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1
Anson, T. C. "Synthesis of potential enzyme inhibitors." Thesis, University of Exeter, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.372033.
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Bichard, Claire J. F. "Synthesis of potential glycogen phosphorylase inhibitors." Thesis, University of Oxford, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.260115.
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Chong, Sannie Siaw Foong. "Anisotropic potential HIV-1 protease inhibitors." Thesis, University of Hull, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.327289.
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Dhanani, Sachin Paryantray. "Biochemical evaluation of potential enzyme inhibitors." Thesis, Kingston University, 2006. http://eprints.kingston.ac.uk/20375/.
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A high proportion of prostate cancer and benign prostatic hyperplasia (BPH) have been shown to be dependent on androgen biosynthesis. The biosynthesis of androgens is undertaken by a number of important enzymes such as 17a-hydroxylase/17,20-lyase and 17[beta]-hydroxysteroid dehydrogenase. Through the inhibition of these enzymes it is possible to. reduce the amount of androgens present, which in turn reduces the stimulation of androgen-dependent prostatic diseases. Within the current study, we have undertaken the biochemical evaluation of a number of compounds of varying structural features and which were synthesised within our group as potential enzyme inhibitors in the tretament of androgen-dependent diseases. In general, the results from the current study show that the compounds evaluated against the enzyme complex 17a-hydroxylase/17,20-lyase possessed good inhibitory activity. In particular, the imidazole-based inhibitors were found to be more potent against 17,20-lyase in comparison to 17a-hydroxylase, and were more potent than the triazole-based compounds. The most potent compounds within the current study include: 1-(7-phenyl-heptyl)-1H-imidazole (171) (lC50=98.5±15.6nM, K¡=55.3±3AnM against 17,20-lyase and IC50=O.32±O.05I-lM, K¡=O.21±O.01¡.¡M against 17a-hydroxylase), 1-[7 -(4-fluoro-phenyl)-heptyl]-1 H-imidazole (179) (IC50=57.5±1.5nM, K¡=21.5±O.1nM against 17,20-lyase and IC50=173.62±7.00nM, K¡=77.5±2.5nM against 17 a-hydroxylase) and 1-[5-(4-bromo-phenyl)-pentyl]-1 H-imidazole (187) (IC50=58.1±5.2nM against 17,20-lyase and IC50=O.50±O.04I-lM against 17a-hydroxylase), these compounds were all potent inhibitors compared to the standard inhibitor ketoconazole (1) (lC50=1.66±O.15¡.JM, K¡=O.67±O.02¡.¡M against 17,20-lyase and IC50=3.76±O.01I-lM, K¡=1.24±O.01¡.¡M against 17a-hydroxylase). In an effort to discover lead compounds in the inhibition of the 17[beta]-hydroxysteroid dehydrogenase (17[beta]-HSD) family of enzymes, a range of commercially available compounds based on phenyl ketones were initially evaluated against type 1 (17[beta]-HSD1) and 3 (17[beta]-HSD3) of 17[beta]-HSD which are responsible for the reduction of estrone and androstenedione to estradiol and testosterone respectively. The majority of these compounds were found to possess weak inhibitory activity, however, some were found to possess good inhibitory activity. As such, a number of compounds were synthesised within our group as potential inhibitors of 17[beta]-HSD1 and 17[beta]-HSD3. The results show that the 4-hydroxyphenyl ketone-based compounds were found to be . highly potent against type 3 in comparison to type 1. For example, 1-(4-hydroxy-phenyl)-nonan-1-one (254) was found to possess (against type 3) inhibitory activity of 83.53±OA8% (at [1]=100¡.¡M) (IC5o of 2.86 ± O.03¡.¡M). Under similar conditions, 254 was found to possess 36.32±O.33% (at [1]=100¡.¡M) inhibitory activity against type1. A range of compounds were also synthesised based on the biphenyl ketones, however, these were found to be weaker inhibitors of type 3 in comparison to the 4- hydroxyphenyl ketones although they possessed greater inhibitory activity against type 1. In an effort to determine the selectivity of these compounds against the overall class of HSD enzymes, all inhibitors were evaluated for 3[beta]-hydroxysteroid dehydrogenase (3[beta]-HSD) inhibitory activity. We discovered that in general, all of the synthesised compounds possessed weak inhibitory activity against this enzyme at inhibitor concentration of 100¡.¡M and 500¡.¡M, as such, these synthesised compounds could be considered to be good lead compounds for the inhibition of 17[beta]-HSD.
5
Casey, Lorraine A. "The synthesis of potential enzyme inhibitors." Thesis, University of Huddersfield, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.290421.
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Haddow, J. "Potential suicide inhibitors of dihydrofolate reductase." Thesis, University of Strathclyde, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.381497.
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Abdeen, Sanofar, Nilshad Salim, Najiba Mammadova, Corey M. Summers, Rochelle Frankson, Andrew J. Ambrose, Gregory G. Anderson, et al. "GroEL/ES inhibitors as potential antibiotics." Elsevier, 2016. http://hdl.handle.net/10150/618724.
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We recently reported results from a high-throughput screening effort that identified 235 inhibitors of the
Escherichia coli GroEL/ES chaperonin system [Bioorg. Med. Chem. Lett. 2014, 24, 786]. As the GroEL/ES
chaperonin system is essential for growth under all conditions, we reasoned that targeting GroEL/ES with
small molecule inhibitors could be a viable antibacterial strategy. Extending from our initial screen, we
report here the antibacterial activities of 22 GroEL/ES inhibitors against a panel of Gram-positive and
Gram-negative bacteria, including E. coli, Bacillus subtilis, Enterococcus faecium, Staphylococcus aureus,
Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter cloacae.
GroEL/ES inhibitors were more effective at blocking the proliferation of Gram-positive bacteria, in particular
S. aureus, where lead compounds exhibited antibiotic effects from the low-lM to mid-nM range.
While several compounds inhibited the human HSP60/10 refolding cycle, some were able to selectively
target the bacterial GroEL/ES system. Despite inhibiting HSP60/10, many compounds exhibited low to no
cytotoxicity against human liver and kidney cell lines. Two lead candidates emerged from the panel, compounds
8 and 18, that exhibit >50-fold selectivity for inhibiting S. aureus growth compared to liver or kidney
cell cytotoxicity. Compounds 8 and 18 inhibited drug-sensitive and methicillin-resistant S. aureus
strains with potencies comparable to vancomycin, daptomycin, and streptomycin, and are promising candidates
to explore for validating the GroEL/ES chaperonin system as a viable antibiotic target.
8
CULLIA, GREGORIO. "ENZYME INHIBITORS AS POTENTIAL ANTIPARASITIC AGENTS." Doctoral thesis, Università degli Studi di Milano, 2017. http://hdl.handle.net/2434/481792.
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Abstract of the PhD thesis
ENZYME INHIBITORS AS POTENTIAL ANTIPARASITIC AGENTS
PhD course in Chemistry, XXIX cycle, University of Milan
PhD student: Gregorio Cullia (R10447)
Tutor: Prof. Paola Conti
Co-tutor: Dr. Lucia Tamborini
Protozoan parasitic diseases, such as Malaria and Human African Trypanosomiasis (HAT), have a tremendous health, social and economic impact on people living in tropical and subtropical regions of the world. While around 3.8 billion people are at risk of infection, [1] available treatments are unsatisfactory, mainly due to constantly increasing drug resistance. Hence, there is an urgent need of developing new chemotherapeutic agents acting on new molecular targets, such as essential parasitic enzymes. One selected target is the glyceraldehyde 3-phosphate dehydrogenase (GAPDH) of P. falciparum, a key glycolytic enzyme with many other important functions. In this thesis, I describe the development of inhibitors that act alkylating, in a selective way, the catalytic cysteine, inspired by (S,S)-3-bromoacivicin [(S,S)-1]. [2]Some of the inhibitors, in particular (S,S)-9 and (S,S)-59, showed sub-micromolar EC50 toward P. falciparum cultures and a considerably low cytotoxicity toward human cell lines (≥ 20 mM).
In the second project, the interesting 3-bromoisoxazoline warhead was coupled to known peptidic recognition moieties generating new inhibitors of rhodesain(TbCatL), an essential protease involved in virulence and defence processes of the parasite. [3] Some low micromolar inhibitors were identified, among which the diastereoisomeric mixture (S,S,S)-138/(S,R,R)-139 showed also an interesting antiparasitic activity.
The third enzyme that was exploited as target is the N5,N10-methylenetetrahydrofolate dehydrogenase/cyclohydrolase (TbFolD), a crucial enzyme involved in the folate pathway. I started synthesizing LY374571 [(S)-149], a known human FolD inhibitor, [4] with the aim of using it as a lead compound: interestingly, following the published synthesis protocol I unambiguously obtained compound (S)-156, with a structure different from the one reported in the literature. I performed a structure-activity relationships study replacing the glutamate tail with other α-, β- and γ-amino acids [compounds (S)-175-181]. Moreover, the first X-ray structure of TbFolD in presence of (S)-156 and NADP+,was obtained. [5]
The last part of this PhD thesis regards the development of new potential agents for the treatment of C. trachomatis infections. This bacterium is the agent trachoma (a neglected tropical disease), an eye infection that causes the impairment of the sight of 1.9 million people, and of one of the most prevalent sexually transmitted infection. [6] In the past, the inhibitory activity of CI-976 (182) of inhibiting human lysophosphatidicacid:acyl-CoA acyl transferase(hLPAAT) was correlated to a delay in the slow recycling pathway of transferrin, that hampered the growth of the bacterium. [7] I performed an exhaustive structure-activity relationships study focusing on the different structural features of 182 (such as the α- and the N- substitutions and the properties of the aromatic ring). Among the synthesized compounds, 185 showed anti-chlamydial activity comparable to 182. This approach represents an innovative strategy to treat microbial infections, based on the inhibition of a trafficking pathway that is disposable for the human host.
References
[1] a. [Online]. Available: http://www.who.int/mediacentre/factsheets/fs094/en/;b. [Online]. Available: http://www.who.int/mediacentre/factsheets/fs259/en/.
[2] S. Bruno, A. Pinto, G. Paredi, L. Tamborini, C. De Micheli, V. La Pietra, L. Marinelli, E. Novellino, P. Conti and A. Mozzarelli, “Discovery of covalent inhibitors of glyceraldehyde-3-phosphate dehydrogenase, a target for the treatment of malaria,” J. Med. Chem., vol. 57, pp. 7465-7471, 2014.
[3] a. R. Ettari, S. Previti, L. Tamborini, G. Cullia, S. Grasso and M. Zappalà, “The inhibition of cysteine proteases rhodesain and TbCatB: a valuable approach to treat human African trypanosomiasis,” Mini-Rev. Med. Chem., 2016; b. R. Ettari, A. Pinto, S. Previti, L. Tamborini, I. C. Angelo, V. La Pietra, L. Marinelli, E. Novellino, T. Schirmeister, M. Zappalà, S. Grasso, C. De Micheli and P. Conti, “Development of novel dipeptide-like rhodesain inhibitors containing the 3-bromoisoxazoline warhead in a constrained conformation,” Bioorg. Med. Chem., vol. 23, pp. 7053-7060, 2015.
[4] A. Schmidt, H. Wu, R. E. MacKenzie, V. J. Chen, J. R. Bewly, J. E. Ray, J. E. Toth and M. Cygler, “Structures of three inhibitor complexes provide insight into the reaction mechanism of the human methylenetetrahydrofolate dehydrogenase/cyclohydrolase,” Biochemistry, vol. 39, pp. 6325-6335, 2000.
[5] T. C. Eadsforth, A. Pinto, R. Luciani, L. Tamborini, G. Cullia, C. De Micheli, L. Marinelli, S. Cosconati, E. Novellino, L. Lo Presti, A. Cordeiro da Silva, P. Conti, W. N. Hunter and M. P. Costi, “Characterization of 2,4-diamino-6-oxo-1,6-dihydropyrimidin-5-yl ureido based inhibitors of TrypanosomabruceiFolD and testing for antiparasitic activity,” J. Med. Chem., vol. 58, no. 20, pp. 7938-7948, 2015.
[6] World Health Organization, “WHO guidelines for the treatment of Chlamydia trachomatis,” 2016. [Online]. Available: http://www.who.int/reproductivehealth/publications/rtis/chlamydia-treatment-guidelines/en/.
[7] a. K. Chambers, B. Judson and W. J. Brown, “A unique lysophospholipidacyltransferase (LPAT) antagonist, CI-976, affects secretory and endocytic membrane trafficking pathways,” J. Cell Sci., vol. 118, pp. 3061-3071, 2005; b. S. P. Ouellette and R. A. Carabeo, “A functional slow recycling pathway of transferrin is required for growth of Chlamydia,” Front. Microbiol.,vol. 1, 2010.
9
chaudhary, Arpana S. "Inhibitors of SecA as Potential Antimicrobial Agents." Digital Archive @ GSU, 2013. http://digitalarchive.gsu.edu/chemistry_diss/77.
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Protein translocation is essential for bacterial survival and the most important translocation mechanism in bacteria is the secretion (Sec) pathway. Thus targeting Sec pathway is a promising strategy for developing novel antibacterial therapeutics.
We report the design, syntheses, mechanistic studies and structure-activity relationship studies using HQSAR and 3-D QSAR Topomer CoMFA analyses of 4-oxo-5-cyano thiouracil derivatives. In summary, introduction of polar group such as –N3 and linker groups such as –CH2-O- enhanced the potency as well as logP and logS several fold.
We also report the discovery, optimization and structure-activity relationship study of 1,2,4-triazole containing pyrimidines as novel, highly potent antimicrobial agents. A number of inhibitors have been found to inhibit microbial growth at high nanomolar concentrations.
10
Marr, Sharon Ann. "The synthesis of potential serine protease inhibitors." Thesis, University of Hull, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.310261.
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Dedola, Simone. "'Click chemistry' to synthesise potential glycosidase inhibitors." Thesis, University of East Anglia, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.502211.
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In this study, "click chemistry" was used to assemble a collection of potential glycosidase inhibitors. Using different "click chemistry" conditions, 21 α-D- and β-D glucopyranosyl triazoles were synthesised and assayed as inhibitors of sweet almond β-glucosidase and yeast α-glucosidase. A set of moderately effective glycosidase inhibitors was identified. In the course of this work significant differences in the reactivity of the α- and β-glucopyranosyl azides under CuAAC conditions was noted. This matter was investigated by X-ray crystallography and, in keeping with the anomeric effect, pointed to a difference in partial charge distribution in the azide and sugar moieties. Starting from maltosyl and maltotriosyl azides another collection of 12 triazoles was synthesised and all of the libraries were assayed against starch degrading enzymes from barley. A moderate inhibitor of α-glucosidase was identified, as were several weak inhibitors of β-amylase.
12
Nazareth, W. M. A. "Synthesis and evaluation of potential aromatase inhibitors." Thesis, Cardiff University, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.381252.
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Nkansah, Peter Appah. "Syntheses of pyridylglucoconjugates as potential glycosidase inhibitors." Thesis, University of East Anglia, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.368182.
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Williams, P. S. "Studies on neuropeptidase inhibitors as potential analgesics." Thesis, Cardiff University, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.378579.
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Allen, Andrew David. "The atomistic simulation of potential angiogenic inhibitors." Thesis, University of Surrey, 1996. http://epubs.surrey.ac.uk/844002/.
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This thesis concerns the atomistic investigation of the extra-cellular protein angiogenin. The main aims of this project are to propose new potential inhibitors to the angiogenin, and to investigate how they might bind to the protein. Two main families of inhibitors have been investigated; firstly, anthracycline antineoplastic antibiotics of which adriamycin is the parent drug; and secondly, uridine and cytidine nucleotide derivatives. The project has been divided into four research areas; conformational analysis of adriamycin; conformational analysis of nucleotide derivatives; a comparative study of the published crystal structure of angiogenin and a published in-house homology model of the protein; finally a series of docking studies to explore the similarity of the active site of angiogenin to ribonuclease A. Angiogenin has been shown to be 68% similar to ribonuclease A on an atom-by-atom basis, and a new sequence alignment has been produced following the release of the crystal structure of angiogenin.
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Marketwala, Nishrin Ismailbhai. "PYRROLE CARBOXAMIDES AS POTENTIAL CARBONIC ANHYDRASE INHIBITORS." Wright State University / OhioLINK, 2006. http://rave.ohiolink.edu/etdc/view?acc_num=wright1166468773.
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McCarthy, Sean Joseph. "Strained amides as potential antibacterials." Thesis, University of Sussex, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.296003.
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McCrudden, Maeliosa Theresa Christine. "Characterisation of small protease inhibitors as potential therapeutics." Thesis, Queen's University Belfast, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.492028.
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Neutrophil-derived serine proteases provide one of the first lines of defense against infection in innate immunity. However, in some disease states, the activity of these proteases becomes excessive and prolonged and so novel lead molecules with the potential to inhibit the excessive activity of these proteases in disease states are constantly being sought. In the current study, three proteinaceous protease inhibitors were chosen for characterisation. The specificity of the Escherichia coli trypsin inhibitor (ecotin) was modulated by site-directed mutagenesis studies; the elastase and cathepsin G-like inhibitor (eglin C) from Hirudo medicinalis was used as a positive control recombinant protein and the functional characteristics of the epididymal protease inhibitor (eppin) were examined. Eppin's anti-bacterial activity had been partially characterised but beyond this, very little functional information was available for the protein. Composed of the Whey acidic protein (WAP) and Kunitz inhibitor motifs, eppin was postulated to have anti-protease and immunomodulatory properties. Expression vectors were constructed for eppin and each of its consensus inhibitor domains and recombinant proteins were subsequently expressed in and purified from E. coli cells. The proteins all had elements of a-helix and p-sheet in their secondary structure, deduced by circular dichrosim (CD) analysis. Eppin and its domains were found to kill E. coli cells via a mechanism of permeabilisation of bacterial membranes resulting in uncoupling of respiratory electron transport but the two domains were required to achieve maximal effect. The Kunitz domain inhibited human neutrophil elastase to a similar extent as the intact protein but the.WAP domain exhibited no such activity. In a model of lipopolysaccharide (LPS)-induced inflammation in a monocytic cell line, eppin was shown 'to inhibit the expression of three pro-inflammatory cytokines. The mechanism of inhibition, in the case of one of the cytokines, was via down-regulation of transcription ofthe cytokine.
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Mann, Maretta Clare, and n/a. "Sialylmimetics as Potential Inhibitors fo Vibrio Cholerae Sialidase." Griffith University. Institute for Glycomics, 2004. http://www4.gu.edu.au:8080/adt-root/public/adt-QGU20061006.083947.
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Cholera is an epidemic infectious diarrhoeal disease that for centuries has proven its frightening ability to cause rapid and widespread loss of human life. All symptoms associated with cholera are a result of rapid dehydration due to infection by pathogenic strains of the bacterium Vibrio cholerae. The damaging effects associated with cholera are mainly attributed to the toxin, which is secreted by the bacterium and infects cells lining the gastrointestinal tract. A sialidase, also secreted by the bacterium, is believed to facilitate toxin uptake by the gastrointestinal epithelium. V. cholerae sialidase is therefore a potential target for therapeutic intervention. A survey of the literature reveals that sialidases from different species share common features with respect to their structure, substrate specificity and catalytic mechanism. The unsaturated sialic acid, Neu5Ac2en, inhibits most exosialidases with a dissociation constant of inhibitor of -10-4 to-10-6 M and has frequently been used as a template in the design of more potent sialidase inhibitors. In the case of V. cholerae sialidase, there have been no inhibitors reported to date that are significantly more potent than Neu5Ac2en itself The present research aimed to develop a range of mimics of Neu5Ac2en, which contain various substituents to replace the C-6 glycerol side chain, as potential inhibitors of V cholerae sialidase. The x-ray crystal structure of V cholerae sialidase was used to explore potential interactions between active site residues and C-6 modified Neu5Ac2en mimetics of known inhibitory potency. Opportunities for interactions within the glycerol side chain pocket in the active site of V cholerae sialidase are discussed. A novel synthetic strategy was developed for the synthesis of a series of glucuronidebased Neu5Ac2en mimetics starting from readily available GIcNAc. This approach was employed for the preparation of Neu5Ac2en mimetics that contained an ether or thioether substituent as replacement of the glycerol side chain of Neu5Ac2en. Progress was also made towards the synthesis of a series of C-6 acylamino Neu5Ac2en mimetics. Analysis by 1H NMR spectroscopy showed that the acylamino derivatives adopted a half-chair conformation that was similar to the conformation of Neu5Ac2en but different to the conformation adopted by the ether and thioether derivatives prepared. The inhibitory activity of the C-6 ether and thioether Neu5Ac2en mimetics prepared was evaluated in vitro using an enzyme assay. It was found that most of the derivatives inhibited V. cholerae sialidase with a K1 of approximately 1O-4 M. The derivatives containing a hydrophobic side chain were found to be slightly more potent compared to derivatives with more hydrophilic side chains. A more detailed study of binding interactions between the C-6 thioether Neu5Ac2en mimetics and V cholerae sialdiase was carried out using STD 1H NMR spectroscopy and computational molecular modelling.
20
Saint, Robert Edward. "The synthesis and evaluation of potential transglutaminase inhibitors." Thesis, University of Nottingham, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.263941.
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Hatzis, Maria Demetra. "Synthetic routes to potential 5#alpha#-reductase inhibitors." Thesis, University of Reading, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.333536.
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Gordge, Philip Charles. "Potential agonists and inhibitors of protein kinase C." Thesis, University College London (University of London), 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.285430.
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Rae, Christine Mary. "Design and synthesis of potential inhibitors of fucosyltransferases." Thesis, University of Edinburgh, 1997. http://hdl.handle.net/1842/11290.
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This thesis describes the design and synthetic approach to a potential transition state inhibitor 26 of an α(1.3)-fucosyltransferase - an important enzyme involved in the inflammatory response where white blood cells are recruited to the site of injury. Fig. 1227A. Chapter 1 reviews the literature of potential inhibitors of both glycosyltransferases and glycosidases and outlines the aim of the project. Chapter 2 reveals the retrosynthetic strategy adopted for the trisubstrate analogue 26 and of the core azasugar portion which is a bis-hydroxymethyl piperidine 27. The synthetic challenge in this project resided in the synthesis of this unit and initially, an asymmetric synthesis of the known azasugar L-deoxyfuconojirimycin (DFJ) 7 which contains four of the required stereogenic centres of the core azasugar 27 was investigated. Chapter 3 describes the successful synthesis of 7 in 14 steps commencing from the readily available amino acid N-Box-L-alanine 51. Fig. 1227B. It was envisaged that the route to DFJ could subsequently be elaborated to the bis-dihydroxymethyl piperidine 27, but due to unforeseen problems a revised approach to the prime target from N-Box-L-alanine 51 was adopted. Chapter 4 outlines 10 steps that have been completed en route to an appropriately functionalised acyclic system which is anticipated to undergo a Lewis acid catalysed 6-exo-tet cyclisation of an amine function onto a gem-disubstituted epoxide to furnish a cyclised precursor to the target azasugar 27.
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Mann, Maretta Clare. "Sialylmimetics as Potential Inhibitors fo Vibrio Cholerae Sialidase." Thesis, Griffith University, 2004. http://hdl.handle.net/10072/367187.
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Cholera is an epidemic infectious diarrhoeal disease that for centuries has proven its frightening ability to cause rapid and widespread loss of human life. All symptoms associated with cholera are a result of rapid dehydration due to infection by pathogenic strains of the bacterium Vibrio cholerae. The damaging effects associated with cholera are mainly attributed to the toxin, which is secreted by the bacterium and infects cells lining the gastrointestinal tract. A sialidase, also secreted by the bacterium, is believed to facilitate toxin uptake by the gastrointestinal epithelium. V. cholerae sialidase is therefore a potential target for therapeutic intervention. A survey of the literature reveals that sialidases from different species share common features with respect to their structure, substrate specificity and catalytic mechanism. The unsaturated sialic acid, Neu5Ac2en, inhibits most exosialidases with a dissociation constant of inhibitor of -10-4 to-10-6 M and has frequently been used as a template in the design of more potent sialidase inhibitors. In the case of V. cholerae sialidase, there have been no inhibitors reported to date that are significantly more potent than Neu5Ac2en itself The present research aimed to develop a range of mimics of Neu5Ac2en, which contain various substituents to replace the C-6 glycerol side chain, as potential inhibitors of V cholerae sialidase. The x-ray crystal structure of V cholerae sialidase was used to explore potential interactions between active site residues and C-6 modified Neu5Ac2en mimetics of known inhibitory potency. Opportunities for interactions within the glycerol side chain pocket in the active site of V cholerae sialidase are discussed. A novel synthetic strategy was developed for the synthesis of a series of glucuronidebased Neu5Ac2en mimetics starting from readily available GIcNAc. This approach was employed for the preparation of Neu5Ac2en mimetics that contained an ether or thioether substituent as replacement of the glycerol side chain of Neu5Ac2en. Progress was also made towards the synthesis of a series of C-6 acylamino Neu5Ac2en mimetics. Analysis by 1H NMR spectroscopy showed that the acylamino derivatives adopted a half-chair conformation that was similar to the conformation of Neu5Ac2en but different to the conformation adopted by the ether and thioether derivatives prepared. The inhibitory activity of the C-6 ether and thioether Neu5Ac2en mimetics prepared was evaluated in vitro using an enzyme assay. It was found that most of the derivatives inhibited V. cholerae sialidase with a K1 of approximately 1O-4 M. The derivatives containing a hydrophobic side chain were found to be slightly more potent compared to derivatives with more hydrophilic side chains. A more detailed study of binding interactions between the C-6 thioether Neu5Ac2en mimetics and V cholerae sialdiase was carried out using STD 1H NMR spectroscopy and computational molecular modelling.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Biomolecular and Physical Sciences
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Silveira, Alvito J. "Synthesis of 6-guanidinobenzoxazinones as potential inhibitors of trypsin-like enzymes." Thesis, Georgia Institute of Technology, 1989. http://hdl.handle.net/1853/26914.
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Mohan, Swathi Groutas William C. "Potential inhibitors of dengue and West Nile virus proteases." Diss., The archival copy of this thesis can be found at SOAR (password protected), 2006. http://soar.wichita.edu/dspace/handle/10057/569.
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Thesis (M.S.)--Wichita State University, College of Liberal Arts and Sciences., Dept. of Chemistry."July 2006." Title from PDF title page (viewed on May 2, 2007). Thesis adviser: William C. Groutas. Includes bibliographic references (leaves 64-66).
27
Leloup, Sophie Elisabeth. "Studies on isosteric peptide analogues as potential enzyme inhibitors." Thesis, University of Oxford, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.257928.
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Haque, Mohammad Rashedul. "Novel STAT3 small-molecule inhibitors as potential anticancer agents." Thesis, University of London, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.535504.
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Guyen, B. "Synthesis of analogues of quindoline as potential telomerase inhibitors." Thesis, Queen's University Belfast, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.273042.
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Griffin, Alice Laura. "The synthesis of potential inhibitors for phospholipase Aâ†2." Thesis, University of Newcastle Upon Tyne, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.358085.
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Abusbeih, Khaled. "Synthesis of potential inhibitors of aconitase and ribonucleotide reductase." Thesis, University of Newcastle Upon Tyne, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.308912.
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Lister, P. M. "The synthesis of potential inhibitors of renin and pepsin." Thesis, University of Southampton, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.373201.
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Tarling, Chris Andrew. "Studies towards the synthesis of potential serine protease inhibitors." Thesis, University of Cambridge, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.621643.
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Jackson, Charlotte. "Nox inhibitors : A potential future medicine for ischemia stroke." Thesis, Högskolan i Skövde, Institutionen för hälsa och lärande, 2018. http://urn.kb.se/resolve?urn=urn:nbn:se:his:diva-15834.
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This study investigated the neuroprotective effects of novel small molecule NOX inhibitors after induction of an ischemic stroke model on Neuroblastoma cells (NB69). Previous findings show that high levels of reactive oxygen species (ROS) have been identified for playing a role in causing inflammation, cellular damage and apoptosis in many cardiovascular diseases. It is believed that by inhibiting the Nox enzymes that generate ROS, the damage caused to the brain (measured as % cell viability) would be decreased. NOX2 and NOX4 gene expression what validated in NB69 cells using PCR, gel electrophoresis and GAPDH as a reference gene. Stroke was modelled by using the oxygen-glucose depletion model and reperfusion injury was modelling by replenishing glucose and oxygen supplies to the cell and incubator for 24-72hrs. Gene expression of NOX4 expression after 1hr ischemia and 24-48hrs reperfusion showed there was an increase in relative expression after 24hrs and a decrease in expression after 48hrs. No gene expression analysis could be shown for NOX2. Cell viability was measured amongst treatment groups using the MTS assay. Statistical analysis consisted of Shapiro Wilk tests, One-way ANOVAs, Tukey tests and ROUT Outlier analysis. Only M114 was seen to have a statistically significant neuroprotective effect on the cells ( after 1hr ischemia, 24+48hrs reperfusion and 2hr ischemia + 48hr reperfusion). After 72hrs reperfusion all three treatments reduced cell viability significantly from the negative control group (p<0.0001) highlighting the importance of ROS signalling in neural cells and the consequences of eradicating it. Media was changed on plates after 48hrs reperfusion. These findings show that all three substances have some effect on the cells and can target their NOX enzymes and identifies M114 as a potential new treatment for stroke patients.
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Iversen, Alexandra, Ebba Nordén, Julia Bjers, Filippa Wickström, Martin Zhou, and Mohamed Hassan. "Characterisation of Potential Inhibitors of Calmodulin from Plasmodium falciparum." Thesis, Linköpings universitet, Institutionen för fysik, kemi och biologi, 2020. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-170268.
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Each year countless lives are affected and about half a million people die from malaria, a disease caused by parasites originating from the Plasmodium family. The most virulent species of the parasite is Plasmodium falciparum (P. falciparum). Calmodulin (CaM) is a small, 148 amino acid long, highly preserved and essential protein in all eukaryotic cells. Previous studies have determined that CaM is important for the reproduction and invasion of P. falciparum in host cells. The primary structure of human CaM (CaMhum) and CaM from P. falciparum (CaMpf) differ in merely 16 positions, making differences in their structures and ligand affinity interesting to study. Especially since possible inhibitors of CaMpf in favor of CaMhum, in extension, could give rise to new malaria treatments. Some antagonists, functioning as inhibitors of CaM, have already been analysed in previous studies. However, there are also compounds that have not yet been studied in regards to being possible antagonists of CaM. This study regards three known antagonists; trifluoperazine (TFP), calmidazolium (CMZ) and artemisinin (ART) and also three recently created fentanyl derivatives; 3-OH-4-OMe-cyclopropylfentanyl (ligand 1), 4-OH-3OMe-4F-isobutyrylfentanyl (ligand 2) and 3-OH-4-OMe-isobutyrylfentanyl (ligand 3). Bioinformatic methods, such as modelling and docking, were used to compare the structures of CaMhum and CaMpf as well as observe the interaction of the six ligands to CaM from both species. In addition to the differences in primary structure, distinguished with ClustalW, disparities in tertiary structure were observed. Structure analysis of CaMhum and CaMpf in PyMOL disclosed a more open conformation as well as a larger, more defined, hydrophobic cleft in CaMhum compared to CaMpf. Simulated binding of the six ligands to CaM from both species, using Autodock 4.2, indicated that TFP and ART bind with higher affinity to CaMhum which is expected. Ligand 2 and ligand 3 also bound with higher affinity and facilitated stronger binding to CaMhum, which is reasonable since their docking is based on how TFP binds to CaM. However, ligand 1 as well as CMZ both bound to CaMpf with higher affinity. Despite promising results for ligand 1 and CMZ, no decisive conclusion can be made solely based on bioinformatic studies. To gain a better understanding on the protein-ligand interactions of the six ligands to CaMhum and CaMpf, further studies using e.g. circular dichroism and fluorescence would be advantageous. Based on the results from this study, future studies on the binding of CMZ and ligand 1 to CaM as well as ligands with similar characteristics would be especially valuable. This is because they, based on the results from this study, possibly are better inhibitors of CaMpf than CaMhum and thereby could function as possible antimalarial drugs.
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Yap, Chee H. "Potential inhibitors of dihydrofolate reductase: synthesis and NMR spectroscopy." Thesis, Aston University, 1985. http://publications.aston.ac.uk/14508/.
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Carvalho, Catarina. "Synthesis of oxygen containing heterocycles as potential IDO inhibitors." Thesis, University of Nottingham, 2013. http://eprints.nottingham.ac.uk/13093/.
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One potentially attractive approach to cancer therapy is to recruit the body’s own immune system to reject solid tumours. The enzyme indoleamine 2,3-dioxygenase (IDO) has been shown to play a major role in supressing immune response, and there is now growing evidence to support the hypothesis that inhibition of IDO produces significant anticancer effects. The development of chemotherapeutic agents for cancer based on the inhibition of indoleamine 2,3-dioxygenase is the purpose of this present work. Chapter I contains an overview of indoleamine 2,3-dioxygenase, describing its structure, activation cycle, catalytic mechanism and inhibitors. Chapter II is divided in two parts. Initially the efforts towards the synthesis of a simple analogue, containing the isobenzofuranquinone moiety of annulins A and C are described. The aim was to verify which part of the molecule was important for IDO inhibiton. Four main approaches to the analogue are described. Next, investigations into the total synthesis of annulins A and C are discussed. These led to the synthesis of the naphthoquinone core of both natural products by performing a Diels Alder reaction. Attempts to introduce the furan ring proved challenging, and different approaches to this problem are described in this Chapter. In Chapter III, the synthetic approaches towards annulin B are discussed. The possibility to access this natural product via Diels Alder reaction, prompted us to investigate the synthesis of the required dienophile – a chroman-3-one substrate. We succeeded in constructing this highly advanced intermediate using two different strategies, namely a Dieckmann condensation and an intramolecular O-H insertion reaction. Finally, the synthesis and biological evaluation of a narrow range of benzofuranquinones with varying substituents are presented in Chapter IV. Their synthesis was based on the structure of the benzofuran ACH488, previously identified as a good IDO inhibitor. The experimental details of the above work are described in Chapter V.
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Webster, Kerri Lesley. "Synthesis of nodularin analogues as potential protein phosphatases inhibitors." Thesis, University of St Andrews, 1998. http://hdl.handle.net/10023/14322.
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Reversible phosphorylation of proteins on serine, threonine and tyrosine residues, is now widely accepted to be the principal mechanism for the control of intracellular events in eukaryotic and prokaryotic cells. The nodularins are known to be potent inhibitors of serine/threonine protein phosphatases, PPlc and PP2Ac, with sub-nanomolar inhibition constants. They have been shown to form covalent adducts with the enzymes and are known to be potent hepatotoxins and liver promoters. Nodularin has the general structure: cyclo [(R)-eryphro-beta-methyl-iso-Asp-(S)-X-Adda-(R)-iso- Glu-N-methyldehydrobutyric acid)], where (S)-X is a variable S-amino acid and Adda is the unique beta-amino acid, (2S,3S,8S,9S)-3-amiao-9-methoxy-2,6,8-trimethyl-10-phenyldeca-4,6- dienoic acid. In order to investigate the mode of inhibition and also to probe the active-site binding interactions, we decided to synthesis new analogues of nodularin. Specific inhibitors for either PP1 or PP2A are not presently available, but would be useful biochemical tools in delineating the individual physiological roles of these enzymes. We decided to syntliesise, the potential inhibitor cyclo [betaAla-(2R)-Glu-alpha-OMe-gamma-Pro-(2R)-Asp-alpha-OMe-gamma-(25)-Phe], a stripped-down nodularin macrocycle, and also an analogue which is suitable for synthetic elaboration at the "Adda position". Using solution phase peptide synthesis (LPPS), four such nodularin analogues (both (25)- and (2R)-proline) were synthesised in seventeen steps. The cyclisation between the Phe and Asp residues were carried out using DIPEA under conditions of high dilution. NMR studies (TOCSY, ROESY) have elucidated the three dimensional structures which have been shown to be similar to the natural product, nodularin. A shorter synthesis of these nodularin analogues was developed using solid phase peptide synthesis (SPPS). Two solid phase synthesise of the nodularin macrocycles, cyclo-[betaAla-(2R)- Glu-alpha-OMe-gamma-Pro-(2R)-Asp-beta-(25)-Phe]; one in which Fmoc-(2S)-Phe-betaAla-(2R)-Glu-alpha-OMe-gamma-Pro-(2R)-Asp(alphaO-Wang Resin)-beta-OAllyl is deprotected and then cyclised on the resin prior to cyclisation were found to be successful. Even though the resin-bound synthesis gave low yields for the cyclisation step, compared to the situation in solution, it offered advantages in the construction of the linear isopentapeptide precursor. Initial studies have shown that the nodualrin analogues 130 and 131 are moderate inhibitors (IC50 2.8 mmol) of PP1 when tested using the malachite green system. Studies towards the synthesis of incorporating more suitable Adda functionalities, and the development of a radiolabelled protein phosphatase assay are currently being investigated within the group.
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Sewell, Alan L. "Coenzyme A biosynthesis inhibitors as potential anti-parasitic agents." Thesis, University of Glasgow, 2014. http://theses.gla.ac.uk/5067/.
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Malaria is a lethal disease responsible for human deaths numbering hundreds of thousands every year. With increasing resistance to most antimalarial drugs, new approaches are of high importance. Coenzyme A (CoA) plays a key role in the biosynthesis of many important compounds and is synthesised from pantothenic acid (Vitamin B5) via a series of five enzyme-mediated steps. Studies have shown that the human malaria parasite P. falciparum is unable to synthesise pantothenic acid, and is therefore dependent on uptake from its environment. CJ-15,801, a naturally occurring pantothenic acid analogue that differs only in the incorporation of a very reactive enamide unit at its core, was isolated in 2001. CJ-15,801 has shown remarkable specificity for inhibiting P. falciparum growth over mammalian cell lines. The enantioselective synthesis of CJ-15,801 from (D)-pantolactone has been achieved along with a library of over 100 related enamide analogues. Biological evaluation of the enamides against P. falciparum has uncovered promising leads, with single figure micromolar level antiplasmodial activity as well as nanomolar activity in pantothenate phosphorylation assays. In an effort to understand the mode of action of the enamide analogues, multiple approaches have been taken. Activity against P. falciparum was assessed in such a way that pantothenate competitive and non-competitive inhibitors could be identified. Additionally, 13C-labelled analogues have been synthesised for metabolomic studies and fluorescently tagged compounds based on the BODIPY scaffold have been synthesised for evaluation using fluorescence microscopy.
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Wills, Veronica Sue. "Synthesis of geminal bisphosphonates as potential inhibitors of GGDPS." Diss., University of Iowa, 2015. https://ir.uiowa.edu/etd/1933.
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The isoprenoid biosynthetic pathway (IBP) plays an important role in cellular metabolism. Currently there are drugs, including lovastatin and the nitrogenous bisphosphonates risedronate and zoledronate, that are used clinically to lower cholesterol levels and treat bone disease, respectively. These drugs work by inhibition of the upstream enzymes, HMG-CoA reductase and farnesyl diphosphate synthase (FDPS), respectively. The enzyme FDPS catalyzes the formation of farnesyl pyrophosphate (FPP), an important intermediate that represents a branch point in the pathway. The post-translational modification known as protein prenylation is mediated by the three prenyltransferase enzymes. Even though compounds like lovastatin, risedronate, and zoledronate indirectly disrupt protein prenylation, they also impair processes downstream from the point of inhibition. Therefore a direct approach would be desirable where downstream enzymes are targeted so that the rest of the cellular processes can continue to function.
One such downstream enzyme is geranylgeranyl transferase II (GGTase II). This enzyme and it catalyzes the transfer of two hydrophobic geranylgeranyl chains from geranylgeranyl pyrophosphate (GGPP) to Rab proteins, which are essential for intracellular membrane trafficking. Inhibition of GGTase II may be a good therapeutic target for diseases such as multiple myeloma characterized by an over secretion of proteins. A known GGTase II inhibitor is the carboxy phosphonate 3-PEHPC, however millimolar concentrations are necessary to observe cellular effects with this compound. In an effort to develop more potent inhibitors of this enzyme, a family of isoprenoid triazole bisphosphonates was initially prepared by click chemistry, first as a mixture of olefin isomers due to an allylic azide rearrangement. These compounds were tested by our collaborators to determine the compounds’ activity as GGTase II inhibitors.
Because some triazole bisphosphonates showed good activity as a mixture of isomers, a family of isoprenoid triazole bisphosphonates as single olefin isomers now has been prepared through the use of epoxy azides to avoid the azide rearrangement. The biological activity of these compounds has been studied and some of these triazole bisphosphonates were found to be potent and selective inhibitors of geranylgeranyl diphosphate synthase (GGDPS). While the enzyme GGDPS is upstream of the geranylgeranyltransferases, it is still downstream of the pathway’s primary branch point and provides GGPP for Rab geranylgeranylation. Two other families of triazole bisphosphonate analogues, homo- and bishomoisoprenoid triazole bisphosphonates, also have been prepared and tested by our collaborators to explore the compounds’ activity as GGDPS inhibitors, as well as the structure-activity-relationship.
Previous research has shown digeranyl bisphosphonate (DGBP) and the bisphosphonate ether C-prenyl-O-geranyl bisphosphonate to be inhibitors of GGDPS. Two C-alkyl-C-homoalkyl DGBP analogues have been synthesized in order to study further the binding of these compounds to GGDPS, and dialkylated triazole bisphosphonates have been prepared to explore the effect of a triazole moiety on the analogue’s ability to inhibit GGDPS. The activity uncovered through these studies encourages further research on inhibitors of GGDPS.
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Omune, Duncan Otieno. "Synthetic analogs of equisetin as potential HIV-1 integrase inhibitors." Diss., Online access via UMI:, 2004. http://wwwlib.umi.com/dissertations/fullcit/3150487.
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Curtis, Kim Louise. "The synthesis of azadisaccharides and aminopyrrolidines as potential glycosidase inhibitors." Thesis, University of Leicester, 2005. http://hdl.handle.net/2381/30094.
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Azadisaccharides e.g. 399 (Figure 1) are known to be potent selective inhibitors of glycosidases and thus have potential as anti-viral, anti-cancer and anti-diabetic agents. We have developed new, efficient, versatile and stereoselective routes to azadisaccharides using non-carbohydrate starting materials. Pinacol methodology has been successfully used to synthesise two (2→6) linked homoaza-O-disaccharides mimics and due to the versatility of the synthetic route, modification has enabled the synthesis of a (2→6) linked homoaza-O-trisaccharide. Complementary to this, RCM (Grubbs catalyst) and stereoselective dihydroxylation (OSO4) has been utilised in the synthesis of (1→6) linked 5-deoxy-pyrrolidine and piperidine homoaza-O- and N- disaccharides as single diastereoisomers. Preliminary biological screening of these compounds has identified 399 as a weak selective inhibitor of naringinase. Aminopyrrolidines are compounds of great chemical and biochemical interest and are versatile chiral intermediates in the synthesis of compounds of considerable therapeutic value. Three novel diastereomeric 2-hydroxymethyl-3-amino-4-hydroxylpyrrolidines have been synthesised from one key homoallylic carbamate. Using a tethered aminohydroxylation and a regio- and stereoselective intramolecular epoxide opening the novel (2S, 3S, 4R) isomer 488 and (2S, 3S, 4 S) isomer 489 (Figure 2) have been synthesised respectively. Access to a third (2S, 3R, 4R) isomer was also achieved using an unprecedented regioselective intermolecular epoxide opening. Preliminary biological screening of 488 and 489 has identified both as weak inhibitors of beta-galactosidase.
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Huang, Yanting. "Design and synthesis of potential inhibitors of HAV-3C proteinase." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp04/mq21175.pdf.
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Sampson, Peter B. "Synthesis of potential inhibitors targeting enzymes involved in methionine biochemistry." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape3/PQDD_0018/NQ53511.pdf.
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Saylor, Melissa Anne. "Isolation of plant-derived signal transduction inhibitors : potential antitumor agents." Thesis, Georgia Institute of Technology, 1992. http://hdl.handle.net/1853/30989.
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Gao, Hong Ying 1967. "Assessing the potential of carboxylic acids as inhibitors of glycation." Thesis, McGill University, 2008. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=116072.
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Glycation is a series of chemical interactions occurring in food and biological systems between reducing sugars and proteins leading to the formation of Advanced Glycation End products (AGEs). Ingestion of dietary AGEs and/or their formation in-vivo are mainly associated with cardiovascular and other age-related diseases and complications of long term diabetes. Potential strategies to prevent AGE formation can help to reduce risk factors associated with thermal processing of many foods. The overall objective of this research was focused on the identification of potential AGE inhibitors and investigation of their activity in glucose and ribose-based model systems containing lysozyme. The carboxylic acid functional group was chosen as a potential candidate based on their ability to interact with Schiff bases in addition to their ability to form amide bonds and carboxylate salts with the lysine side chains of proteins. The model systems were incubated with and without selected carboxylic acids (maleic, acetic, oxalic and citraconic) at 50°C for 12, 24 and 48h at pH 6.5. The effect of carboxylic acids on the glycation of lysozyme was studied by electrospray ionization mass spectrometry (ESI-MS). The experimental results showed that none of the carboxylic acids were able to form amide linkages with lysozyme under the experimental conditions and only maleic acid was able to form carboxylate salts, however, oxalic acid was the only acid able to interact with the Schiff base and form 1,3-oxazolidine-4,5-dione intermediate and thus hinder its rearrangement into Amadori product and consequently inhibit glycation. As a result the percentage of free or unreacted lysozyme was the highest in oxalic acid model systems (9.4% in the case of glucose, 7.1% in the case of ribose system) and was even higher than the control systems (6.0% in the case of glucose, 1.2% in the case of ribose system) of both glucose and ribose. In addition, all carboxylic acids were able to modify the relative distribution of different glycoforms generated during the incubation period however oxalic acid was the most efficient in shifting the distribution of glycoforms to lower molecular weight clusters which can additionally contribute to its anti-glycation activity.
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Gould, Matthew K. "Putative phosphodiesterase inhibitors as potential new chemotherapies against African Trypanosomiasis." Thesis, University of Glasgow, 2009. http://theses.gla.ac.uk/1410/.
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African trypanosomiasis is a disease caused by the Kinetoplastida parasites Trypanosoma brucei rhodesiense and T. b. gambiense. The distribution of the disease is split geographically with T. b. rhodesiense found in eastern sub-Saharan Africa and T. b. gambiense in the west of the continent. Current treatment for this fatal disease is wholly unsatisfactory with problems such as extreme toxicity, affordability and the emergence of resistance. The case for the generation of new potential chemotherapies is compelling and urgent. Phosphodiesterase (PDE) enzymes degrade the secondary signalling molecule cyclic adenosine monophosphate (cAMP) to AMP by hydrolysis, thereby modulating and regulating the signal transduction to the effector proteins. The phosphodiesterase enzymes in the PDEB family in T. brucei were shown to be essential to the host-infective bloodstream forms and validated as good drug targets using RNA-interference (Zoraghi, R. and Seebeck, T., 2002; Oberholzer, M., 2007). Prompted by these findings, two series of putative trypanosomal PDE inhibitors, from different sources, were thoroughly assessed in this project for their anti-trypanosomal activity and their intracellular effects on the trypanosome. The whole-cell in vitro efficacy for each compound, against T. brucei wildtype and the drug-resistant strain TbAT1 knockout, was established by the standard resazurin reduction assay. 25 compounds from Series 1 had EC50 values below 0.5 µM, with 7 under 100 nM and the most active having an EC50 value of 5.8 ± 3.4 nM. For the much smaller Series 2 (GJS Compounds), the most active compound was GJS-128 with an EC50 value of 79.4 ± 10.3 nM. This demonstrates that a number of compounds from both series have potent in vitro activity against trypanosomes that is better than or equal to the current chemotherapeutic compound diminazene, and some Series 1 compounds are on a par with pentamidine and melarsoprol. No major cross-resistance was displayed by the TbAT1 knockout strain to either Series 1 or the GJS series. Similarly, a panel of Series 1 compounds tested against the B48 strain (resistant to pentamidine and melaminophenyl arsenical drugs), and also against Trypanosoma equiperdum wildtype and diminazene resistant (PBR) strains, showed no major cross-resistance displayed by the other resistant strains. This suggests that there would also be little or no cross-resistance from refractory strains in the field, and also that the compounds are active against multiple Trypanosoma species. A small panel of Series 1 compounds were also tested for efficacy against trypanosomes in infected mice. 4 daily doses of 20 mg/kg bodyweight of Compound 48 significantly reduced parasitaemia by approximately 60% compared to untreated controls, however higher concentrations were not tolerated by the mice so a cure could not be demonstrated. A high-throughput method for monitoring the speed of action of test compounds on trypanosomes in real time was developed, based on the fluorescence of propidium iodide when bound with DNA. Optimisation of the protocol to 96-well plates and low cell densities provided higher resolution and accurate traces of the lysis of trypanosomes in a cell suspension compared to previously used methods, as well as a greatly increased capacity. The propidium iodide assay could also be converted to provide end-point EC50 values that were directly comparable to those established by the standard resazurin reduction assay. The majority of Series 1 compounds did not increase the intracellular concentration of cAMP on incubation with bloodstream form trypanosomes; those that did only induced a minor elevation of the intracellular concentration of the signalling molecule. Since genetic disruption to phosphodiesterase enzymes resulted in large increases in cAMP levels (Oberholzer, M. et al, 2007; Zoraghi, R. and Seebeck, T., 2002), the lack of increase in cAMP by the Series 1 compounds strongly suggest that they do not sufficiently inhibit the PDEs in live trypanosomes and kill the cells via an alternative pathway. In contrast, incubation with the GJS compounds did result in significant increases in intracellular cAMP concentration with the most active being GJS-128 recording an approximately 3-fold increase in cAMP over 3 hours at just 30 nM. The concentrations that begin to increase cAMP level are consistent with the EC50 values for trypanosomes cultured in vitro (this study), and is also in line with inhibition data of recombinant TbrPDEB enzymes (work conducted by Dr. Herrmann Tenor, ALTANA Pharma, and Prof. Thomas Seebeck, University of Bern). This gives a clear and consistent link between the cause of cAMP rise (inhibition of PDEB by GJS compounds) and the effect of that concentration increase on bloodstream form trypanosomes (cell death), demonstrating that the GJS series are inhibitors of trypanosomal PDEs and chemically validate PDEs as drug targets for potential new chemotherapies against African trypanosomiasis. The effect of PDE inhibition on the physiology of the bloodstream form trypanosomes was also investigated. Flow cytometry analysis and the assessment of DNA configuration by fluorescence microscopy after DAPI staining determined that PDE inhibition by GJS-128 resulted in a precise block of the cell cycle in cytokinesis. The replicating trypanosome synthesized and segregated its DNA into two nuclei and kinetoplasts as normal and proceeded to initiate the physical separation of mother and daughter cells. The cleavage furrow between the old and new flagella progressed normally until the point of abscission, at which point division was halted with only a small section of plasma membrane connecting the two almost separated cells. Both cells appeared viable and underwent subsequent rounds of DNA replication, segregation and attempted physical separation that was always blocked near completion. This indicates cAMP signalling plays an important role in the correct physical separation of the replicating bloodstream form trypanosomes. A trypanosome cell line resistant to GJS-128 was developed by chemical mutagenesis and continuous culture with gradually increasing, but sub-lethal concentrations of the PDE inhibitor. This cell line, termed R0.8, was >15-fold less sensitive to GJS-128 and displayed significant cross-resistance to the other GJS compounds, as well as to stable, membrane permeable cAMP analogues. The mode of resistance was investigated by comparing the cAMP profile of the R0.8 and parental wildtype strains on incubation with GJS-128. No major differences were observed suggesting that both the adenylyl cyclase and phosphodiesterase activities remained unchanged in the PDE inhibitor-resistant strain. In support of this, the sequencing of TbrPDEB1 and TbrPDEB2 in both strains, while uncovering the loss of heterozygosity in the R0.8 line, revealed no mutations that would impact on enzyme function or inhibitor binding in the resistant cell line. These data strongly suggest that the adaptation resulting in resistance to PDE inhibitors is located in the effector proteins downstream of the PDEs and adenylyl cyclases in the cAMP signalling pathway. Identifying a compound that inhibits phosphodiesterases in trypanosomes and elevates cAMP concentrations, along with the generation of a PDE inhibitor-resistant cell line will allow more detailed examination of all aspects of the cAMP signalling pathway in T. brucei and across the Kinetoplastida. Phosphodiesterases have also been demonstrated to be chemically inhibitable in trypanosomes and could prove to be the target of a new generation of chemotherapies against African trypanosomiasis.
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Score, Claire Marie. "The synthesis of cantharidin anologues as potential protein phosphatase inhibitors." Thesis, Institute of Cancer Research (University Of London), 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.509786.
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Wiggins, Karen. "Synthesis of potential phospholipase Aâ†2 inhibitors, based on manoalide." Thesis, University of East Anglia, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.329412.
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Butler, Paul Ian. "The synthesis and evaluation of potential inhibitors of 5-lipoxygenase." Thesis, University of Reading, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.357783.
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