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1
Stewart, Charlotte. "Structure activity relationships of bisphosphonate analogues." Thesis, University of Aberdeen, 2010. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=128207.
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The nitrogen-containing bisphosphonates (NBPs) are the most widely used treatment for diseases involving excessive osteoclastic bone resorption, such as osteoporosis. The clinical efficacy of NBPs is due in large part to their affinity for bone mineral, but it has been suggested that lowering affinity may have benefits due to altered distribution and duration of action possibly allowing direct anti-tumour effects. In addition, the phosphonocarboxylate (PC) analogues inhibit prenylation more selectively through a different enzyme target, Rab geranylgeranyl transferase (RGGT), which may offer additional benefits by reducing side-effects associated with farnesyl diphosphate synthase (FPPS) inhibition. Using fluorescent analogues of PCs and NBPs demonstrated that mineral affinity not only affects initial bone-binding, but also influences desorption, reattachment and penetration at the bone surface, suggesting that lower affinity compounds have lower retention and increased access to other cell types, such as tumour cells. The work presented aimed to investigate the potential of low affinity analogues by characterising their intracellular potency for inhibiting their target enzymes. The results showed that modification to the phosphonate groups to produce phosphonoalkylphosphinate analogues reduced potency for inhibiting FPPS. By contrast, removal of one of the phosphonate groups to give a monophosphonate changed the target enzyme to RGGT. Modifications to the R1 side-chain (substituting with hydrogen or a halogen) of both NBPs and PCs were studied and showed contrasting results, modifications to the R1 side-chain of NBPs affect their ability to inhibit FPPS whereas the same modification to PCs is insignificant for inhibiting RGGT. This showed the distinction between the structural requirements for inhibition of RGGT and FPPS and furthers the understanding of the structure-activity relationships of both NBPs and PCs which could guide future drug design. Within this thesis the most potent inhibitor of RGGT to date, 3-IPEHPC, was characterised which in addition to having therapeutic potential may be used as tool to investigate the importance of Rab prenylation for cellular function.
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Shahbakhti, Hassan. "Structure/activity relationships of antitumour diazridinylquinones." Thesis, University of Salford, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.308289.
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McFadyen, Iain James. "Structure-activity relationships of opioid ligands." Thesis, Loughborough University, 1999. https://dspace.lboro.ac.uk/2134/33189.
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There are three different types of opioid receptor, namely mu, delta and kappa. Morphine and related clinically useful analgesics exert their actions through the mu opioid receptor. Such compounds represent a huge structural diversity, including both peptides and alkaloids. Nevertheless, there exists a common pharmacophore comprising two critical features, namely an amine nitrogen and an aromatic ring, usually with a hydroxyl substituent; the spatial relationship between them is also vital.
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Moore, Madeleine Henrietta. "Structure-activity relationships in Werner clathrates." Doctoral thesis, University of Cape Town, 1987. http://hdl.handle.net/11427/17038.
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Includes bibliographical references.The synthesis and characterization of a series of inorganic coordination compounds which, upon crystallization, have the ability to include solvent or guest molecules spatially within the lattice are reported. The compounds have the following general formula: [NiX2B4] - where X is isothiocyanate or bromine and B is 4-ethylpyridine, 4-vinylpiridine or 3,5-dimethylpyridine; [NiX2B2]n - where X is isothiocyanate, B is 2-aminopyridine and n indicates it is a polymer; [NiX2AB2]2 - where X is isothiocyanate, B is 3-aminopyridine (two of these four ligands in the dimer are bridging) and A is water. The various guest molecules have been carefully chosen, according to their point symmetry, which is a key factor in yielding structures of a particular type. The structures of seventeen compounds have been elucidated by single crystal x-ray analysis. The difficulty has been found to lie in refining disordered guest molecules. Other techniques employed in the initial characterization of these compounds are Microanalysis, Mass Spectrometry and UV/Visible Spectrophotometry. An intramolecular potential energy study on the [Ni(NCS)2(3,5-diMepy)4] complex reveals that the orthohydrogens on the 3,5-dimethylpyridine ligands control the conformation of the molecule. Packing densities and volume comparisons of the [Ni(NCS)2(4-Etpy)4] and [Ni(NCS)2(4-Vipy)4] complexes and their clathrates have been carried out. The exact sizes and shapes of the cavities in which the guest molecules are located in the x-ray crystal structures have been evaluated by both intermolecular potential energy and molecular volume calculations. Thermodynamic and spectroscopic properties of the [Ni(NCS)2(4-Etpy)4] and [Ni(NCS)2(4-Vipy)4] clathrates have been studied in both solution and the solid state. The techniques used are x-ray powder diffractometry, IR spectroscopy and Thermogravimetry (including Differential Thermal Analysis).
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Wong, Fred Tuck Khai. "Structure-activity relationships of cardiac glycosides." Thesis, The University of Sydney, 1989. https://hdl.handle.net/2123/26271.
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It is over 200 years since William Hithering published his famous treatise on the use of the foxglove. Since that time, digitalis has been in continuous use as a therapeutic agent, and, although its efficacy has often been challenged it continues to occupy a central role in the treatment of chronic congestive heart failure.
Interest in digitalis has been sustained by its therapeutic use and by the scientific interest in its mode of action. The cardiac glycosides, generally referred to by the generic name of digitalis, are unique inhibitors of the enzyme Na*, K*-ATPase. This enzyme is found in the plasma membrane of all eukaryotic cells where it acts as a transmembrane pump that couples the outward transport of Na+ with the inward transport of K*. As a result of this action, Na*, K*-ATPase plays an important role in cell homeostasis and makes a major contribution to the maintenance of the transmembrane resting potential. Such important cellular properties as excitability and conduction of electrical impulses depend very much on the action of Na*, K*-ATPase.
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Centani, Luyanda. "Structure activity and structure property relationships of antimalarial imidazopyridazines." Master's thesis, Faculty of Science, 2019. http://hdl.handle.net/11427/31315.
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Malaria is one of the most pressing human health issues. Despite being an ancient disease, it is estimated to have an annual death rate of 445 000 with out of 216 million malaria related cases in 2016. Malaria is most widespread in developing regions of the world. Forty percent of the world’s population is exposed to varying degrees of malaria. Malaria is caused by different species of the Plasmodium genus and the disease is vector-borne. The disease may be cured if diagnosed early. Most drugs that were once effective in the treatment of malaria have become ineffective due to the emergence of resistance, which has become the main driving force behind efforts to discover and develop new drugs able to circumvent the resistance. Imidazopyridazines have been shown to have potent antiplasmodium activity. The lead compound MMV652103 has been shown to display potent activity against the multidrug resistant K1 strain and the drug sensitive NF54 strain of the human malaria parasite Plasmodium falciparum. However, the majority of the antimalarial imidazopyridazine compounds evaluated to date have solubility and off-target human ether-a-go-go-related gene (hERG) potassium ion channel liabilities. Towards improving solubility and de-risking the hERG liability, a series of analogues was designed and synthesised. Structure-Activity Relationship (SAR) and Structure-Property Relationship (SPR) studies aimed at retaining the good antiplasmodium activity while improving solubility and reducing hERG channel inhibition, were conducted. Previous studies conducted on this series of imidazopyridazines have shown that incorporation of hydrogen bond donors or acceptors resulted in improving solubility and hERG channel inhibition. While the lead compound MMV652103 at pH 6.5 has a sub-optimal solubility of 5 µM, all target compounds showed an improvement in solubility. Five analogues 59, 78, 84, 85, and 86 exhibiting impressive in vitro asexual blood stage antiplasmodium potency (IC50< 100 nM) and aqueous solubility (> 200 µM) were identified from the study. The identified compounds also displayed good activity against the sexual late-stage gametocytes, the transmissible forms of the parasite.
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Price, Craig Justin. "Structure-activity relationships in olefin polymerization catalysts." [College Station, Tex. : Texas A&M University, 2007. http://hdl.handle.net/1969.1/ETD-TAMU-1678.
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Holmes, Victoria. "Structure activity relationships of cytochrome P450 4A1." Thesis, University of Nottingham, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.289361.
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Hargreaves, Martin Bernard. "Substrate structure activity relationships of cytochrome P4502E1." Thesis, University of Leicester, 1995. http://hdl.handle.net/2381/35247.
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Morsman, Janine M. "Structure-activity relationships (SAR) for cytochrome P4502C9." Thesis, University of Aberdeen, 1999. http://digitool.abdn.ac.uk/R?func=search-advanced-go&find_code1=WSN&request1=AAIU536139.
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In this project, an SAR approach was used to assess the putative active site interactions, using analogues of phenytoin (a co-regulated substrate), sulfaphenazole (CYP2C9-specific inhibitor) and bis-triazole antifungals (thought to exhibit less specific inhibition). Ki values were determined for the inhibition of tolbutamide methylhydroxylation. N2 of phenytoin is a postulated H-bond donor. Substitution (CH3 or NH2), reduced inhibitory potency from 46 μM to 74 μM and 98 μM, respectively. Inhibition was competitive. Removal of a phenyl ring removed inhibitory potential, suggesting that an aromatic interaction (π-π stacking) is more influential than the H-bonding. Replacement with a fused-ring structure enhanced potency (Ki = 25 μM). Inhibition was non-competitive, which may be explained by the overall bulk of these analogues, together with less directional lipophilic/π-π stacking interactions. A putative active site model could feature a H-bond acceptor site, a lipophilic pocket, haem interaction with the site of oxidation, and π-π stacking with an appropriate phenyl ring. Sulfaphenazole and methysulfaphenazole (CH2 instead of NH2) were the most potent analogues (Ki values of 0.82 μM and 0.39 μM). Removal of the pyrazole group reduced potency (Ki = 91 μM), as a CYP2C9-haem interaction was prevented (type II difference spectra). Additionally, the N-phenyl function may undergo hydrophobic binding and/or π-π stacking. The bis-triazoles also produced type II spectra, which indicates a haem-ligand interaction (N4 triazole lone pair electrons). Inhibition was non-competitive. The triazole was the dominant determinant of potency, as seen by relatively small decreases in potency on substitution of a proposed H-bonding site. In conclusion, the above work indicates interactions consistent with previous CYP2C9 active site models. SAR data suggest a predominance of lipophilic and π-π stacking interactions, and CYP2C9-haem liganding (if appropriate). Hydrogen-bonding also has a significant role.
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Lock, Ruth E. "Structure-activity relationships (SAR) for cytochrome P4502C19." Thesis, University of Aberdeen, 1999. http://digitool.abdn.ac.uk/R?func=search-advanced-go&find_code1=WSN&request1=AAIU535752.
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Investigation of structure-activity relationships (SAR) for cytochrome P450 isoenzymes has implications for the prediction of drug-drug interactions. To date, the majority of research relating to the structure-activity relationships for P450 isoenzymes has concentrated on CYP2D6, CYP2E1, and CYP2C9. Knowledge of the likelihood of an interaction between a new chemical entity (NCE) and CYP2C19 is also of interest due to the existence of a genetic polymorphism in this enzyme. SAR for CYP2C19 were investigated in human liver microsomes (n=3) and CYP2C19 SUPERSOMESTM (n=2), by determining the inhibition of omeprazole 5-hydroxylation using benzodiazepine, phenytoin and fused-ring phenytoin analogues. (Fig. 8288). The inhibitory potency shown by the phenytoin and fused-ring phenytoin analogues appeared to be due to a combination of factors, including: a lipophilic group at R1, molecular length, surface area and volume of the compound (with the bulky fused-ring analogues showing greatest inhibitory potency), and lipophilicity (as indicated by calculated log P values and log D7.4 octanol values). A number of molecular features of the benzodiazepines proved important for the potent inhibition of CYP2C19-mediated omeprazole 5-hydroxylation. Again, a lipophilic group at R1 was essential. QSAR (quantitative structure-activity relationship) studies showed binding of the benzodiazepines to the active site of CYP2C19 to be governed by this area of lipophilicity. The carbonyl group was important for a CYP2C19 interaction. Benzodiazepines missing the function were not inhibitory. By superimposing chemically similar groups of the inhibitors, an overlay was created from their 3D structures using (S)-mephenytoin as a template. From the preliminary pharmacophore generated, a number of interactions with the CYP2C19 active site seem to be necessary for inhibitory potency. Hydrogen bond formation is possible between particular amino acid residues within the active site and the carbonyl groups of the inhibitory analogues. The aromatic rings are capable of interacting (perhaps via π-stacking interactions) with a number of corresponding lipophilic areas, possibly "pockets" within the CYP2C19 active site.
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Howard, W. Brian. "Structure-Activity Relationships of Retinoids in Developmental Toxicology." DigitalCommons@USU, 1988. https://digitalcommons.usu.edu/etd/4042.
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The teratogenic potency of retinoid analogs was determined in Syrian hamsters and compared to the teratogenic potency of all-trans-retinoic acid (all-trans.-RA, ED50 = 10.5 mg/kg). A total of 15 analogs having variations in the cyclohexene ring were evaluated following various amounts of single oral doses on day 8 of gestation. Retinoids containing a five- or six-membered ring were as teratogenic as all-tmru.-RA, provided they had sufficient lipophilic substituents on the ring. The same pattern emerged for retinoids that had six-membered aromatic ring substitution for the natural cyclohexene ring of vitamin A. Incorporation of a supplementary aromatic ring in the side-chain adjacent to a gem-dimethyl-hexene ring resulted in an increase in teratogenicity by IS-fold compared to all-trans.-RA. Major modifications of the cyclohexene ring can be made without altering teratogenic activity. The ring need not be six-membered and can have decreased lipophilicity through the incorporation of polar groups compared to all-trans.-RA, but must have sufficient lipophilic substituents to provide the necessary mass for interaction with the retinoid receptor. Incorporation of a supplementary aromatic ring adjacent to a gem-dimethyl-hexene ring facilitated π-electron delocalization and restricts side-chain flexibility , thereby increasing teratogenic potency.
The pharmacokinetic disposition of 8 retinoids was investigated. Pregnant hamsters were dosed orally with all-trans-RA, 13-cis-retinoic acid, all-trans.-4- oxoretinoic acid, 9-cis-retinal, all-trans.-retinyl acetate, N-ethyl-all-trans- retinamide, N-ethyl-13-cis-retinamide, and arotinoid. The bioavailability of the retinamides was one-tenth that of the free acid retinoids. The plasma elimination half-life for all-trans-RA was 0.5 h. For 13-cis-retinoic acid and all-trans-4-oxoretinoic acid the elimination half-lives were 4.4 and 5.7 h, respectively.
The binding affinity of various retinoids to cellular retinoic acid-binding protein (cRABP) was determined in day-12 hamster fetuses. Fetal supernatants from the 105,000x g fraction were incubated with high specific-activity [3H]-all-trans-RA in the presence of various concentration of unlabeled retinoids with subsequent isolation of cRABP by size-exclusion HPLC. Teratogenic retinoids, or acidic metabolites of teratogenic retinoids bound to cRABP whereas nonteratogenic retinoids failed to bind.
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Simonsen, Shane M. "Diversity and structure-activity relationships of the cyclotides /." [St. Lucia, Qld.], 2005. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe19079.pdf.
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Nilsson, Ulrika K. "Lysophosphatidic acid : Physiological effects and structure-activity relationships." Doctoral thesis, Linköping : Univ, 2002. http://www.ep.liu.se/diss/med/07/51/index.html.
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Bruce, Craig L. "Classification and interpretation in quantitative structure-activity relationships." Thesis, University of Nottingham, 2010. http://eprints.nottingham.ac.uk/11666/.
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A good QSAR model comprises several components. Predictive accuracy is paramount, but it is not the only important aspect. In addition, one should apply robust and appropriate statistical tests to the models to assess their significance or the significance of any apparent improvements. The real impact of a QSAR, however, perhaps lies in its chemical insight and interpretation, an aspect which is often overlooked. This thesis covers three main topics: a comparison of contemporary classifiers, interpretability of random forests and usage of interpretable descriptors. The selection of data mining technique and descriptors entirely determine the available interpretation. Using interpretable approaches we have demonstrated their success on a variety of data sets. By using robust multiple comparison statistics with eight data sets we demonstrate that a random forest has comparable predictive accuracies to the de facto standard, support vector machine. A random forest is inherently more interpretable than support vector machine, due to the underlying tree construction. We can extract some chemical insight from the random forest. However, with additional tools further insight would be available. A decision tree is easier to interpret than a random forest. Therefore, to obtain useful interpretation from a random forest we have employed a selection of tools. This includes alternative representations of the trees using SMILES and SMARTS. Using existing methods we can compare and cluster the trees in this representation. Descriptor analysis and importance can be measured at the tree and forest level. Pathways in the trees can be compared and frequently occurring subgraphs identified. These tools have been built around the Weka machine learning workbench and are designed to allow further additions of new functionality. The interpretability of a model is dependent on the model and the descriptors. They must describe something meaningful. To this end we have used the TMACC descriptors in the Solubility Challenge and literature data sets. We report how our retrospective analysis confirms existing knowledge and how we identify novel C-domain inhibition of ACE. In order to test our hypotheses we extended and developed existing software forming two applications. The Nottingham Cheminformatics Workbench (NCW) will generate TMACC descriptors and allows the user to build and analyse models, including visualising the chemical interpretation. Forest Based Interpretation (FBI) provides various tools for interpretating a random forest model. Both applications are written in Java with full documentation and simple installations wizards are available for Windows, Linux and Mac.
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McNeany, T. John. "Non-parametric approaches to quantitative structure-activity relationships." Thesis, University of Nottingham, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.431188.
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Boyd, Gary William. "Cyclopenta[a]phenanthren-17-ones : structure/activity relationships." Thesis, University of Surrey, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.334403.
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Jing, Pu. "Purple corn anthocyanins chemical structure, chemoprotective activity and structure/function relationships /." Columbus, Ohio : Ohio State University, 2006. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1155738398.
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Brink, Susanna. "Structure-activity relationships of titanocene complexes with antitumor properties." Pretoria : [s.n.], 2003. http://upetd.up.ac.za/thesis/available/etd-09052005-101713/.
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Fortune, Grady Thomas Jr. "Structure-activity relationships in semisynthetic pyrrolizidine alkaloid antitumor agents." Diss., Georgia Institute of Technology, 1989. http://hdl.handle.net/1853/27371.
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Gutsell, S. J. "Structure-activity relationships for the allergenic potential of diketones." Thesis, Swansea University, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.505579.
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Dicarbonyl compounds have been implicated in the process of skin sensitisation. It is widely accepted that the mechanism involved in this allergic reaction relies upon the reactions of these electrophilic compounds with the amino acid side chains of cellular proteins. The most likely points of reaction for dicarbonyl compounds are the side chains of the amino acids lysine and arginine. As such, model compounds were selected to mimic these nucleophilic groups. Butylamine was chosen to represent the lysine side chain. A series of mono- and di-alkylguanidine compounds were synthesised and their reactions with dicarbonyl compounds were evaluated. This led to butylguanidine being selected to mimic the arginine side chain. A series of 1,2- and 1,3-dicarboxyl compounds was selected which included some compounds for which biological data was available. Additional compounds were included in the series to investigate the effects of substituents on the carbonyl group. The majority of the 1,3-dicarbonyl compounds had to be synthesised. The reactions of these compounds towards the model nucleophiles were investigated and kinetic parameters were obtained. Reactions were monitored by HPLC. As part of the method development a study in to the effects of temperature and pH on the separation of 1,3-dicarbonyl compounds was undertaken. A short molecular modelling study was undertaken to investigate the dicarbonyl compounds. The parameters obtained were compared to the experimental orders of reactivity observed from the kinetic studies. Biological data was obtained for the additional compounds in the series. Both the kinetic and the computational parameters were then compared with this biological data. By using (Q)SAR approaches it was possible to identify correlations in the data and in the case of the 1,3-dicarbonyl compounds to develop a predictive model. This study also highlighted a possible structural alert associated with increased allergenic potency that could be used in rule-based prediction systems.
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Otara, Claire Bochaberi. "Structure-activity relationships and solution conformation of SALMFamide neuropeptides." Thesis, Queen Mary, University of London, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.582574.
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The SALMFamides SI (GFNSALMFamide) and S2 (SGPYSFNSGLTFamide) are neuropeptides that act as muscle relaxants in the starfish, with S2 ten times more potent than S 1. The aim of this study was to investigate the structural basis for this difference in potency. Synthetic analogues of SI and S2 were synthesized with the N-terminal SGPY sequence of S2 removed from S2 (SS2) and added to SI (LS 1) or with the penultimate amino-acid residues exchanged between SI and S2, SI (T) and S2(M). Analysis of the effects of SI, S2, LS 1, SS2, SI (T) and S2(M) on starfish cardiac stomach and tube preparations indicated that sequence differences in the C-terminal region of S 1 and S2 are the primary determinants ofS2's increased potency compared to SI and not the presence and absence of the N-terminal SGPY sequence in S2 and SI, respectively. To further investigate the structural basis for the differing potencies of SI and S2, the solution conformations of SI, S2, LS 1, SS2, SI (T) and S2(M) were investigated using CD and IH NMR spectroscopy. All the peptides except S2 and LSl have a random coil conformation in water. Interestingly, however, S2 has a single well-defmed conformation with a main-chain RMSD of 0.s03A for residues 2-11, comprising three loops in which aromatic side-chains form hydrophobic clusters with side-chains of other non-polar amino acids. In contrast, LS 1 has a single loop in its C-terminal region with an RMSD of 0.909 A for residues 6-12, which results from clustering of the hydrophobic side-chains ofPhe12, Met 11 , LeulO and Phe6• The remarkably well-defmed conformation of S2 is unusual amongst neuropeptides of comparable size without disulphide bridges. The N-terminal region of S2 (SGPy) may be important for induction and stabilisation of the conformation adopted by S2 in water.
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Berrin, Jean-Guy. "Structure activity relationships of a human cytosolic beta-glucosidase." Thesis, University of East Anglia, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.268546.
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Fitzsimmons, Sara Ann. "Enzymology and structure-activity relationships of quinoxaline bioreductive cytotoxins." Thesis, University of Glasgow, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.295320.
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Place, G. A. "Structure-activity relationships of inhibitors of intracellular protein catabolism." Thesis, University of Liverpool, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.383450.
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Pies, Tanja. "9-substituted paullones synthesis and analysis of structure activity relationships /." [S.l. : s.n.], 2003. http://deposit.ddb.de/cgi-bin/dokserv?idn=968952399.
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Betancor, Fernández Alejandro José. "Biological properties of micronutrients: antioxidant capacity and structure activity relationships." [S.l.] : [s.n.], 2003. http://deposit.ddb.de/cgi-bin/dokserv?idn=970026293.
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Andersson, Patrik. "Physico-chemical characteristics and quantitative structure-activity relationships of PCBs." Doctoral thesis, Umeå University, Chemistry, 2000. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-17.
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The polychlorinated biphenyls (PCBs) comprise a group of 209 congeners varying in the number of chlorine atoms and substitution patterns. These compounds tend to be biomagnified in foodwebs and have been shown to induce an array of effects in exposed organisms. The structural characteristics of the PCBs influence their potency as well as mechanism of action. In order to assess the biological potency of these compounds a multi-step quantitative structure-activity relationship (QSAR) procedure was used in the project described in this thesis.
The ultraviolet absorption (UV) spectra were measured for all 209 PCBs, and digitised for use as physico-chemical descriptors. Interpretations of the spectra using principal component analysis (PCA) showed the number of ortho chlorine atoms and para-para substitution patterns to be significant. Additional physico-chemical descriptors were derived from semi-empirical calculations. These included various molecular energies, the ionisation potential, electron affinity, dipole moments, and the internal barrier of rotation. The internal barrier of rotation was especially useful for describing the conformation of the PCBs on a continuous scale.
In total 52 physico-chemical descriptors were compiled and analysed by PCA for the tetra- to hepta-chlorinated congeners. The structural variation within these compounds was condensed into four principal properties derived from a PCA for use as design variables in a statistical design to select congeners representative for these homologue-groups. The 20 selected PCBs have been applied to study structure-specific biochemical responses in a number of bioassays, and to study the biomagnification of the PCBs in various fish species.
QSARs were established using partial least squares projections to latent structures (PLS) for the PCBs potency to inhibit intercellular communication, activate respiratory burst, inhibit dopamine uptake in synaptic vesicles, compete with estradiol for binding to estrogen receptors, and induce cytochrome P4501A (CYP1A) related activities. By the systematic use of the designed set of PCBs the biological potency was screened over the chemical domain of the class of compounds. Further, sub-regions of highly potent PCBs were identified for each response measured. For risk assessment of the PCBs potency to induce dioxin-like activities the predicted induction potencies (PIPs) were calculated. In addition, two sets of PCBs were presented that specifically represent congeners of environmental relevance in combination with predicted potency to induce estrogenic and CYP1A related activities.
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Zembower, David Ewing. "The synthesis and structure-activity relationships of biologically active anthraquinones." Diss., Georgia Institute of Technology, 1990. http://hdl.handle.net/1853/26250.
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De, Cecco Martin. "Biophysical studies to elucidate structure-activity relationships in β-defensins." Thesis, University of Edinburgh, 2011. http://hdl.handle.net/1842/4931.
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β-defensins are a class of mammalian defence peptides with therapeutic potential because of their ability to kill bacteria and attract host immune cells. In order to realise this potential, it is necessary to understand how the functions of these peptides are related to their structures. This thesis presents biophysical analysis of β- defensins and related peptides in conjunction with biological assays. These studies provide new insights into the structure-activity relationships of β-defensins. Ion mobility-mass spectrometry (IM-MS) is used throughout this thesis to probe the tertiary structure of peptides in vacuo and, by inference, make conclusions about their conformations in solution prior to ionisation. Where appropriate, IM-MS is complemented by other techniques, including high performance liquid chromatography and circular dichroism spectroscopy. First, the importance of a C-terminal cysteine residue within the murine β-defensin Defb14 is investigated. The functional and structural implications of chemically modifying the cysteine residue are examined. Second, the N-terminal region of Defb14 is modified by the substitution and deletion of amino acids. Again, the effects on biological activity and structure are discussed. Finally, the functional and structural overlap of β-defensins with another family of proteins – the chemokines – is considered. The oligomerisation of β-defensins and their interaction with glycosaminoglycans is of particular interest: structural data for human β-defensins 2 and 3 in the absence and presence of polysaccharides are presented.
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Mistry, Shailesh Natvarbhai. "Structure activity relationships of novel and selective beta1-adrenoreceptor ligands." Thesis, University of Nottingham, 2009. http://eprints.nottingham.ac.uk/28448/.
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Of the numerous l3-blockers clinically available to treat conditions such as angina pectoris, hypertension and heart failure, none possess antagonist activity specific to the beta1-adrenoceptor. Those described as 'cardioselective', such as nebivolol and bisoprolol, generally show less than 50-fold beta1/beta2-selectivity, which can be lost at higher doses. Others, such as propranolol and sotalol are actually more beta2-selective. Overall, a degree of concomitant beta2-adrenoceptor blockade (risking compromised respiratory function and loss of peripheral vasodilatation) by current therapeutic agents precludes their use in patients with disorders such as asthma and peripheral vascular disease. This project aims to develop novel molecules with much improved beta1/beta2-selectivity over current beta1-blocker therapy as well as improving knowledge of ligand-receptor interaction at the beta1-adrenoceptor, through an analogue-based drug discovery approach. A highly selective or specific beta1-adrenoceptor antagonist is likely to cause fewer side-effects and be suitable for use in previously contraindicated disease states. This thesis reports the design, synthesis and pharmacological data (provided by Dr. Jillian Baker) of a library of novel ligands for the beta1- adrenoceptor, based upon the lead compound LK 204-545. LK 204-545 was selected based on reported high potency at the beta1-adrenoceptor as well as good beta1/beta2-selectivity. Modification of various motifs on structures derived from LK 204-545 allowed the generation of new structure-activity relationships and ultimately afforded the highly 131-adrenoceptor selective compound, 1-(2-(3-(4-(2-(cyclopropylmethoxy)ethoxy)phenoxy)-2-hydroxypropyl amino)ethyl)-3-(4-hydroxyphenyl)urea hydroformate (12Sc). This compound acted as a highly-selective beta1-adrenoceptor antagonist in a pilot in-vivo study in the regional hemodynamic rat model (carried out by Prof. Sheila Gardiner).
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Godavarti, Ranganathan S. "Protein engineering of Heparinase I : elucidation of structure-activity relationships." Thesis, Massachusetts Institute of Technology, 1996. http://hdl.handle.net/1721.1/40208.
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Kunz, Kenneth Robert. "Structure-activity relationships for mitomycin C and mitomycin A analogues." Diss., The University of Arizona, 1996. http://hdl.handle.net/10150/187488.
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A set of 30 mitomycin C and mitomycin A analogues, including 5 new compounds, was screened against 3 different solid human tumor cell lines using the MTT tetrazolium dye assay. A statistically significant correlation among antitumor activity, quinone reduction potential (E½) and the logarithm of the partition coefficient (log P) was obtained, with the most easily reduced and the most lipophilic compounds being the most potent. When these analogues were separated into mitomycin C and mitomycin A subsets, the former gave a correlation only with E½, whereas the latter (which differ little in their E½ values) gave a correlation only with log P. These correlations are in contrast to those made in the P388 leukemia assay in mice wherein the most active mitomycin C and mitomycin A analogues were the most hydrophilic ones. When the same compounds were tested against P388 leukemia cells in the MTT assay, the results were the same as those of the solid tumor assays. Thus, the substantial differences in relative potencies of mitomycins are related not to the kind of tumor cell, but to the type of assay performed, cell culture versus whole animal. No correlation was found between antitumor potency in the cell culture systems and calculated relative DNA binding strengths, probably because the limiting factors in antitumor potency of mitomycins appear to be tumor cell uptake (log P) and/or bioreductive activation (E½).
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Cronin, Mark T. D. "Quantitative structure-activity relationships of comparative toxicity to aquatic organisms." Thesis, Liverpool John Moores University, 1990. http://researchonline.ljmu.ac.uk/4989/.
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Quantitative Structure-Activity relationship (QSAR) attempt statistically to relate the physico-chemical properties of a molecule to its biological activity. A QSAR analysis was performed on the toxicities of up to 75 organic chemicals to two aquatic species, Photobacterium phospherum (known as the Microtox test), and the fathead minnow. To model the toxicities 49 physico-chemical and structural parameters were produced including measures of hydrophobicity, molecular size and electronic effects from techniques such as computational chemistry and the use of molecular connectivity indices. These were reduced to a statistically more manageable number by cluster analysis, principal component analysis, factor analysis, and canonical correlation analysis. The de-correlated data were then used to form relationships with the toxicities. All the techniques were validated using a testing set. Some good predictions of toxicity came from regression analysis of the original de-correlated variables. Although successful in simplifying the complex data matrix, principal component analysis, factor analysis, and canonical content analysis were disappointing as predictors of toxicity. The performance of each of the statistical techniques is discussed. The inter-species relationships of toxicity between four Commonly utilised aquatic endpoints, fathead minnow 96 hour IC50, Microtox 5 minute EC50, Daphnia magna 48 hour IC50, and Tetrahymena pyriformis 60 hour IG50, were investigated. Good relationships was found between the fathead minnow and both T. pyriformis and D. magna toxicities indicating that these species could be used to model fish toxicity. The outliers from individual relationships were assessed in order to elucidate if any molecular features may be causing greater relative toxicity in one species as compared to another. It is concluded that in addition to the intrinsic differences between species, the greater length of the test time for any species may result in increases bioaccumulation, metabolism, and detoxification of certain chemical classes. The relationships involving fish toxicity were moderately improved by the addition of a hydrophobic parameter.
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Gooch, Carolyn A. "Quantitative structure-activity relationships : a biophysical, chemical and calorimetric study." Thesis, Royal Holloway, University of London, 1988. http://repository.royalholloway.ac.uk/items/26719d55-b208-4995-bef0-92e4f0f80c0e/1/.
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Quantitative structure-activity relationships (QSAR) rationalize interrelation between molecular structure and biological response in terms of either physicochemical parameters, as in linear free energy relationships (LFER), or via purely empirical parameters, as is the case for De Novo schemes. In LFER the leading process is often the partitioning of a compound between two solvent phases, taken to represent the transfer of a drug molecule across a biological membrane. This study has investigated the partitioning behaviour of three series of hydroxybenzoate esters, viz. o-, m- and predominantly p-esters, the latter being preservatives in pharmaceutical formulations. The thermodynamic parameters AH, AG and AS for the transfer process were derived in an attempt to establish a QSAR. on a fundamental thermodynamic basis. Such parameters have identifiable physicochemical meaning and lend themselves more readily to interpretation. This facilitates application to alternative systems. A new Gibbs function factor analysis was developed and utilized to obtain thermodynamic contributions for parent and incremental methylene group portions of thestudy molecules. The empirical Collander equation for interrelation of various solute/solvent systems was also rationalized on a thermodynamic basis. Further extension of the Gibbs function factor analysis allowed scaling of "solvent" systems including chromatographic packings, solvents and liposomes. The scheme indicated capacity for optimized selection of bulk solvent systems to mimic biological membranes. A novel analytical procedure for direct measurement of biological response was developed. The bioassay appeared capable of discrimination i) between the closely related structural homologues, ii) between gram-negative and gram-positive bacteria, and further, iii) between certain cell batches of the same bacteria type. Also, the bioassay demonstrated a Collander interrelation between the two bacteria types. Flow microcalorimetry was the technique employed to measure thermal response of respiring E. coli and Staph, aur. bacteria. The modification of biological response with drug concentration was quantitated and a log dose max term was derived for each homologue. The results indicated potential for a predictive, additive structure-activity scheme based on assessment of biological response (BR) direct rather than through f(BR) via physicochemical or empirical parameters.
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Yang, Emma. "Chemical, metabolic and structure-activity relationships to probe abacavir toxicity." Thesis, University of Liverpool, 2014. http://livrepository.liverpool.ac.uk/2008286/.
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Adverse drug reactions (ADRs) are responsible for an increasing number of hospitalised patients, with the large majority of these ADRs classed as either type A or type B. Drug hypersensitivity reactions fall within the type B category and one such drug responsible for this form of ADR is abacavir (ABC). ABC, a nucleoside reverse transcriptase inhibitor, is used to treat the HIV-1 virus. It is responsible for a potentially life-threatening type IV hypersensitivity reaction which occurs in patients bearing the HLA-B*57:01 allele. Although many mechanisms have been proposed, it was the objective of this research to examine all these previous proposals to further extend and develop the mechanism of ABC toxicity. In Chapter 2, deuterated-ABC (D2-ABC) was designed and synthesised where the two 5'-H atoms were replaced with two 5'-D atoms. The design of this analogue was intended to retard the oxidative metabolism of ABC to its aldehyde and carboxylic acid metabolites. The synthesis of this compound was paramount to investigating this metabolism and through a series of metabolic experiments, described in Chapter 3, a kinetic isotope effect between ABC and D2-ABC was determined, ultimately showing an altered metabolism between the two compounds. To investigate binding of ABC within the HLA-B*57:01 protein, analogues of ABC, with alterations at varying positions within the molecule, were required. Using a racemic method, ABC enantiomers were synthesised and ABC’s enantiomer failed to stimulate T-cells in vitro. The creation of further analogues required the development of an asymmetric synthetic route. A total synthetic method was desired to synthesise intermediates to be used in future analogue synthesis. Finally, as described in Chapter 5, a range of 6-position analogues were designed, using a structure-activity relationship method, and synthesised, to further investigate the altered repertoire mechanism. These analogues, consisting of primary and secondary amine and oxy moieties, were subjected to in vitro immunological assays to determine their stimulation of T-cells. Additionally, the synthesised analogues were modelled in silico using molecular docking within the HLA protein. The in silico results assisted in explaining the basis of such T-cell activation/inactivation and will direct future analogue design. IC50 and EC50 values were determined for analogues that presented a negative T-cell response and a compound showing positive values was subjected to further pharmacokinetic testing. The oxidative metabolism of ABC was affected by isotopic substitution, but initial results have shown no altered T-cell stimulation of D2-ABC compared to ABC. This mechanism cannot be discarded, with further investigational work required. However, the synthesised 6-position analogues have assisted in further examining the altered repertoire mechanism and initial findings have enabled further understanding of the binding of ABC within HLA-B*57:01. This mechanism of ABC toxicity appears paramount to others proposed and the results presented in this thesis support this. Additional analogue synthesis and in vivo experiments will assist in confirming this further.
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Pritchard, Iain David. "PYY(3-36) analogues : structure-activity relationships in energy homeostasis." Thesis, Imperial College London, 2012. http://hdl.handle.net/10044/1/9243.
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The developed world is currently in the grip of an obesity epidemic. As a result, there is much ongoing research into the development of an effective anti-obesity agent. Peptide YY (PYY) is a 36 amino acid gastro-intestinal hormone released post-prandially by L-cells in the gastro-intestinal tract in proportion to the calorie content of a meal. The predominant form of the hormone found in circulation is the truncated PYY(3-36). Administration of PYY(3-36) at physiological doses to humans has been shown to reduce food intake. However, due to enzymatic degradation these effects are short lived, reducing the hormone’s utility as an anti-obesity pharmaceutical agent. A series of analogues of PYY(3-36) were designed either with amino acid substitutions in specific parts of the peptide sequence and/or with chemical modifications to the native sequence with the aim of increasing resistance to enzymatic activity whilst retaining or even enhancing the peptide’s bioactivity. The analogues were tested for resistance to degradation by different proteolytic enzymes in comparison to natural PYY(3-36). Their affinity to the Y2 receptor, for which PYY(3-36) is a natural agonist was then investigated. Finally, the effects of peripheral administration of selected analogues on food intake in overnight fasted mice were investigated. These studies suggest that PYY(3-36) analogues may be a useful approach for the treatment of obesity, but further development work is required.
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Bourin, Marie-Claude. "Thrombomodulin: a novel proteoglycan : studies on structure-function relationships /." Uppsala : Sveriges lantbruksuniv, 1990. http://epsilon.slu.se/avh/1990/91-576-4149-8.gif.
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Hutchinson, Francis. "Structure and energetics of trivalent metal halides." Thesis, University of Oxford, 1999. http://ora.ox.ac.uk/objects/uuid:0fdaf43d-0414-491c-a3dc-04414b84a164.
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Metal trihalide (MX3) systems represent a stern challenge in terms of constructing transferable potential models. Starting from a previously published set of potentials, 'extended' ionic models are developed which, at the outset, include only anion polarization. Deficiencies in these models, particularly for smaller (highly polarizing) cations, are shown to be significant. For example, crystal structures different to those observed experimentally are adopted. The potentials are improved upon by reference to ab initio information available for alkali halides with the 'constraint' that the parameters transfer systematically in a physically transparent manner, for example, in terms of ion radii. The possible influence of anion compression ('breathing') and the relative abundance of anion-anion interactions are considered. Simulation techniques are developed to allow for the effective simulation of any system symmetry and for the study of transitions between different crystals (constant stress). The developed models are fully tested for a large range of metal trichloride (MCl3) systems. Particular attention is paid to the comparison with recent neutron and X-ray diffraction data on the liquid state. Polarization effects are shown to be vital in reproducing strong experimental features. The excellent agreement between simulation and experiment allows for differences in experimental procedures to be highlighted. The transferability is further tested by modelling mixtures of the lanthanides with alkali halides with potentials unchanged from the pure systems. The complex evolution of the melt structure is highlighted as the concentration of MCl3 increases. The effectiveness of the models is tested by reference to dynamical properties. Particular attention is paid to the comparison with Raman scattering data available for a wide range of systems and mixture concentrations. The simulated spectra are generated both by a simple molecular picture of the underlying vibrations and by a more complex (fluctuating polarizability) model in which the spectra are broken down into contributions from different mechanisms. This comparison allows for the validity of treating network-like systems as a series of 'isolated' molecules to be assessed. The transferability of the potentials is pushed to the limits by modelling metal tribromides, in which the parameters are obtained from the trichlorides by the same simple scaling arguments.
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Hattotuwagama, Channa Karunadasa. "Computational studies of sweet-tasting molecules." Thesis, University of Reading, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.270841.
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Chang, Cheng. "In silico approaches for studying transporter and receptor structure-activity relationships." Connect to this title online, 2005. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1117553995.
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Thesis (Ph. D.)--Ohio State University, 2005.Title from first page of PDF file. Document formatted into pages; contains xvii, 271 p.; also includes graphics. Includes bibliographical references (p. 245-269). Available online via OhioLINK's ETD Center
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Meyers, Ross Owen. "Anticancer Structure-Activity Relationships of Semi-Synthetic Analogs of Nordihydroguaiaretic Acid." Diss., Tucson, Arizona : University of Arizona, 2005. http://etd.library.arizona.edu/etd/GetFileServlet?file=file:///data1/pdf/etd/azu%5Fetd%5F1086%5F1%5Fm.pdf&type=application/pdf.
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Marchetti, Francesco. "Structure-activity relationships for alkoxypirimidine inhibitors of cyclin-dependent kinases (CDK’s)." Thesis, University of Newcastle Upon Tyne, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.556141.
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Cyclin-dependent kinases (CDKs) are a family of serine/threonine protein kinases that play a fundamental role in the regulation of eukaryotic cell-cycle progression, particularly at cell- cycle checkpoints. Cell-cycle alterations result in a loss of checkpoint function, which correlates with increased or aberrant CDK activity in human tumours. CDK inhibitors are therefore recognised to have potential therapeutic effects in the treatment of cancer and other proliferative diseases. This research project centres on the medicinal chemistry of a new class of CDK inhibitors, based on the 2,6-diamino-4-alkoxy- 5-nitrosopyrimidine pharmacophore (77). Previous studies, employing a structure-based inhibitor design approach, have resulted in the identification of 2-arylamino-06- alkylguanines exhibiting potent inhibitory activity against CDK2, and exemplified by NU6102 (31; IC50 = 5 nM). Structure-activity relationship studies revealed that the purine pharmacophore is not a prerequisite for CDK-inhibitory activity. Thus, comparable activity resides in the corresponding pyrimidines, where an intramolecular hydrogen bond between a 5-nitroso substituent and a 6-amino group confers a 'purine-mimetic' structure (164; CDK2/A, IC50 = 1 nM). Guided by results obtained previously for the corresponding 06-alkylguanines, systematic structural modifications have been made at the pyrimidine 2-, 4- and 5- positions, via the development and optimisation of efficient synthetic pathways Replacement of the 5-nitroso substituent of the parent inhibitors (77, 164) by groups that are more acceptable from a toxicological standpoint has been a prominent target of this work. Formyl, ketone and oxime functionalities have been successfully introduced at the pyrimidine 5-position, while different alkoxy and arylamino substituents were introduced at the pyrimidine 4-position and 2-position, respectively, to probe additional potential interactions within the ATP ribose-binding domain and CDK2 specificity pocket. The synthesis and structure-activity relationships for this new series of CDK inhibitors have been investigated, as exemplified by (220) (CDK2/A, IC50 = 49 nM), (239) (CDK2/A, IC50 = 7.4 nM) and (109) (CDK2/A, IC50 = 23.3 μM). These studies have resulted in the identification of novel compounds, such as (225), exhibiting improved potency against CDKs, with sub-nanomolar inhibitory activity versus CDK2/A (IC5o = 0.77 nM) and good cell growth inhibition properties (G150 = 0.57 μM).
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Cheuka, Peter Mubanga. "Antimalarial imidazopyridazines and aminopyrazines: synthesis, physicochemical optimization and structure-activity relationships." Doctoral thesis, Faculty of Science, 2018. http://hdl.handle.net/11427/29985.
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According to the World Health Organization (WHO) world malaria report released in 2017, about 445,000 malaria deaths were recorded in 2016, a similar mortality as that recorded in the preceding year (446,000 deaths in 2015). Once effective and cheap drugs such as chloroquine and sulfadoxine-pyrimethamine have suffered widespread drug resistance. Additionally, despite the remarkable effectiveness of the currently recommended first line treatment, the artemisinin combination therapies (ACTs), resistance to artemisinin and the partner drugs is beginning to emerge in South East Asia. Furthermore, the current portfolio of medicines, both in clinical use and development has several other shortfalls which need redress. In addition, prevention of transmission and relapse with better safety profiles than current medicines are some of the important features that should be a prioritized characteristic of new medicines. Most importantly, these new regimens should be able to offer chemoprotection and prevent reinfection. Thus, there is need for constant research efforts aimed at identifying and developing novel chemotherapeutic agents for malaria, which are structurally diverse with novel mechanisms of action. In this PhD thesis, the medicinal chemistry optimization of two antimalarial chemotypes, the imidazopyridazines and aminopyrazines, is reported. In earlier studies, Le Manach and coworkers reported the impressive in vitro antiplasmodial activity and in vivo antimalarial efficacy of the imidazopyridazine lead compound 19 (Figure 1). However, this compound was plagued by poor solubility and a cardiotoxicity risk as shown from its inhibition of the hERG (human ether-a-go-go-related gene)-encoded potassium channel. Further medicinal chemistry optimization led to identification of other derivatives which, albeit exhibiting complete cure of P. berghei-infected mice, still displayed poor solubility and hERG inhibition issues. In this project, chemical modification approaches such as the introduction of water solubilizing groups, disruption of molecular planarity and making subtle changes (SAR 1 – 6, Figure 1) were adopted towards improving the solubility and countering hERG inhibition of this class of molecules. Through the thesis work undertaken, analogues with a combination of reduced hERG inhibition (IC50 = 7.8 – 32 μM) and submicromolar antiplasmodial activity (NF54, IC50 = 0.15 – 0.92 μM) were identified. Likewise, the modifications made delivered analogues with moderate to high solubility (60 – 200 μM) while exhibiting submicromolar antiplasmodial potency (NF54, IC50 = 0.14 – 0.99 μM). Furthermore, cytotoxicity assessment of selected analogues against the Chinese Hamster Ovarian (CHO) cell line revealed that most analogues were relatively noncytotoxic (selectivity indices in the range 72 - > 874). Selected compounds were also screened against gametocyte and liver stage parasites in order to assess transmission blocking and chemoprotection potential, respectively. In this regard, analogues with good gametocytocidal activity (IC50 = 0.098 – 0.75 μM) against late stage gametocytes and potent liver stage activity (IC50 = 0.045 μM) were identified. On the other hand, aminopyrazines have also recently shown potential as new antimalarial agents exhibiting promising in vivo efficacy in animal models of malaria infection with one analogue having progressed to an optimised late lead stage. However, this aminopyrazine lead compound 24 (Figure 2) as well as the first generation aminopyridine human Phase 2a clinical candidate MMV390048 showed sub-optimal solubility. In this aspect of the project, chemical modifications mainly focusing on replacing the two aromatic rings with fully and partially saturated heterocyclic systems, hypothesized to potentially disrupt intermolecular π – π stacking thereby improving aqueous solubility, were introduced. The first set of analogues corresponded to the replacement of the trifluoromethylpyridyl ring with partially and fully saturated heterocyclic rings as well as the 4-carboxyphenyl ring while keeping the 4- methylsulfonylphenyl group on the right-hand side portion of the aminopyrazine core scaffold fixed (SAR 1). In SAR 2, the trifluoromethylpyridyl group was fixed on the left-hand side of the aminopyrazine core scaffold while introducing partial and full saturation on the right-hand side of the core. SAR 3 analogues with both aromatic groups simultaneously replaced with partially and fully saturated heterocyclic rings were further generated. Compared to the lead compound 24 (NF54, IC50 = 0.008 μM), the introduced modifications drastically reduced antiplasmodial potency with only one analogue retaining submicromolar activity (NF54, IC50 = 0.51 μM). However, the introduced molecular features positively influenced solubility with the new analogues showing 4 - > 20-fold increase in aqueous solubility compared to the lead compound 24. For both imidazopyridazines and aminopyrazines, docking studies on a homology model of PfPI4K (P. falciparum phosphatidylinositol 4 kinase) were retrospectively undertaken. In both cases, the docking experiments showed that the introduction of the new molecular features was accompanied by loss of key binding interactions to the ATP binding pocket. This was in conformity with the generated parasite-based SAR.
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Loedolff, Michiel Christiaan. "Synthesis and structure-activity relationships of ring D alkyl 19-norsteroids." Doctoral thesis, University of Cape Town, 1996. http://hdl.handle.net/11427/18380.
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Studies have been conducted in synthesising ring D alkyl 19- norsteroids. The aim was to investigate methods for the stereoselective introduction of alkyl groups at C(14) and C(15), for eventual conversion of the intermediates into 14- and 15-alkyl analogues of estradiol hormones. In the first phase of this investigation, 17β-tert-butyldimethylsilyloxyestra-1,3,5(10),14-tetraen-l6-one was synthesised as starting material for alkylation experiments. Estrone 3-methyl ether was converted into the derived 17β-hydroxy 16-ketone by standard methods. This conversion involved the introduction of a 16α-hydroxyl group by bromination-hydrolysis, followed by base-mediated rearrangement of the hydroxy ketone to the thermodynamically preferred 16-ketone. Protection of the 17β-hydroxyl group as a TBS ether, followed by palladium acetate-mediated dehydrosilylation of the derived ∆¹⁵-16-trimethylsilyloxy enol ether gave the ∆¹⁴-16-ketone.The 17β-silyloxy ∆¹⁴-16-ketone resisted conjugate addition reactions, leading only to products of 1,2-alkylation. Stereoselective introduction of a 16-allyl group gave the corresponding ∆¹⁴-16-allyl 16-alcohols, but these compounds showed no sigmatropic reactivity and failed to undergo anionic oxy-Cope rearrangement. Hydride reduction of the 16-oxo group gave the corresponding At4-16-alcohols. The stereoselectivity was dependant on the choice of reagent. The ∆¹⁴-l6α-alcohol underwent ·stereodirected cyclopropanation to give 17β-tert-butyldimethylsilyloxy-14,15α-methyleneestra-1,3,5(10)-trien-16α-ol. Oxidation of this compound gave the corresponding 14α,15α methylene16-ketone, dissolving metal reduction of which furnished the 16β-alcohol. Routine deprotection of the epimeric pair of methylene 16-alcohols gave the derived estriol analogues, which were subjected to biological evaluation. Treatment of the 14α,15α methylene16-ketone with lithium in liquid ammonia gave 17β-tert-butyldimethylsilyloxy-14-methylestra-l,3,5(10)-trien-16-one. Stereoselective reduction of the 16-oxo group gave the epimeric 14α-methyl 16-alcohols. Deprotection of these compounds at C(3) gave a second pair of estriol analogues, which were also assayed for receptor binding affinity.
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Jardine, Mogamad Anwar. "Synthesis and structure activity relationships of ring D modified steroidal hormones." Doctoral thesis, University of Cape Town, 1995. http://hdl.handle.net/11427/17900.
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Includes bibliographical references.The synthesis of steroidal 14α,16-methano, 14α,17-methano-, 14α,17-ethano- and 14α,17-propano estradiol analogues as well as 14α-alkyl and 14α-functionalised-alkyl estradiol analogues was investigated. Furthermore, the synthesis of 17β-hydroxy-17α, 14-(epoxymethano)androst-4-en-3-one was undertaken and acid-mediated rearrangement of the 14,17-etheno bridged testosterone analogue gave the 14,16-ethano analogue of androst-4-en-3,17-dione. Established ring D cycloaddition and oxidative cleavage methodology gave ring D 14α-formyl and 14α, 17α-diformyl compounds as key intermediates in the overall synthetic plan. Chemoselective- and stereoselective nucleophilic addition at C-14¹ of the 14α-formyl-3-methoxyestra-1,3,5(10)-trien-17-one provided access to 14α-alkyl- and 14α-alkyl-functionalised 19-norsteroids for elaboration toward 14α,17-propano- and 14α-alkylamide estradiol analogues. Synthesis of the 14α,17-methano bridged steroid was attainable indirectly through intramolecular pinacol coupling between the 17-oxo- and 14-formyl group of 14αformyl- 3-methoxyestra-1,3,5(10)-trien-17-one. The 14α, 16-methano bridged steroid was synthesised via base-mediated intramolecular cyclisation of 14-(toluene-p-sulfonyloxy)methyl-3-methoxyestra-1,3,5( 1 0)-trien-17-one. Novel compounds were characterised with the aid of high field NMR techniques. A X-ray crystal structure determination of the strained ring D 14α, 17-methano bridged estriol analogue corroborated its structure. The minimum energy conformation of novel estradiol analogues were superimposed on estradiol, and their least square fit values determined and discussed in relation to biological activity. These analogues will contribute toward defining the structural parameters responsible for certain pattern of hormonal activity, and hence, the ultimate goal of predictive drug design.
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Rao, Paluri Sai Shantanu. "Structure-activity relationships for a series of M5 muscarinic receptor modulators." University of Toledo Health Science Campus / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=mco1321650900.
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Ruark, Christopher Daniel. "Quantitative Structure-Activity Relationships for Organophosphates Binding to Trypsin and Chymotrypsin." Wright State University / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=wright1278010674.
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Batchellor, Adam. "STRUCTURE-ACTIVITY RELATIONSHIPS IN NI-FE (OXY)HYDROXIDE OXYGEN EVOLUTION ELECTROCATALYSTS." Thesis, University of Oregon, 2017. http://hdl.handle.net/1794/22268.
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The oxygen evolution reaction (OER) is kinetically slow and hence a significant efficiency loss in electricity-driven water electrolysis. Understanding the relationships between architecture, composition, and activity in high-performing catalyst systems are critical for the development of better catalysts.
This dissertation discusses areas both fundamental and applied that seek to better understand how to accurately measure catalyst activity as well as ways to design higher performing catalysts. Chapter I introduces the work that has been done in the field to date. Chapter II compares various methods of determining the electrochemically active surface area of a film. It further discusses how pulsed and continuous electrodepostition techniques effect film morphology and behavior, and shows that using a simple electrodeposition can create high loading films with architectures that outperform those deposited onto inert substrates. The reversibility of the films, a measure of the films transport efficiency, is introduced and shown to correlate strongly with performance. Chapter III uses high energy x-ray scattering to probe the nanocrystalline domains of the largely amorphous NiFe oxyhydroxide catalysts, and shows that significant similarities in the local structure are not responsible for the change in performance for the films synthesized under different conditions. Bond lengths for oxidized and reduced catalysts are determined, and show no significant phase segregation occurs. Chapter IV seeks to optimize the deposition conditions introduced in Chapter II and to provide a physical representation of how tuning each of the parameters affects film morphology. The deposition current density is shown to be the most important factor affecting film performance at a given loading. Chapter V highlights the different design considerations for films being used in a photoelectrochemical cell, and how in situ techniques can provide information that may otherwise be unobtainable. Chapter VI serves as a summary and provides future directions.
This dissertation contains previously published coauthored material.
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Ptchelintsev, Dmitri Stanislav. "Structure-activity relationship studies in chemoreception, toxicology and medicinal chemistry." Case Western Reserve University School of Graduate Studies / OhioLINK, 1993. http://rave.ohiolink.edu/etdc/view?acc_num=case1060866168.
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