) and mallow-leaves (Malva sylvestris) were the most effective extracts reaching different cell types and present high selectivity indices. With the accomplishment of this work we can conclude that the natural extracts of plants presented antiproliferative activity in cancer lines and their phytochemicals can be used to study new herbal medicines. The next step, then, is to understand the molecular mechanisms where they act.
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36

Murthi, Krishna Kumar. "Chapter 1. Spatol: Synthesis and biological chemistry of allylic diepoxides. Chapter 2. Levuglandins: Detection and biological chemistry." Case Western Reserve University School of Graduate Studies / OhioLINK, 1992. http://rave.ohiolink.edu/etdc/view?acc_num=case1059672042.

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37

Catti, Federica. "4,5-dihydropyrazoles : novel chemistry and biological activity." Thesis, St Andrews, 2007. http://hdl.handle.net/10023/351.

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38

Evans, Louise A. "Electroanalytical chemistry for biological and environmental applications." Thesis, University of Hull, 2008. http://hydra.hull.ac.uk/resources/hull:1616.

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Electroanalytical chemistry provides an elegant technique by which to explore, amongst others, various biological and environmental applications. To this end, four areas of electroanalytical chemistry are investigated in order to develop biologically- and environmentally-relevant sensors, together with exploring the electro-generation of a biologically important molecule and the diffusional factors that may affect this generation.The first study involves the dynamics of the bond cleavage involved in the electro-generation of nitric oxide from a range of N-nitrosoamines. Adsorption phenomena is found to be of pivotal significance in the release of nitric oxide from two of the compounds explored, namely cupferron and N-itrosodiphenylamine, whilst bis(nitroso)phenylenediamine released, as hoped, two moles of nitric oxide in a single step. The challenge is to isolate the product, and to determine which form of nitric oxide was generated, i.e. the cation, NO+ or nitric oxide, NO. Isolation remains a challenge, however analysis of the reaction mechanism does allow a prediction of the product, be it NO+ or NO. NO+ is a highly oxidising species and hence is difficult to isolate, therefore it is far more preferable to electro-generate NO, which cupferron was the only compound investigated that achieved this.The second study involved the investigation of axiosymmetric anisotropic diffusion to disc shaped microelectrodes, with theoretical expressions examined with experimental data in order to examine the factors. A ferrocene/PEG in acetonitrile system was examined in order to test this theory and to determine the effect of viscosity on the diffusion coefficients, and also if it was possible to investigate the anisotropy by effectively "blocking" either Dr or Dz. Excellent symmetry between theory and experiment was found, hence the focus turned to a ferricyanide in caesium pentadecafluorooctanoate/D2O system where once again the calculated value of root(Dr.Dz) affords a theoretical waveshape with reasonable agreement between theory and experiment. Potential step chronoamperometry then determined separate values for Dr and Dz, with the resulting values affording an anisotropic ratio of 1.7, suggesting radial diffusion dominance over planar diffusion.Third, the modification of electrodes is explored in order to develop biologically and environmentally relevant sensors. In a first strand, two liquid crystal ferrocene compounds are examined, immobilised on the surface of a glassy carbon electrode simply via solvent evaporation. Both compounds demonstrated typical ion transfer processes across the liquid | liquid interface, with both anion insertion and cation expulsion processes demonstrated. The differing voltammetry observed in the presence of different anions formed the basis of the anion sensor.In a second avenue in this modified electrode work a cation sensor is developed, working on the basis of a biofilm, i.e. developing a modification of the electrode surface to mimic the action of a biofilm in chelating with cations. With this in mind, a basal plane graphite electrode was modified with a diazonium salt and polyphenol, and through the introduction of alginic acid into the polyphenol layer a degree of selectivity between the Group 2 cations was demonstrated, although quantitative properties eluded the work.Last, an environmental sensor for cyanide was developed using an electrochemical probe, tetramethylphenylenediamine (TMPD). The reaction between the electro-generated TMPD.+ and cyanide is successfully followed colorimetrically, before product characterisation studies help to determine the reaction mechanism. Voltammetric studies form the basis of a sensor, with square wave voltammetry achieving a detection limit of 4.4 microM. The reaction between TMPD and cyanide allowed remediation studies to be undertaken, with river freshwater samples from North Yorkshire (54deg 15' 19.19" N, 1deg 46' 13.49" W) and the Rodalquilar mine, Spain, (36deg 50' 52.9" N, 2deg 02' 36.87" W) demonstrating the removal of cyanide by an impressive three orders of magnitude.
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39

Davidson, Nicola E. "Glucosinolates and isothiocyanates : chemistry and biological activity." Thesis, University of St Andrews, 1999. http://hdl.handle.net/10023/14230.

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The ability of glucosinolates to act as host recognition cues and oviposition stimulants for root flies has been previously established. To further investigate the interactions between pest and glucosinolate a number of simple and complex glucosinolates were synthesised and tested by contact chemoreception. A crude structure-activity relationship was identified whereby the stimulatory activity of the glucosinolate increased as the alkyl side chain was increased from propyl to pentyl, heptyl and nonyl. Comparison of the novel synthetic glucosinolate, naphthylmethyl glucosinolate, with glucobrassicin, a naturally occurring indole derivative, showed the former to have little or no activity whereas the latter is the most active natural stimulant. The synthetic glucosinolates were also demonstrated to act as substrates for the enzyme myrosinase, being hydrolysed to ?-D-glucose and the corresponding isothiocyanate. In addition, (7-methoxycarbonylheptyl) glucosinolate, prepared as a precursor to (7-carboxyheptyl) glucosinolate, was found to be a substrate. High resolution NMR studies of the latter compound showed this acidic glucosinolate and indeed alkyl glucosinolates to adopt an unexpected conformation in aqueous solution. Furthermore, a number of alkyl thiohydroximates were synthesised and used as HPLC and LC-MS standards to aid glucosinolate identification. Isothiocyanates have been identified as chemopreventative agents which inhibit carcinogen activation mediated by cytochrome P450 enzymes. The postulated oxidation of isothiocyanates to isocyanates by these enzymes, was studied using a number of chemical model systems. Oxidation of isothiocyanates was efficiently achieved using dimethyl dioxirane (DMD). Although, the resulting isocyanates could not be isolated, their production was confirmed by GC/MS and FT-IR analysis of reaction solutions. A number of ureas were also prepared by trapping the isocyanates in situ. These compounds were demonstrated to arise from the isocyanate and not oxidation of the corresponding thiourea. In addition, peracids were found to produce isocyanates, although less efficiently.
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40

Bunyapaiboonsri, Taridaporn. "Dynamic combinatorial chemistry : Exploration using biological receptors." Université Louis Pasteur (Strasbourg) (1971-2008), 2003. http://www.theses.fr/2003STR13065.

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La chimie combinatoire dynamique a été récemment introduite comme une approche nouvelle et attractive pour générer et cribler un grand nombre de bibliothèques de composés en une seule étape. Basé sur l'interconnexion réversible entre les composés de la bibliothèque, le processus d'auto-ajustement donne accès à la sélection et à l'amplification du meilleur inhibiteur en présence d'une cible. Au cours de cette thèse, nous avons choisi deux cibles biologiques qui nous ont permis d'explorer l'approche de la chimie combinatoire dynamique. La réversibilité du système a été rendue possible en utilisant l'échange de disulfures ou la formation réversible d'acyl hydrazones. Premièrement, une bibliothèque dynamique d'inhibiteurs d'acétylcholinestérase a été générée grâce à l'échange de disulfures. Nous avons observé la réversibilité du système à l'aide de la spectroscopie de RMN. A partir d'un mélange initial de 5 homodisulfures en présence d'un agent réducteur, une bibliothèque contenant 15 composantes a été obtenue. Les composantes de cette bibliothèque ont été mises en évidence par SM-ES et par EC. Deuxièmement, une bibliothèque combinatoire dynamique d'inhibiteurs d'acétylcholinesterase a été générée en se basant sur la formation réversible d'acyl-hydrazones. Le processus pré-équilibré a été utilisé pour obtentir d'une bibliothèque dynamique composée de 66 espèces possibles, à partir de 13 unités de bases. Nous avons ensuite identifié l'inhibiteur très puissant (IC50 et Ki de l'ordre de nM), en utilisant la méthode de la déconvolution dynamique. Finalement, le processus pré-équilibré combiné à la technique de la déconvolution dynamique a été employé pour identifier les inhibiteurs de la HPr kinase/phosphatase. Ainsi, nous avons pu préparer une bibliothèque dynamique constituée de 440 composés possibles, en une seule étape, à partir de 21 unités de bases. Le ligand hétérocyclique bis-cationique s'est révélé un inhibiteur relativement puissant (IC50 de l'ordre de mM)
Dynamic combinatorial chemistry (DCC) has recently been introduced as a new and attractive approach for generating and screening large numbers of library compounds in one step. Based upon the reversible interconnection between library components, the self-adjusting process give access to selection and amplification of the best binder in the presence of a target. In this thesis, two biological targets were chosen to explore the DCC approach. The reversibility of the system was achieved using disulfide interchange or reversible acyl hydrazone formation. Firstly, a dynamic library of acetylcholinesterase inhibitors was generated through disulfide exchange. The reversibility of the system was observed by NMR spectroscopy. Upon scrambling 5 initial homodisulfides in the presence of a reducing agent, a 15-compound library was produced. The library components were analyzed by ESI-MS and CE. Secondly, a dynamic combinatorial library of acetylcholinesterase inhibitors was further generated through reversible acyl hydrazone formation. The pre-equilibrated process was applied to produce a dynamic library composed of 66 possible species, from a set of 13 initial aldehyde and hydrazide building blocks. Using a technique called dynamic deconvolution, a highly potent inhibitor was identified with IC50 in the nanomolar range. Finally, the pre-equilibrated process combined with the dynamic deconvolution technique was further studied to identify HPr kinase/phosphatase inhibitors. From a set of 21 initial aldehyde and hydrazide builiding blocks, a dynamic library of 440 possible compounds was formed in one operation. A bis-cationic heterocyclic ligand was identified as a relatively potent inhibitor, displaying an IC50 in the micromolar range
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41

Mukhitov, Nikita. "Microfluidic Methods for the Study of Biological Dynamics." Thesis, The Florida State University, 2018. http://pqdtopen.proquest.com/#viewpdf?dispub=10633959.

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The work in this dissertation presents microfluidic methods developed for the study of biological dynamics. The requirements for the methods development was to create approaches with the ability to perform dynamic cell stimulation, measurement, and sample preparation. The methods presented herein were initially developed for the study of pancreatic islet biology but are expected to be translatable to other applications. In another study, a method to interface transmission electron microscopy (TEM) with microfluidics methods was developed.

The primary biological topic of interest investigated was the mechanisms of inter-islet synchronization. To test this, a microfluidic device fabricated from poly(dimethylsiloxane) (PDMS) was used to culture and stimulate pancreatic islets. Intracellular calcium ([Ca2+]i) imaging was performed with a fluorescent indicator, Fura-2-acetoxymethyl ester (Fura-2 AM). Under constant glucose (11 mM), islets demonstrated asynchronous and heterogeneous [Ca2+]i oscillations that drifted in period. However, when exposed to a glucose wave (11+/– 1 mM, 5 min period) islets were entrained to a common and consistent [Ca2+]i oscillation mode. The effect of islet entrainment on cellular function was investigated by measuring gene expression levels with microarray profiling. Calcium-dependent genes were found to be differentially expressed. Furthermore, it was speculated that islet entrained produced a beneficial effect on cell function and upkeep.

While [Ca2+]i imaging is an acceptable proxy measurement for insulin, it is not a viable reporter for other islet peptides and direct measurement is desired. Electrophoretic affinity assays can be performed on a microfluidic device in a serial manner to measure peptide release from an on-chip cell culture in near real-time. Successful analysis of electrophoretic affinity assays depends strongly on the preservation of the affinity complex during separations. Elevated separation temperatures due to Joule heating promotes complex dissociation leading to a reduction in sensitivity. To address this limitation, a method to cool a glass microfluidic chip for performing an affinity assay for insulin was achieved by a Peltier cooler localized over the separation channel. The Peltier cooler allowed for rapid stabilization of temperatures, with 21 °C the lowest temperature that was possible to use without producing detrimental thermal gradients throughout the device. Kinetic capillary electrophoresis analysis was utilized as a diagnostic of the affinity assay and indicated that optimal conditions were at the highest attainable separation voltage, 6 kV, and the lowest separation temperature, 21 °C, leading to 3.4% dissociation of the complex peak during the separation. These optimum conditions were used to generate a calibration curve and produced 1 nM limits of detection (LOD), representing a 10-fold improvement over non-thermostated conditions.

To date, most approaches for measurement of rapid changes in insulin levels rely on separations, making the assays difficult to translate to non-specialist laboratories. To enable rapid measurements of secretion dynamics from a single islet in a manner that will be more suitable for transfer to non-specialized laboratories, a microfluidic online fluorescence anisotropy immunoassay was developed. A single islet was housed inside a microfluidic chamber and stimulated with varying glucose levels from a gravity-based perfusion system. The total effluent of the islet chamber containing the islet secretions was mixed with gravity-driven solutions of insulin antibody and cyanine-5 (Cy5) labeled insulin. After mixing was complete, a linearly polarized 635 nm laser was used to excite the immunoassay mixture and the emission was split into parallel and perpendicular components for determination of anisotropy. Key factors for reproducible anisotropy measurements, including temperature homogeneity and flow rate stability were optimized, which resulted in a 4 nM LOD for insulin with < 1% RSD of anisotropy values. The capability of this system for measuring insulin secretion from single islets was shown by stimulating an islet with varying glucose levels. As the entire analysis is performed optically, this system should be readily transferable to other laboratories.

To increase the number of analytes that can be simultaneously monitored by a fluorescence anisotropy immunoassay, frequency encoding was introduced. As a demonstration of the method, simultaneous competitive immunoassays for insulin and glucagon were performed by measuring the ratio of bound and free Cy5-insulin and fluorescein isothiocyanate (FITC)-glucagon in the presence of their respective antibodies. A vertically polarized 635 nm laser was pulsed at 73 Hz and used to excite Cy5-insulin, while a vertically polarized 488 nm laser pulsed at 137 Hz excited FITC-glucagon. The total emission was split into parallel and perpendicular polarizations and collected onto separate photomultiplier tubes. The signals from each channel were demodulated using a fast Fourier transform, resolving the contributions from each fluorophore. Anisotropy calculations were carried out using the magnitude of the peaks in the frequency domain. The method produced the expected shape of the calibration curves with LOD of 0.6 and 5 nM for insulin and glucagon, respectively. (Abstract shortened by ProQuest.)

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42

Chavan, Archana G. "Exploring the molecular architecture of proteins| Method developments in structure prediction and design." Thesis, University of the Pacific, 2014. http://pqdtopen.proquest.com/#viewpdf?dispub=3609082.

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Proteins are molecular machines of life in the truest sense. Being the expressors of genotype, proteins have been a focus in structural biology. Since the first characterization and structure determination of protein molecule more than half a century ago1, our understanding of protein structure is improving only incrementally. While computational analysis and experimental techniques have helped scientist view the structural features of proteins, our concepts about protein folding remain at the level of simple hydrophobic interactions packing side-chain at the core of the protein. Furthermore, because the rate of genome sequencing is far more rapid than protein structure characterization, much more needs to be achieved in the field of structural biology. As a step in this direction, my dissertation research uses computational analysis and experimental techniques to elucidate the fine structural features of the tertiary packing in proteins. With these set of studies, the knowledge of the field of structural biology extends to the fine details of higher order protein structure.

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43

Higgs, Paul G. "Biological and synthetic polymer networks." Thesis, University of Cambridge, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.306415.

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44

Wisner, Daniel A. "Biophysical studies of biological phosphates /." The Ohio State University, 1987. http://rave.ohiolink.edu/etdc/view?acc_num=osu148732651171337.

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45

Lunn, Jennifer H. J. D. "The Architecture of Macromolecules: Their Functions as Sensor and Drug Delivery Reagents in Biological and Non-biological Environments." University of Cincinnati / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1421921436.

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46

Ferguson, Ronald Dale 1966. "Design, synthesis and biological screening of combinatorial chemical libraries." Thesis, The University of Arizona, 1996. http://hdl.handle.net/10150/278584.

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Although combinatorial libraries owe their inception to applications in peptide and bacteriophage libraries, the breadth of current applications include solution phase chemical reaction optimization, material science investigation, natural products modifications, and agricultural research. As a conceptual application, combinatorial library techniques can enhance a researcher's ability to transcend beyond the examination of one or several compounds to that of thousands or millions of these species simultaneously. The work described here, limited to scaffolded combinatorial chemical libraries, focuses primarily on the design and synthesis of these systems and how they have been analyzed against biological targets. Of the three scaffolded libraries, two were developed from aromatic templates (3,5-diaminobenzoic acid and 1,2,4-benzenetricarboxylic acid) while the last was built upon the cyclohexyl, Kemp's triacid platform. Although these libraries did not provide compounds with high affinity for the receptors investigated, they served to improve the understanding of combinatorial chemistry as a practice.
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47

Malvezzi, Alberto. "Modelos de virtual Screening de inibidores da cruzaína: desenvolvimento e validação experimental." Universidade de São Paulo, 2008. http://www.teses.usp.br/teses/disponiveis/46/46135/tde-10082016-115529/.

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Com o objetivo de buscar e identificar novo(s) inibidor(es) da cruzaína uma cisteíno-protease do Trypanosoma cruzi, o agente etiológico da doença de Chagas foram propostos, validados e, a seguir, aplicados sobre a biblioteca de compostos ZINC (3.294.714 compostos), dois modelos de virtual screening (Modelos I e II). Os modelos de virtual screening propostos, contendo seqüências de filtros físicoquímicos, farmacofóricos, de docking e de seleção por inspeção visual, foram construídos a partir de informações de 13 complexos da cruzaína e de 20 complexos de outras cisteínoprotease, cujas estruturas estão disponíveis no PDB. Numa primeira etapa, o reconhecimento detalhado das características estruturais da cruzaína foi realizado por inspeção visual; pelos campos de interação molecular, gerados pelo programa GRID; pela identificação das propriedades de interação molecular na superfície da cavidade, geradas pelo programa CA VBASE e; por simulações de dinâmica molecular. O Modelo I de virtual screeníng - obtido a partir do reconhecimento das estruturas dos 13 complexos da cruzaína depositadas no PDB - foi aplicado sobre o ZINC, selecionando 10 compostos, dos quais 6 compostos foram adquiridos e submetidos ao teste de inibição enzimática da cruzaína, para a validação experimental do modelo. Observou-se que 3 destes compostos (ZINC02470662, ZINC02682879 e ZINC03192044, respectivamente) não mostraram inibição significativa da cruzaína, nas condições experimentais utilizadas, até a concentração de 7 mM, enquanto que os 3 restantes (ZINC02663001, ZINC01936854 e ZINC03326243, respectivamente) apresentaram inibição enzimática inespecífica, sugerindo que estes últimos agem pelo mecanismo promíscuo. O mecanismo promíscuo de inibição enzimática, foi verificado pela adição de 0,1% Triton X-100 no ensaio enzimático, observando-se a correspondente perda de inibição da cruzaína. Para estes compostos, a confirmação do mecanismo promíscuo foi feita observando-se a perda de inibição da enzima, após o aumento em dez vezes da concentração da cruzaína no ensaio enzimático. O Modelo II - obtido a partir do reconhecimento das estruturas dos 13 complexos da cruzaína e dos 20 complexos de outras cisteíno-proteases, identificadas na busca por cavidades similares à cruzaína - foi aplicado sobre o banco de dados ZINC,selecionando 55 compostos dos quais 19 foram adquiridos e submetidos ao teste de inibição enzimática da cruzaína, para validação experimental do modelo. Observou-se que o composto ZINC01794422 apresentou inibição específica da enzima com constante de inibição no valor de Ki = 21 µM, enquanto que os demais 18 compostos não mostraram inibição significativa, nas condições experimentais utilizadas, até a concentração de 592 µM. O mecanismo promíscuo de inibição enzimática não foi observado, uma vez que todos os testes foram realizados com 0,1% de Triton X-100. O Modelo II identificou, ainda, mais dois inibidores da cruzaína (ZINC04899534 e ZINC01547017) que, por serem estruturalmente semelhantes aos utilizados na construção do modelo e já terem sido descritos na literatura, não foram adquiridos ou testados nos ensaios enzimáticos. Considerando apenas o novo inibidor identificado, o Modelo II apresentou uma taxa de acerto de 5,3%. Este valor esta de acordo com as taxas de acerto encontradas na literatura que variam entre 1 a 50% .
In order to search and identify new cruzain inhibitor(s) - a cysteine-protease of Trypanosoma cruzi, the etiologic agent of Chagas disease - two virtual screening schemes(Models I and II) were proposed, validated- and applied to the ZINC database (3.294.714 compounds). The proposed virtual screening models, bearing a sequence of different physicalchemical, pharmacophore and docking filters, as well as a visual inspection filter, were built from information taken from 13 cruzain complexes and from 20 complexes of other cysteine proteases, having their structures available in PDB. In a first step, a detailed recognition of the cruzain structural features and characteristics was performed through visual inspection of the enzyme environment; followed by the analysis of GRID generated molecular interaction fields; through the identification of molecular interaction properties exposed at the enzyme cavity surface, generated by the CAVBASE program; and by molecular dynamics simulations. The virtual screening Model I, - generated from the structural characteristics recognized from 13 PDB cruzain complexes - when applied to the ZINC database selected 10 compounds. For the experimental validation ofthe model, six ofthese compounds have been acquired and were tested as cruzain inhibitors. It was observed that three of the tested compounds (ZINC02470662, ZINC02682879 and ZINC03192044, respectively) did not show any significant cruzain inhibition, up to 7 mM. Meanwhile the other three tested compounds (ZINC02663001, ZINC01936854 and ZINC03326243, respectively) showed an unspecific cruzain inhibition, suggesting that an enzyme inhibition by promiscuous mechanism occurred. This mechanism was verified by the addition of 0.1% Triton X-100 on the enzymatic assay with a concomitant loss of cruzain inhibition activity. For these compounds, the confirmation of the promiscuous mechanism was also done, observing the loss of enzyme inhibition, after a ten times increase in the cruzain concentration on the enzymatic assay. The virtual screenmg Model II - generated from the structural characteristics recognized from 13 cruzain complexes and 20 complexes of other cysteine proteases, that have been identified on a search for cavities similar to cruzain - selected 55 compounds, when applied to the ZINC database. In order to experimentally validate the model, nineteen compounds have been acquired and were tested as cruzain inhibitors. It has been observed that one compound, ZINC01794422, showed a specific cruzain inhibition (Ki = 21 µM), while the other eighteen showed no significant inhibition, up to 592 µM concentration. The promiscuous mechanism of enzymatic inhibition was not observed, since 0.1% of Triton X-100 was added in ali assays. Additionally, Model II identified two other cruzain inhibitors (ZINC04899534 and ZINC01547017). However, these compounds have not been acquired or tested, since they are known cruzain inhibitors - already described in the literature and are structurally similar to the inhibitors used in the construction of the mode!. Referring to new inhibitors found, Model II showed a hit rate of 5,3%. This value is in agreement with those found in the literature, which ranges from 1 to 50%.
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48

Zhang, Yizhe. "Drop-Based Microfluidics for Biological Applications." Thesis, Harvard University, 2015. http://nrs.harvard.edu/urn-3:HUL.InstRepos:17467232.

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Drop-based microfluidic technology has been attracting great attention since the prevalence of soft-lithography techniques in poly-dimethylsiloxane (PDMS) microfluidic device fabrication a decade ago. The miniaturized isolated confinement of the droplet provides an ideal environment to study single cell behaviors in vitro that might otherwise be buried in the ensemble measurements. The effective confinement of the target and its secretion, together with the high-throughput processing capability, holds the promise for efficient target search through large-scale library screening. In fact, in the past seven years, considerable efforts have been made in developing this platform towards the applications in biology and great advances in drops have been reported in areas such as directed evolution, DNA sequencing, drug screening, etc. This thesis systematically describes our work that has been done in advancing the biological application of drop-based microfluidics through three major projects that are of significance in both fundamental research and clinical applications. Encapsulating in vitro transcription and translation reactions in the 0.5 pL drops enables us to synthesize a variety of functional RNAs and proteins from the single DNA templates in a drop environment, which not only provides a novel approach for single DNA molecule detection, but also paves the way for the high-throughput screening of the artificial proteins with drop-based microfluidics. Through successful enrichment of the restriction enzyme genes from a library consisting its truncated mutants, we demonstrated the high-throughput sorting capability of microfluidics for target gene screening that is beneficial for gene therapy applications. Finally, a non-invasive hydrogel synthesis method with microfluidic drop-maker and pico-injector is described, as a demonstration of microfluidic platform in the application of controllable synthesis of micro-sized gel particles as the 3D scaffold of, for example, mesenchymal stem cells, for the in vitro study of cell behaviors induced by cell-cell interactions and cell-environment interactions.
Chemical Physics
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49

Zimmer, John P. (John Philip). "Quantum dot-based nanomaterials for biological imaging." Thesis, Massachusetts Institute of Technology, 2006. http://hdl.handle.net/1721.1/37888.

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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2006.
Vita.
Includes bibliographical references.
Quantum dot-based fluorescent probes were synthesized and applied to biological imaging in two distinct size regimes: (1) 100-1000 nm and (2) < 10 nm in diameter. The larger diameter range was accessed by doping CdSe/ZnS or CdS/ZnS quantum dots (QDs) into shells grown on the surfaces of pre-formed sub-micron SiO2 microspheres. The smaller diameter range was accessed with two different materials: very small InAs/ZnSe QDs and CdSe/ZnS QDs, each water solubilized with small molecule ligands chosen for their ability not only to stabilize QDs in water but also to minimize the total hydrodynamic size of the QD-ligand conjugates. Indium arsenide QDs were synthesized because nanocrystals of this material can be tuned to fluoresce in the near infrared (NIR) portion of the electromagnetic spectrum, especially in the 700-900 nm window where many tissues in the body absorb and scatter minimally, while maintaining core sizes of 2 nm or less. The QD-containing microspheres were used to image tumor vasculature in living animals, and to generate maps of size-dependent extravasation. With subcutaneously delivered nAs/ZnSe QDs, multiple lymph node mapping was demonstrated in vivo for the first time with nanocrystals. When administered intravenously, < 10 nm QDs escaped from the vasculature, or were efficiently cleared from circulation by the kidney. Both of these behaviors, previously unreported, mark key milestones in the realization of an ideal fluorescent QD probe for imaging specific compartments in vivo. Also presented in this thesis is the growth of single-crystalline cobalt nanorods through the oriented attachment of spherical cobalt nanocrystal monomers.
(cont.) When administered intravenously, < 10 nm QDs escaped from the vasculature, or were efficiently cleared from circulation by the kidney. Both of these behaviors, previously unreported, mark key milestones in the realization of an ideal fluorescent QD probe for imaging specific compartments in vivo. Also presented in this thesis is the growth of single-crystalline cobalt nanorods through the oriented attachment of spherical cobalt nanocrystal monomers.
by John P. Zimmer.
Ph.D.
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50

Garnett, Emily R. (Emily Rose). "Biological Functions of ribonuclease 1 and angiogenin." Thesis, Massachusetts Institute of Technology, 2018. http://hdl.handle.net/1721.1/118260.

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Thesis: Ph. D. in Biological Chemistry, Massachusetts Institute of Technology, Department of Chemistry, 2018.
Cataloged from PDF version of thesis.
Includes bibliographical references (pages 128-142).
Pancreatic-type ribonucleases (ptRNases) are a large family of vertebrate-specific secretory endoribonucleases. They catalyze degradation of many RNA substrates, mediating a variety of biological functions. The homology shared by ptRNases has enabled extensive biochemical characterization and evolutionary study of these enzymes, yet understanding of their biological roles is still incomplete. The goal of this thesis is to identify novel physiological functions for two ptRNases, RNase 1 and angiogenin, through characterization of murine model systems. In Chapter 1, I introduce the ptRNase superfamily and highlight evidence of biological function for RNase 1 and angiogenin that has motivated and informed our study of these enzymes. Extracellular RNA drives blood coagulation, which is preventable by administration of RNase A. In Chapter 2, I demonstrate that loss of RNase 1, a nonspecific and extracellular ptRNase similar to RNase A, results in the potentiation of blood coagulation by activation of coagulation factors in mice. Angiogenin is a ptRNase with unique angiogenic activity and suggested biological function in cancer and amyotrophic lateral sclerosis, as well as in cellular growth and quiescence. My studies demonstrate a fundamental role for angiogenin. In Chapter 3, I find that this enzyme is essential for the development of mice, with heterozygosity for angiogenin resulting in impaired vascularization of the placenta and reduced survival of offspring. Biological study of ptRNases is hampered by the high degree of conservation of the family, which engenders antibody nonspecificity. In Chapter 4, I describe efforts to generate novel specific anti-ptRNase antibodies by producing tagged ptRNases for use in an antibody phage-display workflow. Finally, Chapter 5 outlines future directions for the study of RNase 1 and angiogenin. Taken together, this thesis reveals a more complete picture of the physiological niches of these two enzymes, confirming some previously suspected roles, ascribing new ones, and providing groundwork for future characterization of the biology of these and other ptRNases.
by Emily R. Garnett.
Ph. D. in Biological Chemistry
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