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Attardo, Giorgio G. (Giorgio Giovanni). "Drug design and synthesis of novel heteroanthracycline antitumor drugs." Thesis, McGill University, 1990. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=74641.
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Novel heteroanthracycline antitumor drugs were designed based on structure activity relationship studies and known mechanisms of drug action. Their preparation required the development of a general synthetic approach.After extensive studies, three methodologies were developed for the general synthetic plan. The first method involved photoenolisation of 2,5-dimethoxybenzaldehyde and SO$ sb2$ entrapment of the o-quinodimethane to give 4,7-dimethoxy-1-hydroxy-1,3-dihydrobenzo(2,3-c) thiophene-2,2-dioxide. This compound served as a general intermediate towards the synthesis of several heteroanthracyclinones. It could be reduced to the oxathiin-2-oxide derivative which thermally extruded SO$ sb2$ to yield the o-quinodimethane. Reentrapment of this latter intermediate with various glyoxalates gave key isochroman derivatives. The second method is an improvement over the first. Isochromandiones with a C-1 hydroxyl functionality were prepared from oxidative demethylation of 1-hydroxyisochromans. These were obtained after acid hydrolysis of the coupling products between epoxides and the cuprate of 2,5-dimethoxy-6-methylbenzaldehydedioxane acetal. The third method involved a sequential cycloaddition routine with two o-quinodimethanes.
By combining newly developed techniques with known methods, a general synthetic plan was developed. Consequently, the total synthesis of six tetracyclic structural hybrids of the naphthoquinone(2,3-c) pyranyl class of antibiotics was accomplished; along with the total synthesis of (R) and (S) 1-(4$ sp prime$-O-p-nitrobenzoyl-N-trifluoroacetyldaunosamine)-$ 1,3$-dihydrothioxantho(2,3-c) thiophene-2,2-dioxide, p-nitrobenzyl(5,12-dihydroxy-3,4-dihydrothioxantho(2,3-c) and (3,2-c) pyran-3-yl)formate, and eight novel heteroanthracyclines with the 5,12-dioxo-2,3,5,12-tetrahydroanthraceno(2,3-c) pyranyl backbone. The diastereomeric mixture of (1$ sp prime$S, 1R, 3S) and (1$ sp prime$S, 1S, 3R) methyl(11-hydroxy-1-$(2 sp prime,3 sp prime,6 sp prime $-trideoxy-3-trifluoroacetamido-L-lyxohexopyranose)-$5,12 $-dioxo-3,4,5,12-tetrahydroanthraceno(2,3-c) pyran-3-yl) formate was found to possess equipotent antileukemic activity to doxorubicin with no cross resistance.
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Zhang, Huarui. "Design, synthesis and activity evaluation of novel exosome inhibitors." HKBU Institutional Repository, 2020. https://repository.hkbu.edu.hk/etd_oa/849.
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Background: Exosomes are extracellular vesicles (EVs) that produced in the endosomal compartment of most eukaryotic cells, and have observed increasing attentions over the past decades. They play important roles in cell- to-cell communications, they can carry varieties of substances, like proteins, nucleic acids and lipids, to the target cells they encounter. These cargos could influence the function of recipient cells. This novel mode of intercellular communication is found to be of critical importance to many cellular activities. However, exosomes are involved in various diseases processes. Tumor- derived exosomes could promote cancer progression, and our preliminary study indicated that exosome released from osteoclasts could inhibit bone formation. We also found that osteoarthritis (OA) progression in OA mice could be attenuated by inhibiting exosomes released by osteoclasts. Therefore, inhibition of exosome release has potential value in the treatment of diseases. The exosome release is under control by RAB27A, which is a protein involved in protein transport and signal transduction. It is reported that a compound named Nexinhib20 could selectively inhibit RAB27A, but this compound is highly toxic to RAW264.7 cells, which IC 50 is 1.5 µM. Therefore, for safety concerns, it has to be chemically modified to reduce toxicity. Aim: (1) To design and synthesize a series compounds based on the structure of Nexinhib20. (2) To evaluate the toxicity and exosome inhibiting activity of the synthesized compounds and discuss the structure-activity relationships (SAR) of them. Materials and Methods: Nexinhib20 derivatives were synthesized by aldol reaction. The cytotoxicity of these compounds was evaluated by MTT assay. The exosome inhibiting activity of these compounds was evaluated through exosome isolation and quantitation. Result: A series of compounds were synthesized and their structures were confirmed by LC-MS and NMR. The structure-activity relationships of these compounds were discussed, and the results showed that compounds A3, A23 and B2 exhibited lower toxicity compared to Nexinhib20 and strong exosome inhibiting ability. Conclusion: The results of this project indicate that A3, A23 and B2 exhibited low toxicity and good exosome inhibiting activity. Based on this, further chemical modification could be applied to develop new exosome inhibitors with better efficacy
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McCallum, Emma Clare. "Adaptive phase II clinical trial design using nonlinear dose-response models." Thesis, University of Cambridge, 2015. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.709013.
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Ma, Haiqiu. "The formulation, manufacture and evaluation of capsules containing freeze-dried aqueous extracts of Leonotis Leonorus or Mentha Longifolia." Thesis, University of the Western Cape, 2006. http://etd.uwc.ac.za/index.php?module=etd&action=viewtitle&id=gen8Srv25Nme4_3777_1181559333.
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Leonotis leonorus and Mentha longifolia are two herbs commonly used in South Africa, mostly in oral liquid dosage forms. Several disadvantages are associated with these traditional dosage forms which can perhaps be remedied by using an appropriate oral solid dosage form, provided the actual plant material in the latter still resemble, as closely as possible, the traditionally used material and provide products of suitable pharmaceutical quality. The objectives of this study were to prepare and evaluate the pharmaceutical suitability of the freeze-dried aqueous extracts of Leonotis Leonorus and Mentha Longifolia as plant raw material for the capsule dosage of these two therapies and to formulate and manufacture capsules of Leonotis Leonorus and Mentha Longifolia aqueous extract that would contain amounts of the plant materials equivalent to that found in their traditional liquid dosage forms, and have immediate release characteristics and suitability stability.
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Gustafsson, Jörgen. "Synthesis of cyclohexenedicarbaldehydes and studies of their biologic activity." Lund : Organic Chemistry 2, Lund Institute of Technology, University of Lund, 1994. http://books.google.com/books?id=ULpqAAAAMAAJ.
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Moorad, Razia. "Computer-aided drug design and the biological evaluation of anti-cancer drugs." Doctoral thesis, University of Cape Town, 2016. http://hdl.handle.net/11427/20715.
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Computer-aided drug design has become a promising alternative to high-throughput screening by identifying potential hits in silico for in vitro evaluation. In this study a combination of ligand-based and structure-based virtual screening was performed to identify in silico hits. This was based on finding similar inhibitors to 6-amino-4-(4-phenoxyphenylethylamino) quinazoline, a potent inhibitor of the Nuclear Factor kappa B (NF-κB), a transcription factor that has a pivotal role in cancer survival and Pentamidine, an anti-parasitic drug that has recently been demonstrated to possess tumour-killing activity. A hierarchical methodology consisting of a similarity search followed by structure-based virtual screening of the ZINC database was performed. In order to perform the docking studies, binding sites for 6-amino-4-(4-phenoxyphenylethylamino) quinazoline on the NF-κB/IκBα complex were identified through blind docking. In addition, the National Cancer Institute (NCI) database was screened, utilising existing structure-activity relationship data from literature. A pharmacophore search was designed to test the hypothesis of the structural features necessary for activity as seen with quinazoline inhibitors of NF-κB. No virtual hits from the ZINC database were confirmed with in vitro activity. On the other hand, three compounds identified from the pharmacophore search were confirmed to inhibit cancer cell proliferation in vitro, with compound NSC727152 demonstrating the most potent activity. In order to determine if NSC727152 acted similarly to 6-amino-4-(4-phenoxyphenylethylamino) quinazoline by inhibiting NF-κB, the effects of NSC727152 on the expression of NF-κB targeted genes, including the Growth Arrest and DNA Damage 45 (GADD45) α and γ and the Interleukin 6 (IL-6) genes were evaluated. GADD45 α and γ have been shown to be regulated by NF-κB during cancer progression and aberrant IL-6 gene expression has been implicated in cancer progression and mortality and its expression is at least partially mediated via constitutive activation of NF-κB. In this study, it has been demonstrated that GADD45 α and γ are upregulated after treatment with NSC727152. A down-regulation of the IL-6 promoter activity and mRNA expression in cancer cells treated with NSC727152 has also been demonstrated in this study. However, no hits similar to Pentamidine were confirmed with in vitro activity. In conclusion, the compound NSC727152 has been shown to inhibit NF-κB and further analysis is necessary to determine its full potential as an NF-κB inhibitor.
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IACUZZI, VALENTINA. "Design of detection systems for the therapeutic drug monitoring of anticancer drugs." Doctoral thesis, Università degli Studi di Trieste, 2020. http://hdl.handle.net/11368/2967986.
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Considerato che la maggior parte dei farmaci antitumorali risulta caratterizzata da un'alta variabilità interindividuale nelle concentrazioni plasmatiche, che si riflette sull'efficacia del trattamento, durante il progetto di dottorato qui descritto sono state sviluppate tecniche per il loro monitoraggio terapeutico (TDM).
In primo luogo, è stato sviluppato, validato e cross-validato un metodo LC-MS/MS per la quantificazione di imatinib (IMA) e del suo metabolita attivo, norimatinib (norIMA), in pazienti affetti da tumore stromale gastrointestinale utilizzando la tecnica del dried blood spot (DBS). Il DBS consente di ridurre costi e tempi di campionamento e migliorare la compliance dei pazienti, poiché l’analisi viene effettuata tramite una goccia di sangue capillare depositata su carta. Da questa gli analiti vengono estratti con MeOH acidificato e l'estratto viene iniettato in un sistema LC (configurato con una cromatografia 2D per la pulizia on-line del campione), accoppiato ad un API-4000QT. Il metodo ha mostrato una buona linearità (R2> 0,996) nei range di 50-7500 ng/mL e 10-1500 ng/mL per IMA e norIMA. La precisione e l’accuratezza intra-day sono state, rispettivamente, ≤3.1% e tra 88.9-112.8%, mentre quelle inter-day erano ≤6,6% e tra 95.7-104.3%, per entrambi gli analiti. Sono stati valutati inoltre: l'influenza dell'ematocrito (Hct), del volume depositato e dell'omogeneità del campione sull’analisi; la correlazione tra la concentrazione in DBS da prelievo venoso e da finger-prick (differenza tra -12 e 3.8%) e la stabilità dei DBSs (fino a 16 mesi). Il metodo è stato applicato per la quantificazione di 67 campioni DBSs di pazienti. Le concentrazioni in DBS, normalizzate per Hct e per un fattore di correzione che prescinde dall’Hct, correlano con quelle plasmatiche.
Parte del lavoro di questo progetto è stato anche dedicato allo sviluppo di strategie alternative a LC-MS/MS per favorire ulteriormente l’applicazione del TDM. In particolare, è stata eseguita la sintesi di polimeri (molecularly imprinted polymers - MIPs), con l'obiettivo futuro di applicarli come recettori in un sistema di rilevamento fluorimetrico per IMA. I MIPs sono stati sintetizzati sfruttando l'approccio non covalente e la polimerizzazione radicale ad alta diluizione. Tramite questa tecnica, i MIPs ottenuti, sintetizzati in DMSO e con acido metacrilico come monomero funzionale, presentano dimensioni nanometriche (dati acquisiti tramite dynamic light scattering). I tests di rebinding hanno dimostrato che solo 2 MIPs sono stati in grado di legare IMA con una buona specificità (rispetto ai corrispondenti polimeri non-imprinted) e selettività.
È stato infine sviluppato e validato un metodo LC-MS/MS per la quantificazione di ribociclib (RIBO), palbociclib (PALBO) e letrozolo (LETRO) in plasma. RIBO e PALBO sono farmaci appartenenti alla famiglia dei CDKIs recentemente approvati per il trattamento del carcinoma mammario in combinazione con LETRO. Il metodo messo a punto risulta adatto per l’applicazione nella pratica clinica, grazie ad una semplice preparazione del campione e ad una rapida analisi (6.5 min). Il metodo risulta lineare (R2 tra 0.992-0.983) nei range di concentrazione di 0.3-250 ng/mL per PALBO, 10-10000 ng/mL per RIBO e 0.5-500 ng/mL per LETRO (che coprono le concentrazioni plasmatiche terapeutiche). La precisione e l’accuratezza intra-day sono state, rispettivamente, ≤3.6% e tra 94.5-112.3% per tutti e gli analiti, mentre quelle inter-day erano rispettivamente ≤7.3% e tra 94.5-112.9%. Il metodo è stato applicato con successo alla quantificazione di campioni plasmatici di pazienti.
In conclusione, con lo sviluppo di queste strategie si spera di implementare l’utilizzo del TDM per i farmaci oncologici nella pratica clinica.Despite the continuous progress in drug therapy, most anticancer drugs appear to be characterized by a high interindividual variability in plasma concentrations that is reflected in the efficacy of the treatment. From this arises the need of a personalized approach, so that the drug concentrations in plasma are adequate in each patient. On this basis, during the PhD project reported hereby, different techniques for therapeutic monitoring (TDM) of anticancer drugs were developed. First, a LC-MS/MS method for the quantification of imatinib (IMA) and its active metabolite, norimatinib (norIMA), was developed, validated and cross-validated in patients affected by gastrointestinal stromal tumour. This method allows to perform the quantification directly on a drop of capillary blood, exploiting the dried blood spot (DBS) technique, reducing sampling time, costs and improving patients’ compliance. Analytes were extracted from DBS samples by adding acidified methanol and the extract is injected into a LC system (configured with a 2D chromatography for online cleaning of the sample), coupled with an API-4000QT. The method showed good linearity (R2> 0.996) in the ranges of 50-7500 ng/mL and 10-1500 ng/mL for IMA and norIMA. Intra-day precision and accuracy were ≤3.1% and between 88.9-112.8%, respectively, while inter-day ones were ≤6.6% and between 95.7-104.3 %, for both analytes. Moreover, were also evaluated: the influence of the haematocrit (Hct), of the spot size and of the sample homogeneity on the analysis; the correlation between the concentration in DBS from venous sampling and from finger-prick (% difference between -12 and 3.8%) and the stability of DBSs (up to 16 months). Then, the method was applied for the quantification of 67 DBSs patients’ samples. Good agreement was obtained between IMA and norIMA concentrations found in DBS and plasma samples applying either the Hct normalization or avoiding it, simply multiplying the DBS concentration with a correction factor. Part of the work of this project was also dedicated for the development of alternative strategies for the quantification of anticancer drugs, to promote the application of TDM. In particular, the synthesis of molecularly imprinted polymers (MIPs) was performed, with the future goal of applying them as receptors in a fluorimetric detection system for IMA. MIPs were synthesized using the non-covalent approach and high dilution radical polymerization. Through this synthesis, the MIPs obtained, synthesized in DMSO with methacrylic acid as functional monomer, shown nanometric size (data acquired by dynamic light scattering). The rebinding tests then showed that 2 MIPs in particular were able to bind IMA with a good specificity (compared to the corresponding non-imprinted polymers) and selectivity. Finally, a LC-MS/MS method was developed and validated for the quantification of ribociclib (RIBO), palbociclib (PALBO) and letrozole (LETRO) in human plasma. RIBO and PALBO are drugs belonging to the CDKIs family, recently approved for breast cancer treatment in combination with LETRO. The method developed is suitable for its application in clinical practice, thanks to simple sample preparation and rapid analysis (6.5 min). The method showed a good linearity (R2 between 0.992-0.983) in the concentration ranges of 0.3-250 ng/mL for PALBO, 10-10000 ng mL for RIBO and 0.5-500 ng/mL for LETRO (covering the therapeutic plasma concentrations). Intra-day precision and accuracy were ≤3.6% and between 94.5-112.3% for all and analytes, respectively, while inter-day ones were ≤ 7.3% and 94.5-112.9%. The method has been successfully applied for patients’ plasma samples quantification. In conclusion, with the development of these strategies there is the hope to implement the application of TDM for anticancer drugs in the clinical practice.
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Gupta, Sona. "Rational design and delivery of peptide drugs." Thesis, Bangor University, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.323850.
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Soldevila, Barreda Joan Josep. "Design of catalytic organometallic anti-cancer drugs." Thesis, University of Warwick, 2014. http://wrap.warwick.ac.uk/63808/.
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This thesis is concerned with the design of organometallic half sandwich complexes which can catalyse the conversion of oxidised coenzyme nicotinamide adenine dinucleotide to its reduced form. The coenzyme pair NAD+/NADH is involved in many biological processes, such as regulation of the redox balance, and DNA repair. Disturbance of the NAD+/NADH ratio can lead to cell death. In particular, cancer cells are under constant oxidative stress and therefore might be more susceptible to changes in the NAD+/NADH levels. A series of neutral Ru(II) complexes of the type [(η6-arene)Ru(N,N’)(L)] (arene = p-cymene (p-cym), hexamethylbenzene (hmb), biphenyl (bip), benzene (bn); N,N’ = N-(2-aminoethyl)-4-(trifluoromethyl)benzenesulfonamide (TfEn), N-(2-aminoethyl)-toluensulfonamide (TsEn), or N-(2-aminoethyl)-4-methylensulfonamide (MsEn)) were synthesized and fully characterized. The complexes were shown by 1H-NMR to catalyse region-selectively the transfer hydrogenation of NAD+ to 1,4-NADH. Comparison of the turnover frequencies (TOF) for the complexes show a trend in which a decrease in catalytic activity with the arene ligand follows the order bn > bip > p-cym > hmb and TfEn > TsEn > MsEn. Complex [(η6-bn)Ru(TfEn)Cl] (12) was found to be the most active with a TOF of 10.4 h-1. The catalytic cycle for the transfer hydrogenation reaction was studied for complex [(p-cym)Ru(TsEn)Cl] (2). The monotosylate ethylenediamine Ru(II) complexes were used to carry out, for the first time, transfer hydrogenation reactions in cellulo (A2780 ovarian cancer cells) using formate as a hydride source. The antiproliferative activity of six complexes on co-administration with non-toxic doses of sodium formate were studied. A significant potentiation of the antiproliferative activity by formate was observed. The concentrations of NAD+ and NADH in cells showed an important reduction in the NAD+/NADH ratio. This study demonstrates that it may be possible to use catalytic transfer hydrogenation as a strategy for multi-targeted redox mechanisms of action for anticancer drugs. In order to compare the anticancer mechanism of the monotosylate ethylenediamine Ru(II) complexes with the corresponding ethylenediamine (en) complexes, DNA binding studies were carried out. The complexes were shown to bind to nucleobases only moderately strongly and no direct coordination to calf thymus DNA was observed. The complexes can destabilize DNA, but they display low affinity towards DNA, which suggests that DNA is probably not involved in the mechanism of these family of compounds. Interaction of complex [(p-cym)Ru(TsEn)] (2) with glutathione (GSH) was also studied. The complex undergoes ligand substitution. Two Ru(II) dimers were formed as the main products of the reaction: ([((p-cym)Ru)2(μ-GS)3] and [((p-cym)Ru)2(μ-GS)2]). These dimers share structural similitudes with other reported Ru(II) arene anticancer drugs, which suggests that they could be responsible for the moderate antiproliferactive activity of complex 2. A series of CpxRh(III) (CpX = CpXPhPh, CpXPh or Cp*) complexes containing en or TfEn were synthesised and fully characterised. The complexes were shown to catalyse regioselectively the transfer hydrogenation of NAD+ to 1,4-NADH with higher TOF than their Ru(II) analogues. Rh(III)-en compounds were shown to be more active than the Rh(III)-TfEn analogues. The nature of the Cpx ring was shown to influence significantly the catalytic activity of the complexes following the trend: CpXPhPh > CpXPh > Cp*. Complex [(CpXPhPh)Rh(en)Cl]+ (19) was the most active, with a TOF of 24.2 h-1. The catalytic cycle for the transfer hydrogenation reaction was studied using complex [(Cp*)Rh(en)Cl]+ (17) and compared to that of the Ru(II) analogues, and was found to be similar. Antiproliferative activity of the complexes in combination with formate, in A2780 cells, was investigated, but the potentiation due to the transfer hydrogenation was much lower than that obtained with Ru(II) compounds.
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Tripathi, Ashutosh. "DEVELOPMENT OF HINT BASED COMPUTATIONAL TOOLS FOR DRUG DESIGN: APPLICATIONS IN THE DESIGN AND DEVELOPMENT OF NOVEL ANTI-CANCER AGENTS." VCU Scholars Compass, 2009. http://scholarscompass.vcu.edu/etd/1866.
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The overall aim of the research is to develop a computational platform based on HINT paradigm for manipulating, predicting and analyzing biomacromolecular-ligand structure. A second synergistic goal is to apply the above methodology to design novel and potent anti-cancer agents. The crucial role of the microtubule in cell division has identified tubulin as an interesting target for the development of therapeutics for cancer. Pyrrole-containing molecules derived from nature have proven to be particularly useful as lead compounds for drug development. We have designed and developed a series of substituted pyrroles that inhibit growth and promote death of breast tumor cells at nM and μM concentrations in human breast tumor cell lines. In another project, stilbene analogs were designed and developed as microtubule depolymerizing agents that showed anti-leukemic activity. A molecular modeling study was carried out to accurately represent the complex structure and the binding mode of a new class of tubulin inhibitors that bind at the αβ-tubulin colchicine site. These studies coupled with HINT interaction analyses were able to describe the complex structure and the binding modes of inhibitors. Qualitative analyses of the results showed general agreement with the experimental in vitro biological activity for these derivatives. Consequently, we have been designing new analogs that can be synthesized and tested; we believe that these molecules will be highly selective against cancer cells with minimal toxicity to the host tissue. Another goal of our research is to develop computational tools for drug design. The development and implementation of a novel cavity detection algorithm is also reported and discussed. The algorithm named VICE (Vectorial Identification of Cavity Extents) utilizes HINT toolkit functions to identify and delineate a binding pocket in a protein. The program is based on geometric criteria and applies simple integer grid maps to delineate binding sites. The algorithm was extensively tested on a diverse set of proteins and detects binding pockets of different shapes and sizes. The study also implemented the computational titration algorithm to understand the complexity of ligand binding and protonation state in the active site of HIV-1 protease. The Computational titration algorithm is a powerful tool for understanding ligand binding in a complex biochemical environment and allows generating hypothesis on the best model for binding.
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Deanda, Felix. "Development and application of software tools for computer-assisted drug design /." Digital version accessible at:, 1999. http://wwwlib.umi.com/cr/utexas/main.
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Munday, Dale Leslie. "Design, development and evaluation of encapsulated oral controlled release theophylline mini-tablets." Thesis, Rhodes University, 1991. http://hdl.handle.net/10962/d1003255.
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Conventional solid dosage forms often lead to fluctuations which exceed the maximum safe therapeutic level and/or decline below the minimum effective level. It is recognised that many drugs for chronic administration should be administered on a schedule that maintains plasma drug concentration within the therapeutic window. Research in controlled release dosage forms aims at designing a system with a zero-order input (eg, ideally to deliver 8.33% of the dose per hour over a 12 hour duration), producing steady state plasma drug levels. Oral dministration of drugs prepared as a controlled release formulation is extremely popular, and has attracted the attention of pharmaceutical scientists during the last decade. This has been due to the simultaneous convergence of various factors (eg, discovery of novel polymers and devices, better understanding of formulation and physiological constraints, expiration of existing patents, prohibitive cost of developing new drug entities), involved in the development of these delivery systems. Controlled release oral products can be formulated as single or multiple unit dosage forms and the relative merits of multiple unit forms with their own rate controlling systems are well established. This work describes the development of a relatively inexpensive multiple-unit capsule dosage form of theophylline containing coated mini-tablets for drug delivery throughout the gastrointestinal tract. Preformulation studies on theophylline anhydrous included solubility and dissolution rate determinations. Techniques including X-ray powder diffraction, differential scanning colorimetry and infrared spectroscopy provided no evidence of true polymorphism after recrystallisation from various solvents. However, scanning electron micrographs showed the effects of solvent polarity and cooling rate on the size and shape of recrystallised particles. Theophylline granules were manufactured by using various binders and were film coated by fluidised bed technology with various proportions of ethylcellulose, containing varying amounts of PEG 1540. In vitro release rates were dependent upon coating thickness and the proportion of PEG, which, being water soluble, created pores in the coating during dissolution studies as observed by a scanning electron microscope. However, substantial proportions of the drug remained unreleased from the granules. In order to overcome the problems of drug retention, plain granules were used and theophylline mini-tablets (3 mm diameter, weighing 15 - 20 mg) were manufactured and film coated with various Eudragits ® and other polymeric mixtures (soluble and insoluble). In vitro dissolution profiles from samples enclosed in hard gelatin capsules were determined using the USPXXI paddle apparatus in test media at pH 1.2 (HCI), pH 5.4 and 7.4 (phosphate buffers) at 37'C. Monitoring of in vitro theophylline release over 12 h, under identical hydrodynamic conditions, showed that the dissolution rate at pH 1.2 is substantially greater (95% of total drug content released in < 10 h) than that in phosphate buffers. The maximum release after 12 h was approximately 20 and 30% of total drug content of the tablet at pH 5.4 and 7.4, respectively. However, in vivo bioavailability after oral administration of tablets to rabbits corresponded to over 95% of total drug, compared with the same dose administered intravenously. The retarded drug release during in vitro dissolution in phosphate buffer was attributed to a possible interaction of phosphate ions with theophylline molecules at the tablet core-coat interface. These findings indicate that both rate and extent of theophylline release from the slow release coated mini-tablets are highly sensitive to phosphate buffers. The data also emphasise the usefulness of an animal model for assessment of in vivo drug release and subsequent absorption during the development of modified release dosage forms. Mini-tablets were subjected to isothermal and cyclic stresses to reach conditions for up to 6 months at different temperatures and relative humidity. The film integrity was maintained but ageing of the coating occurred which impeded dissolution. Reduced drug release was temperature related while the effect of relative humidi% was insignific~t. Encapsulated mini-tablets (uncoated and coated with Eudragit RL and RS 2% w/w) equivalent to a 300 mg dose, were evaluated both in vitro and in vivo using beagle dogs. The pharmacokinetic parameters from single and multiple dose studies showed several advantages over Theo-Dur® 300 mg tablets. Precise dosage titration is possible by careful adjustment of the number of encapsulated mini-tablets. This multiple unit mini-tablet delivery system will allow for greater flexibility in dosage adjustment compared to the currently available preparations, allowing individualised fine dose titration in those patients requiring therapeutic drug monitoring. The developmentof the multiple unit mini-tablet formulation appears to provide an optimal dosage form with maximum flexibility in respect of dose, duration range and ease of production.
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Zhang, Liang. ""Fleximers" design and synthesis of a new class novel shape-modified nucleosides." Diss., Georgia Institute of Technology, 2003. http://hdl.handle.net/1853/26207.
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Young, Charlene Rebecca. "Rational drug design : an information driven approach to the design of an anthracycline analog /." [Boise, Idaho] : Boise State University, 2009. http://scholarworks.boisestate.edu/td/10/.
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Cochrane, Wolf. "In silico synthesis of analogous lead libraries for drug design by molecular enumeration." Diss., Pretoria : [s.n.], 2007. http://upetd.up.ac.za/thesis/available/etd-04212008-135220/.
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Haule, Ambrose Francis. "Design of tryptophan analogues as novel tryptanocidal drugs." Thesis, University of Sunderland, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.277923.
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Searle, Natalie Louise. "Design and synthesis of novel endoperoxide antimalarial drugs." Thesis, University of Liverpool, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.366699.
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Duffy, Judith Clare. "Design of novel non-steroidal anti-inflammatory drugs." Thesis, Liverpool John Moores University, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.521744.
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White, Alex William. "The design of novel inhibitors of poly (ADP-ribose) polymerase to potentiate cytotoxic drugs." Thesis, University of Newcastle Upon Tyne, 1996. http://hdl.handle.net/10443/1025.
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The abundant nuclear enzyme poly (ADP-ribose)polymerase (P ARP) catalyses the formation of long homopolymeric chains of ADP-ribose, utilising NAD+ as a substrate, as the immediate cellular response to DNA damage. PARP recognises a damaged section of DNA and initiates polymer synthesis, which is believed to act as a signal to effect the repair of the lesion. A selective, potent PARP inhibitor could block the recognition, and hence repair, of DNA damage induced by cancer chemotherapy. Since increased DNA repair is regarded as a mechanism whereby tumour cells can become resistant to treatment, PARP inhibitors have therapeutic potential as resistance modifying agents. From a study of PARP inhibitors such as 3-hydroxybenzarnide (A), benzimidazole derivatives (B) were proposed as inhibitors of the enzyme, and the synthesis and biological evaluation of a series of such molecules has been achieved. Substituted 2-aryl benzirnidazoles have proved to be highly potent PARP inhibitors (B;R= 4'NO2Ph, IC5o= 59 nM), under a permeabilised cell assay the nitro phenyl derivative (B; R= 4'N02Ph) is the most potent compound reported to date (IC50= 19 nM). 2-Methyl benzirnidazole-4-carboxamide (B; R= Me) has been shown to potentiate the in vitro cytotoxicity of the antitumour agent temozolomide in L1210 cells, and the synthesis of benzimidazole inhibitors suitable for pre-clinical in vivo eluation has also been investigated, This thesis demonstrates that benzimidazole PARP inhibitors have promising potential for clinical development as resistance modifying agents.
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Lloyd, Edward John, and mikewood@deakin edu au. "A common structural basis for central nervous system drug design." Deakin University. School of Biological Sciences, 1986. http://tux.lib.deakin.edu.au./adt-VDU/public/adt-VDU20050902.115505.
Full textAbstract:
The main theme of this thesis is that there is a common structural basis for drugs acting on the central nervous system (CNS), and that this concept may be used to design new CNS-active drugs which have greater specificity and hence less side-effects.
To develop these ideas, the biological basis of how drugs modify CMS neurotransmission is described, and illustrated using dopaminergic pathways. An account is then given of the use of physicochemical concepts in contemporary drug design. The complete conformational analysis of several antipsychotic drugs is used to illustrate some of these techniques in the development of a model for antipsychotic drug action.
After reviewing current structure-activity studies in several classes of CNS drugs (antipsychotics, anti-depressants, stimulants, hal1ucinogens, anticonvulsants and analgesics), a hypothesis for a common structural basis of CNS drug action is proposed- This is based on a topographical comparison of the X-ray structures of eight representative CNS-active drugs, and consists of three parts: 1.there is a common structural basis for the activity of many different CNS-active drug classes; 2. an aromatic ring and a nitrogen atom are the primary binding groups whose topographical arrangement is fundamental to the activity of these drug classes;
3. the nature and placement of secondary binding
determines different classes of CNS drug activity. A four-Point model for this common structural basis is then defined using 14- CNS-active drug structures that include the original eight used in proposing the hypothesis. The coordinates of this model are: R1 (0. 3.5, 0), R2 (0, -3.5, O), N (4.8. -0.3, 1.4), and R3 (6.3, 1.3, 0), where R1 and R2 represent the point locations of a hydrophobic interaction of the common aromatic ring with a receptor, and R3 locates the receptor point for a hydrogen bond involving the common nitrogen, N. Extended structures were used to define the receptor points R1, R2 and R3, and the complete conformational space of each of the 14 molecules was considered.
It is then shoun that the model may be used to predict whether a given structure is likely to show CNS activity: a search over 1,000 entries in the current Merck Index shows a high probability (82%) of CNS activity in compounds fitting the structural model.
Analysis of CNS neurotransmitters and neuropeptides shows that these fit the common model well. Based on the available evidence supporting chemical evolution, protein evolution, and the evolution of neurotransmitter functions, it is surmised that the aromatic ring/nitrogen atom pharmacophore proposed in the common model supports the idea of the evolution of CNS receptors and their neurotransmitters, possibly from an aromatic amine or acety1cho1ine acting as a primaeval communicating molecule.
The third point in the hypothesis trilogy is then addressed. The extensive conformation-activity analyses that have resulted in well-defined models for five separate CNS drug classes are used to map out the locations of secondary binding groups relative to the common model for anti-psychotics, antidepressants, analgesics, anticholinergics, and anticonvulsants. With this information, and knowledge derived from receptor-binding data, it is postulated that drugs having specified activity could be designed.
In order to generate novel structures having a high probability of CNS-activity, a process of drug design is described in which known CNS structures are superimposed topographically using the common model as a template. Atoms regarded as superfluous may be selectively deleted and the required secondary binding groups added in predicted locations to give novel structures.
It is concluded that this process provides the basis for the rational design of new lead compounds which could further be optimized for potent and specific CNS activity.
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Schreiber, Kimberly C. M. "Assay development for use in drug discovery against Bovine Trichomoniasis." Scholarly Commons, 2007. https://scholarlycommons.pacific.edu/uop_etds/650.
Full textAbstract:
Bovine trichomoniasis is a venereal disease that affects cattle. The causative agent of this disease is Tritrichomonas foetus, a flagellated protozoan. There is no current FDA approved treatment for this disease. The purpose of this study was to develop new compound screening assays that will make the discovery of new compounds faster and more accurate. The CellTiter-Glo Luminescent Cell Viability Assay, a high throughput screening (HTS) assay from Promega, was found to be as affective at measuring cytotoxicity as traditional assaying techniques. For the first time. preen florescent protein. a reporter gene used in cell viability assavs was successfully transformed into T. foetus for use in HTS systems. This study also identified new compounds that can potentially be used as new treatments for this disease.
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Thovarai, Vishal. "In silico drug design of potential novel anti malarial agents /." Online version of thesis, 2009. http://hdl.handle.net/1850/8689.
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Canzoneri, Joshua Craig. "Interaction of small molecules with nucleic acid targets: from RNA secondary structure to the riobosome." Diss., Georgia Institute of Technology, 2012. http://hdl.handle.net/1853/45769.
Full textAbstract:
Nucleic acids have proven to be viable targets for small molecule drugs. While many examples of such drugs are detailed in the literature, only a select few have found practical use in a clinical setting. These currently employed nucleic acid targeting therapies suffer from either debilitating off-target side effects or succumb to a resistance mechanism of the target. The need for new small molecules that target nucleic acids is evident. However, designing a novel drug to bind to DNA or RNA requires a detailed understanding of exactly what binding environments each nucleic acid presents. In an effort to broaden this knowledge, the work presented in this thesis details the binding location and affinity of known and novel nucleic acid binding small molecules with targets ranging from simple RNA secondary structure all the way to the complex structure of ribosomal RNA. Specifically, it is shown that the anthracycline class of antineoplastics prefer to bind at or near mismatch base pairs in both physiologically relevant iron responsive element RNA hairpin constructs as well as DNA hairpin constructs presenting mismatched base pairs. Also characterized in this thesis is a novel class of topoisomerase II / histone deacetylase inhibitor conjugates that display a unique affinity for DNA over RNA. Finally, the novel class of macrolide-peptide conjugates, known as peptolides, are shown to retain potent translation inhibition of the prokaryotic ribosome. The binding pocket of the peptolides, including a crevice previously unreachable by macrolides that extends away from the peptidyl transferase center toward the subunit interface, is confirmed in detail via chemical footprinting of the 70S ribosome. Overall, the identification of a novel binding site for the anthracycline class of drugs and the characterization of the two novel drug designs presented in this thesis will undoubtedly aid in the effort to design and discover new molecules that aim for nucleic acid targets. For example, the anthracycline derivative topoisomerase II / histone deacetylase inhibitor conjugates, with their differential mode of nucleic acid binding, may prove to have a unique side effect profile in a therapeutic application. The peptolide compounds also have the potential to be applied as novel antibiotics as they bind to an area of the prokaryotic ribosome unrelated to known macrolide resistance mutations. Furthermore, as a result of the observation of this thesis work that some peptolides also posses eukaryotic translation inhibition capabilities, they could prove to be useful in preventing the growth of rapidly proliferating eukaryotic cells such as plasmodium, leishmania, or tumor cells. Additionally, different head groups could be utilized in creating new peptolides; for example, an oxazolidinone antibiotic could be employed to sample a different binding area of the ribosome.
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Chieng, Heng Liang Norman, and n/a. "Amorphous drug preparation using ball milling." University of Otago. School of Pharmacy, 2008. http://adt.otago.ac.nz./public/adt-NZDU20081209.162001.
Full textAbstract:
Polymorphism and crystallinity are now recognised as important issues in drug development. This is shown by the increased amount of research in this area over recent years. In pharmaceutical development milling is an important unit operation for size reduction to improve powder handling, processing and dissolution rate. The aim of this thesis was to investigate the effect of ball milling (and cryo-milling) on the solid state properties, including amorphous drug formation, of pharmaceutical solids.
Milling was carried out using an oscillatory ball mill (Mixer Mill MM301, Retsch GmbH & Co., Germany). In cryo-milling the milling jars were immersed in liquid nitrogen for three min before milling. XRPD was used as the main technique to evaluate the milled samples. Ranitidine hydrochloride (RAN) and indomethacin (INDO) were the model drugs used in this study.
It was found that upon milling, RAN form 1 converts to RAN form 2 via an amorphous phase. A faster amorphization rate was observed when the crystalline samples were cryo-milled. Amorphous ranitidine hydrochloride was characterized to have a glass transition (T[g]) range of 13 to 30 �C and a crystallization exotherm (T[c]) between 30 and 65 �C. Conversion was found to occur faster when the temperature of the solid powder was greater than the T[c]. Under various storage conditions, similarly, crystallization of the amorphous phase mainly led to RAN form 2. However, some form 1 and amorphous phase was also detected on the XRPD diffractograms. Using partial least squares regression, the amount of solid form components in the ternary RAN mixtures were successfully quantified. RAN form 2 did not convert to form 1 under any milling (including cryo-milling) or storage conditions used in this study. Overall, RAN form 2 was found to be the thermodynamically stable form and the two (RAN) polymorphs are likely to be a monotropic pair.
In a co-milling study of INDO and RAN, the two crystalline drugs were successfully converted into a single amorphous phase after 60 min of co-milling in a cold room (4 �C). The T[g] range (26-44 �C) was also characterized for these mixtures. DRIFTS spectra of the co-milled amorphous samples indicated an interaction had occurred between the carboxylic acid carbonyl (HO-C=O) and benzonyl amide (NC=O) of the INDO molecule with the aci-nitro (C=NO₂) of RAN. Depending on the ratio of INDO to RAN, in general, the amorphous mixtures were stable at 4 �C after 30 days of storage. Crystallization was faster when the binary mixtures were stored at higher temperature or contained higher amounts of RAN in the mixture. Although XRPD and DRIFTS suggested an interaction between the two drugs, co-crystal formation was not observed between INDO and RAN.
Ball milling can be used to produce amorphous drug. The rate and extent of amorphization is dependent on the milling conditions. A faster rate of amorphization was observed when the crystalline drugs were cryo-milled. Amorphous drug formation can be made either alone or in combination with another crystalline drug. Amorphization could offer a significant improvement on the dissolution profile and the bioavailability of the poorly water soluble drug - indomethacin. Furthermore, ball milling can also be used to produce a homogenous mix between solids. The �goodmix� effect can be used for seed-induced crystallization or, when the XRPD or Raman data were combined with partial least squares regression, to create a reliable calibration model for quantitative analysis.
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Yeap, S. K. "The design of tyrosinase inhibitors as novel chemotherapeutic agents." Thesis, University of Sunderland, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.378608.
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Athri, Prashanth. "Application of Computer-Aided Drug Discovery Methodologies Towards the Rational Design of Drugs Against Infectious Diseases." Digital Archive @ GSU, 2008. http://digitalarchive.gsu.edu/chemistry_diss/20.
Full textAbstract:
Computer-aided drug discovery involves the application of computer science and programming to solve chemical and biological problems. Specifically, the QSAR (Quantitative Structure Activity Relationships) methodology is used in drug development to provide a rational basis of drug synthesis, rather than a trial and error approach. Molecular dynamics (MD) studies focus on investigating the details of drug-target interactions to elucidate various biophysical characteristics of interest. Infectious diseases like Trypanosoma brucei rhodesiense (TBR) and P. falciparum (malaria) are responsible for millions of deaths annually around the globe. This necessitates an immediate need to design and develop new drugs that efficiently battle these diseases. As a part of the initiatives to improve drug efficacy QSAR studies accomplished the formulation of chemical hypothesis to assist development of drugs against TBR. Results show that CoMSIA 3D QSAR models, with a Pearson’s correlation coefficient of 0.95, predict a compound with meta nitrogens on the phenyl groups, in the combinatorial space based on a biphenyl-furan diamidine design template, to have higher activity against TBR relative to the existing compound set within the same space. Molecular dynamics study, conducted on a linear benzimidazole-biphenyl diamidine that has non-classical structural similarity to earlier known paradigms of minor groove binders, gave insights into the unique water mediated interactions between the DNA minor groove and this ligand. Earlier experiments suggested the interfacial water molecules near the terminal ends of the ligand to be responsible for the exceptianlly high binding constant of the ligand. Results from MD studies show two other modes of binding. The first conformation has a single water molecule with a residency time of 6ns (average) that is closer to the central part of the ligand, which stabilizes the structure in addition to the terminal water. The second conformation that was detected had the ligand completely away from the floor of the minor groove, and hydrogen bonded to the sugar oxygens.
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Mungongo, Singfrid Gasper. "The design, synthesis and biological evaluation of novel antitrypanosomal drugs." Thesis, University of Sunderland, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.284073.
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Carmichael, Samantha Jane. "Optimisation of study design in the pharmacokinetics of anticancer drugs." Thesis, University of Edinburgh, 2001. http://hdl.handle.net/1842/23290.
Full textAbstract:
"Optimal sampling strategies" are based upon the concept of 'information-rich' times within a concentration-time profile. In this thesis, the selection of optimal sampling times was based on sensitivity analysis and applied to the one and two-compartment PK models. Simulation studies were used to show that parameter estimates obtained using an optimal design method with a reduced number of samples were as good as, if not better than, those obtained from PK studies in which the sampling times were selected empirically. In addition, the effect of adding sampling windows around the "optimal" times offered improved estimation of the inter-subject variability parameters, when compared to designs with fixed sampling times. This result has particular relevance in a clinical setting where a sample may not be collected at the stipulated time, but is still useful in the analysis if the "actual" sampling time is recorded accurately. Further simulations were based on published sampling designs for the anticancer drug carboplatin, and these were used for comparison with the results when an "optimal design" was used. Finally, a population analysis was carried out on data from a phase I clinical trial of the broad-spectrum neuropeptide antagonist, Antagonist G. The parameter values were used to design on "optimal" sampling strategy. As the sample times of the optimal strategy were different to those used in the clinical study, further simulations were used to compare the design. Using sensitivity analysis to design sampling strategies for population PK studies allowed the selection of a minimum number of sampling times, but still resulted in accurate estimation of the parameters of the one and two-compartment PK models. These sampling times provide a basis for PK study design, around which further samples could be added to improve the identification of the model and also the estimation of parameters and their inter and intra-subject of variability.
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Gibson, Victoria. "Design, synthesis and evaluation of anthraquinone-oligodeoxynucleotide conjugates." Thesis, University of Sunderland, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.242343.
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Ling, Xiang. "Adaptive design in dose-response studies." Columbus, Ohio : Ohio State University, 2005. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1133365136.
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LA, FRANCA Mery. "Design, synthesis and biological evaluation of new anticancer drugs: FGFR inhibitors." Doctoral thesis, Università degli Studi di Palermo, 2021. http://hdl.handle.net/10447/475964.
Full textAbstract:
Fibroblast growth factor receptors (FGFRs) constitute a family of tyrosine kinases receptors (RTKs) that exert pivotal physiological functions in human embryonic and adult tissues.
Hyperactivated FGFR signaling drives tumorigenesis in multiple cancer types, including lung and brain cancers. Great effort has been laid on the development of new compounds that specifically target the FGFR axis. However, cancer cell- based and microenvironmental resistance mechanisms against FGFR inhibitors often arise and are currently poorly understood. Furthermore, FGFR-targeted therapy often presents different side effects, e due to the broad biological spectrum of the FGFR signaling axis as well as to its involvement in the homeostasis of many tissue types.
It is well known that metal complexes, e.g. of copper(II), zinc(II), nickel(II) and platinum(II) ions, may exhibit in vitro anti-proliferative activity against different human cancer cell lines. Usually, their cytotoxic activity has been related to their binding capabilities toward biological macromolecules.
In this thesis, the recently reported in vitro anticancer properties of copper(II) compounds, coupled to the known Cu2+ ! Cu+ redox activity, have been exploited to design and synthesize, new compounds as specific inhibitors of FGFR targets. The ligands were designed on the basis of the crystal structures of FGFR1 and FGFR4 co-crystallized with their known inhibitor Ponatinib. It is worth mentioning that the onset of drug resistance to of Ponatinib has been associated to its low water solubility, which partially hinders cell membrane permeability and release to the cytosol and also increases its accumulations in lipid compartments like adiposomes. For this reason, in the following thesis work, an attempt has been taken to design, synthesize and test new ligands with structural similarity to Ponatinib, as well as their positively charged derivatives, as a consequence of their coordination to cationic metal ions such as Cu2+.
The anti-proliferative activity of the most promising molecules was evaluated in vitro and in vivo, in order to understand their possible mechanism of action. In details, 22 ligands and 3 copper(II) complexes have been synthesized as potential drugs against FGFR targets. In particular, the copper complexes were identified to act as pro-drugs that are spontaneously activated by hypoxia.
After a screening of several tumor cell lines to test the activity of the newly synthesized drug candidates, lung cancer and brain tumor turned out to be the most sensitive cancer types. This study shows that the most active drugs are able to inhibit the FGF/FGFR axis efficiently.
32
O'Daniel, Peter Ivo. "Exploring structural diversity in nucleoside and nucleic acid drug design." Diss., Available online, Georgia Institute of Technology, 2005, 2005. http://etd.gatech.edu/theses/available/etd-08252005-130946/.
Full textAbstract:
Thesis (Ph. D.)--Chemistry and Biochemistry, Georgia Institute of Technology, 2006.Barefield, E. Kent, Committee Member ; Beckham, Haskell W., Committee Member ; Doyle, Donald F., Committee Member ; Weck, Marcus, Committee Member ; Seley, Katherine L., Committee Chair.
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Long, Stephen. "Combinatorial methods in drug design : towards modulating protein-protein interactions./." St. Lucia, Qld, 2003. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe17525.pdf.
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Elmagbari, Fatin M. Ali. "Synthesis and design of ligand copper complexes as anti-inflammatory drugs." Doctoral thesis, University of Cape Town, 2015. http://hdl.handle.net/11427/15767.
Full textAbstract:
Rheumatoid arthritis is a debilitating disease for which there is no cure. Copper has been used for centuries to alleviate the inflammation associated with the disease. The aim of this research was to design and test new ligands which are able to promote the percutaneous absorption of copper and/or mobilize endogenous copper reserves. Formation constants of H+, Cu(II), Ni(II) and Zn(II) with five low molecular ligands 2-((2-aminoethyl)amino)-N-(pyridin-2- ylmethyl)acetamide) [H(555)NH2], 2-((2-dimethyl-amino)ethyl)amino)-N-(pyridin-2-ylmethyl) acetamide [H(555)NMe2], N-(2-aminoethyl)-N'-(pyridin-2-ylmethyl)ethanediamide [H2(555)NH2], 3-(2-aminoacetamido)-N-(pyridin-2-ylmethyl)propanamide [H2(565)NH2], 3-amino-N-(pyridin-2-lmethyl)-propanamide [H(56)NH2] were measured at 25±0.01oC and at an ionic strength of 0.15M (NaCl) using glass electrode potentiometry. The structures of the different Cu(II) species formed with these ligands were investigated using ultraviolet-visible (Uv-visible), nuclear magnetic resonance (NMR) spectroscopy and X-ray crystallography as well as molecular mechanics calculations. The Uv-visible spectra obtained for the different species in solution were typical of tetragonally distorted Cu(II) complexes. The active binding sites were identified as the pyridine nitrogen, the amide nitrogen and the terminal amino group. The pyridine nitrogen was involved in coordination first, followed by the amide and then the terminal amine groups. The X-ray crystal structure of two of the Cu(II) complexes were solved; one formed a rectangular pyramidal geometry and the other a distorted square planar geometry. Molecular mechanics was used to determine the lowest energy conformation of different possible geometries. Since the preferred route of administration is through the skin, the rate of dermal absorption and the bioavailability of copper are important. For this reason, the drugs were designed so that they could be administered dermally and be selective for Cu(II) so that they do not affect the speciation of other metal ions in blood plasma. Speciation calculations using a blood plasma model were used to estimate the complexing ability of the ligands in vivo. This result showed that [H(555)NH2] was the best at mobilising copper in vivo.
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LA, FRANCA Mery. "Design, synthesis and biological evaluation of new anticancer drugs: FGFR inhibitors." Doctoral thesis, Università degli Studi di Palermo, 2021. http://hdl.handle.net/10447/491643.
Full textAbstract:
Fibroblast growth factor receptors (FGFRs) constitute a family of tyrosine kinases receptors (RTKs) that exert pivotal physiological functions in human embryonic and adult tissues.
Hyperactivated FGFR signaling drives tumorigenesis in multiple cancer types, including lung and brain cancers. Great effort has been laid on the development of new compounds that specifically target the FGFR axis. However, cancer cell- based and microenvironmental resistance mechanisms against FGFR inhibitors often arise and are currently poorly understood. Furthermore, FGFR-targeted therapy often presents different side effects, e due to the broad biological spectrum of the FGFR signaling axis as well as to its involvement in the homeostasis of many tissue types.
It is well known that metal complexes, e.g. of copper(II), zinc(II), nickel(II) and platinum(II) ions, may exhibit in vitro anti-proliferative activity against different human cancer cell lines. Usually, their cytotoxic activity has been related to their binding capabilities toward biological macromolecules.
In this thesis, the recently reported in vitro anticancer properties of copper(II) compounds, coupled to the known Cu2+ ! Cu+ redox activity, have been exploited to design and synthesize, new compounds as specific inhibitors of FGFR targets. The ligands were designed on the basis of the crystal structures of FGFR1 and FGFR4 co-crystallized with their known inhibitor Ponatinib. It is worth mentioning that the onset of drug resistance to of Ponatinib has been associated to its low water solubility, which partially hinders cell membrane permeability and release to the cytosol and also increases its accumulations in lipid compartments like adiposomes. For this reason, in the following thesis work, an attempt has been taken to design, synthesize and test new ligands with structural similarity to Ponatinib, as well as their positively charged derivatives, as a consequence of their coordination to cationic metal ions such as Cu2+.
The anti-proliferative activity of the most promising molecules was evaluated in vitro and in vivo, in order to understand their possible mechanism of action. In details, 22 ligands and 3 copper(II) complexes have been synthesized as potential drugs against FGFR targets. In particular, the copper complexes were identified to act as pro-drugs that are spontaneously activated by hypoxia.
After a screening of several tumor cell lines to test the activity of the newly synthesized drug candidates, lung cancer and brain tumor turned out to be the most sensitive cancer types. This study shows that the most active drugs are able to inhibit the FGF/FGFR axis efficiently.Fibroblast growth factor receptors (FGFRs) constitute a family of tyrosine kinases receptors (RTKs) that exert pivotal physiological functions in human embryonic and adult tissues. Hyperactivated FGFR signaling drives tumorigenesis in multiple cancer types, including lung and brain cancers. Great effort has been laid on the development of new compounds that specifically target the FGFR axis. However, cancer cell- based and microenvironmental resistance mechanisms against FGFR inhibitors often arise and are currently poorly understood. Furthermore, FGFR-targeted therapy often presents different side effects, e due to the broad biological spectrum of the FGFR signaling axis as well as to its involvement in the homeostasis of many tissue types. It is well known that metal complexes, e.g. of copper(II), zinc(II), nickel(II) and platinum(II) ions, may exhibit in vitro anti-proliferative activity against different human cancer cell lines. Usually, their cytotoxic activity has been related to their binding capabilities toward biological macromolecules. In this thesis, the recently reported in vitro anticancer properties of copper(II) compounds, coupled to the known Cu2+ ! Cu+ redox activity, have been exploited to design and synthesize, new compounds as specific inhibitors of FGFR targets. The ligands were designed on the basis of the crystal structures of FGFR1 and FGFR4 co-crystallized with their known inhibitor Ponatinib. It is worth mentioning that the onset of drug resistance to of Ponatinib has been associated to its low water solubility, which partially hinders cell membrane permeability and release to the cytosol and also increases its accumulations in lipid compartments like adiposomes. For this reason, in the following thesis work, an attempt has been taken to design, synthesize and test new ligands with structural similarity to Ponatinib, as well as their positively charged derivatives, as a consequence of their coordination to cationic metal ions such as Cu2+. The anti-proliferative activity of the most promising molecules was evaluated in vitro and in vivo, in order to understand their possible mechanism of action. In details, 22 ligands and 3 copper(II) complexes have been synthesized as potential drugs against FGFR targets. In particular, the copper complexes were identified to act as pro-drugs that are spontaneously activated by hypoxia. After a screening of several tumor cell lines to test the activity of the newly synthesized drug candidates, lung cancer and brain tumor turned out to be the most sensitive cancer types. This study shows that the most active drugs are able to inhibit the FGF/FGFR axis efficiently.
36
Saito, Takashi. "DESIGN AND CHARACTERIZATION OF GELATIN HYDROGELS INCORPORATING LOW-MOLECULAR-WEIGHT DRUGS FOR TISSUE REGENERATION." 京都大学 (Kyoto University), 2015. http://hdl.handle.net/2433/199334.
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Cong, Ze. "Value of pharmaceutical innovation the access effects, diffusion process, and health effects of new drugs /." Santa Monica: RAND, 2009. http://www.rand.org/pubs/rgs_dissertations/2009/RAND_RGSD242.pdf.
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Bahceci, Suleyman. "The electron-conformational method of molecular modeling in drug design and structure-activity relationships /." Digital version accessible at:, 1999. http://wwwlib.umi.com/cr/utexas/main.
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Dube, Admire. "The design, preparation and evaluation of Artemisia Afra and placebos in tea bag dosage form suitable for use in clinical trials." Thesis, University of the Western Cape, 2006. http://etd.uwc.ac.za/index.php?module=etd&action=viewtitle&id=gen8Srv25Nme4_2915_1188480959.
Full textAbstract:
Artemisia Afra, a popular South African traditional herbal medicine is commonly administered as a tea infusion of the leaves. However, clinical trials proving it safety and efficacy are lacking mainly due to the absence of good quality dosage forms and credible placebos for the plant. The objectives of this study were to prepare a standardized preparation of the plant leaves and freeze-dried aqueous extract powder of the leaves, in a tea bag dosage form and to design and prepare credible placebos for these plant materials.
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Ward, D. J. "Further development of methods for the computer-aided design of neuropeptide-based drugs." Thesis, University of Manchester, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.280534.
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Shi, Yun, and 施昀. "Escalation with overdose control for phase I drug-combination trials." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2013. http://hub.hku.hk/bib/B49799733.
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The escalation with overdose control (EWOC) method is a popular modelbased dose finding design for phase I clinical trials. Dose finding for combined drugs has grown rapidly in oncology drug development. A two-dimensional EWOC design is proposed for dose finding with two agents in combination based on a four-parameter logistic regression model. During trial conduct, the posterior distribution of the maximum tolerated dose (MTD) combination is updated continuously in order to find the appropriate dose combination for each cohort of patients. The probability that the next dose combination exceeds the MTD combination can be controlled by a feasibility bound, which is based on a prespecified quantile for the MTD distribution such as to reduce the possibility of over-dosing. Dose escalation, de-escalation or staying at the same doses is determined by searching the MTD combination along rows and columns in a two-drug combination matrix. Simulation studies are conducted to examine the performance of the design under various practical scenarios, and illustrate it with a trial example.published_or_final_version
Statistics and Actuarial Science
Master
Master of Philosophy
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Mosley, Sylvester L. "Base-modified carbocyclic nucleosides as medicinal agents." Thesis, Georgia Institute of Technology, 2001. http://hdl.handle.net/1853/27041.
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Lu, Jun. "Toward the next generation of smart anti-tumor drugs: a highly water-soluble Nucleolin Aptamer-Paclitaxel conjugate with a Cathespin B-labile linker for tumor-specific targareting in ovarian cancer." HKBU Institutional Repository, 2017. https://repository.hkbu.edu.hk/etd_oa/440.
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Paclitaxel (PTX) is among the most commonly used first-line drugs for cancer chemotherapy. However, its poor water solubility and indiscriminate distribution in normal tissues remain clinical challenges. Here we designed and synthesized a highly water-soluble nucleolin aptamer-paclitaxel conjugate (NucA-PTX) that selectively delivers PTX to the tumor site. By connecting a tumor-targeting nucleolin aptamer (NucA) to the active hydroxyl group at 2' position of PTX via a cathepsin B sensitive dipeptide bond, NucA-PTX could remain stable and inactive in the circulation. The tumor-recognition component NucA facilitates the uptake of the conjugated PTX specifically in tumor cells. Once inside cells, the dipeptide bond linker of NucA-PTX will be cleaved by cathepsin B and then the conjugated PTX will be released for action. The stability of NucA-PTX in human serum and the cathepsin-B dependent release of the conjugated PTX in tumor cells were verified by monitoring the fluorescence resonance energy transfer (FRET) of a dual fluorescence-labeled conjugate FAM-NucA-PTX-Rd. In addition, the PTX conjugation did not considerably affect the binding affinity between NucA and its target protein nucleolin, which was supported by both molecular dynamic simulation and isothermal titration calorimetry (ITC). The NucA modification was shown to facilitate the uptake of the conjugated PTX in ovarian cancer cells mainly by macropinocytosis in a nucleolin expression-dependent manner. Moreover, the NucA modification increased the in vitro cytotoxicity and mitosis inhibition of the conjugated PTX in ovarian cancer cell lines. The in vivo data collected from a human xenograft model of ovarian cancer demonstrated that the NucA modification facilitated the selective accumulation of the conjugated PTX in ovarian tumor tissue, and subsequently resulting in notably improved antitumor activity and reduced toxicity.
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Sheeka, Hendrika Maria. "Design and synthesis of novel nucleotide pro-drugs as anti-HIV agents." Thesis, University of Southampton, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.295004.
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Clement, Ella Chow. "Design and Syntheses of Potential Drugs Based on GABA(A) Receptor Pharmacophores." Diss., Virginia Tech, 2005. http://hdl.handle.net/10919/28271.
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Numerous previous studies of GABAAR ligands have suggested that GABAAR agonists must be zwitterionic and feature an intercharge separation similar to that of GABA (approx. 4.7-6.0 Ã ). We have demonstrated that monomeric, homodimeric and heterodimeric non-zwitterionic GABA amides are partial, full, or superagonists at the murine GABAA receptor (GABAAR). The agonism of these GABA amides is comparable to that of THIP, as shown by in vitro assay results. The assay data indicate that the agonism of GABA amides is tether length-dependent. Optimum agonism is achieved with a tether length of four methylenes in GABA amide dimers and in GABA amides bearing pendant amide or amino groups. We have further investigated the structure-activity relationship for GABA amides on the GABAAR by performing structural modifications to both the superagonist 2c and the agonist 6c. Synergism and [3H]muscimol binding experiments show that 2c binds to the same sites as GABA. Structural modification of 2c demonstrated that partial rigidification of the tether eliminated agonism and caused ligands to behave as weak competitive antagonists. We have also investigated the agonism of four ZAPA derivatives in 36Cl- uptake functional assay. Two of them are found to be as potent as GABA. In our studies of 1,4-benzodiazepines, our goal was to synthesize three different subtypes of quaternary 1,4-benzodiazepines by use of the memory of chirality (MOC) strategy. Disappointingly, most of the deprotonation/alkylations failed, due to various reasons. The failure of the reactions of (S)-alanine-derived tetrahydro-1,4-benzodiazepin-3-ones was probably due to either the unexpected side reactions or the steric hindrance of enolate alkylation. In the case of tetrahydro-1,4-benzodiazepin-2-ones, computational studies suggested that steric hindrance by both the benzo ring and N4-allyl group might retard deprotonation at C3 by bulky bases like KHMDS or LDA. Finally, (S)-serine-derived 1,4-benzodiazepin-2-ones and their elimination products (ï ¡-methylene benzodiazepines) were prepared. These proved unreactive towards deprotonation/alkylations and conjugate additions, respectively. The low reactivity of the ï ¡-methylene benzodiazepines towards nucleophiles was attributed to highly delocalized LUMOs that failed to direct nucleophiles to the ï ¢-carbons.Ph. D.
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Botta, Antonio. "Design, synthesis and biological studies of novel heterocyclic compounds as anticancer drugs." Doctoral thesis, Universita degli studi di Salerno, 2015. http://hdl.handle.net/10556/1971.
Full textAbstract:
2012 - 2013Heterocyles are an essencial class of molecules, assuming a role in many aspect of our life. Indeed heterocyclic nucleus is a common feature of several biomolecule and bioactive compounds including agrochemical products and drugs. In this work we focused on two important class of heterocyclic compounds: carbazoles and NHCs (N-heterocyclic carbenes). Carbazoles, prevalent as structural motifs in various synthetic materials and naturally occurring alkaloids, as is known, have many applications such as optoelectronic materials, conducting polymers and especially as promising bioactive compounds due to their biological properties, known since 1965. Furthermore NHCs are a class of stable carbenes that over the last few years have entered the field as “new” ligands for bioactive coordination compounds. It has been demonstrated that metal NHC complexes can be used to develop highly efficient metal based drugs with possible applications in the treatment of cancer or infectious diseases. We aimed to design, synthesize and characterize novel carbazole derivatives and NHC metal complexes with the purpose of identify new biologically active heterocyclic compounds. [edited by Author]
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Casati, F. "DESIGN AND DEVELOPMENT OF CAPSULAR MOLDED DEVICES FOR MODIFIED RELEASE OF DRUGS." Doctoral thesis, Università degli Studi di Milano, 2017. http://hdl.handle.net/2434/473424.
Full textAbstract:
The present work focused on the formulation and manufacturing of modified-release drug delivery systems employing injection molding (IM) technique. IM is based on the injection, under high pressure and temperature, of thermoplastic materials into a mold. The interest in applying IM as well as micromolding (μIM) techniques, commonly used within the plastic industry, in the pharmaceutical field is driven by the possible reduction of development and manufacturing costs related to the simplification of industrial scalability, to the patentability of the new drug products and to the product versatility in terms of size and shape.
The PhD research activity was focused on the design and the development of prolonged release drug delivery systems and site specific one, both in the form of capsular devices.
A large part of the work was aimed at the setup of methods for the screening of polymeric carriers and composites and on the identification of parameters as well as procedures for the evaluation of hot-processability of materials and physico-technological characterization of molded prototypes.
Considering the development of extended release drug delivery systems, the first step was the selection of the most appropriate polymer candidate for evaluating the feasibility of μIM for the manufacturing of capsular containers intended for prolonged release of drug. The following step was the development of an investigation protocol to assess the processability by micromolding of EC-based materials through tests performed on a screening disk, in addition to the performance studies conducted on such molded disk-shaped specimens.
As regards the development of site specific drug delivery systems for colon targeting manufactured by µIM, the possibility to combine the time-controlled and the enzyme-triggered approaches was attempted in order to make up for the respective limitations of the individual approaches thus reducing the variability and achieving a fine-tuning of the release performance.
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Said, Najeeb Barrah. "The design and synthesis of non-peptide bradykinin B2 receptor antagonists." Thesis, University College London (University of London), 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.285827.
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Jones, Garry B. "Design, synthesis and evaluation of DNA-binding oxazolo[2,3-c][1,4]benzodiazepines and pyrrolo[2,1-c][1,4]benzodiazepines." Thesis, University of Portsmouth, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.293269.
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Isaacs, Nasreen. "Formulation and process optimisation of ethionamide 250 MGtablets using quality by design principles." Thesis, Nelson Mandela Metropolitan University, 2015. http://hdl.handle.net/10948/3979.
Full textAbstract:
The traditional approach of Quality by Testing (QbT) limits the assurance of product quality to in-process and post-production testing. To overcome these limitations, a more proactive and systematic means to product development and optimisation is required. Quality by Design (QbD) is an example of such an approach which focuses on understanding the product and its manufacturing process and emphasises that quality should be built into the product and not merely tested. The study aims to optimise ethionamide tablets, an immediate release oral solid dosage form using QbD.