1,720,980 research outputs found
Stereoselective synthesis 2-C-alkylglucosides, potential inhibitors of mycobacterial MshB and related enzymes
No full textIncludes bibliographical references (leaves 69-72).Tuberculosis (TB) is one of the world's most deadly diseases and kills approximately 1.7 million people each year. The developing resistance of TB to the two most common anti-TB drugs (isoniazid and rifampicin) proves the urgency of the current situation. The MshB reducing agent exclusively in the actinomycetes is used as a model for the development of new anti-TB drugs. It was shown that the stereoselectivity synthesis of C-2 alkyl glucoside gave a key intermediate for the suitable synthesis of glycosyl donors. In addition, we achieved the preparation of D-inositol derivative chirally pure and having the hydroxyl at the 1-position. However, the attempted glycosylation reaction failed to give the desired product
Synthesis of side-chain-modified mycothiol analogues incorporating carbazole quinones, and evaluation as inhibitors of enzymes in the Mycobacteria
No full textMycothiol is found only in Actinobacteria including M. tuberculosis, and appears to play an important role in the bacterium's defence against xenobiotics and oxidative stress. The biosynthetic pathway to this pseudo-disaccharide has been elucidated and a range of mycothiol-dependent enzymes have been identified. Compounds A.3, which have naphthoquinonyl units tethered to the pseudodisaccharide core, have significant inhibitory activity against mshB and mca in the biosynthetic pathway. These findings, together with the independent discovery of anti-TB activity associated with carbazole quinones such as B, led to the design and synthesis of a new class of hybrid molecules C which have the carbazole quinone motif tethered to the pseudodisaccharide core. The synthesis of these hybrid molecules involved initial preparation of phenylthio- or methyl-glucosides having either an amine or a suitably-functionalized carbon side-chain at C-2. Carbazole-quinones 37 and 39, bearing carboxyalkyl substituents, were prepared using Knölker methodology, and coupled to phenylthio-2-amino-glucoside 36 to generate, after deprotection, the desired hybrid structures 38 and 40. The preferred strategy for preparing 2-C-alkylglucosides was via initial preparation of a 2-C-carboxymethyl glucoside 44 from D-glucal, and conversion of this to the Weinreb amide 45 for intended coupling with Grignard and other organometallic reagents to form ketones. The Weinreb amide was shown to only react with simple metal-aryl reagents, and but not with those derived from the required tri-substituted benzenes. In the exploration of alternative strategies, the side-chain in 44 was successfully converted to either a 2-C-vinyl or the corresponding (E)-vinyl bromide side-chain, but both proved unreactive in attempts at Pd-mediated cross-coupling reactions to further develop the side-chain. Compound 44 could also be readily converted to either a 2-C-haloethyl or 2-C-aminoethyl derivative: the former resisted conversion to Wittig reagents, while the latter was unreactive in attempted Buchwald-Hartwig amination but successfully underwent reductive amination with a substituted benzaldehyde to give an advanced Abstract precursor of the target hybrid molecules. Compounds 38 and 40 together with similar analogues prepared in parallel with this study showed significant inhibitory activity against mshB, allowing for a preliminary SAR conclusion that the inhibitory activity is dependent on the covalent association of the glycoside and the carbazole-quinone, the point of attachment of the sugar unit to the carbazole quinone, and the length of the tether
Development of new methodologies for functionalizing glycals and 1,2-cyclopropanated sugars, and applications in the synthesis of inhibitors of enzymes in the Mycobacteria
No full textIncludes bibliographical references (p. 177-186).Tuberculosis (TB) is a contagious respiratory disease caused by Mycobacterium tuberculosis. Due to lack of an efficient and short-term treatment of TB, the bacterium has become resistant to the first line antibiotics and the disease has ranked next to HIV/AIDS. A low molecular weight thiol called myctothiol protects the bacteria from many foreign stress factors and secures its survival. Studies have shown the mycothiol-deficient bacteria are hypersensitive to external stresses and hence inhibition of the biosynthesis of mycothiol could be a drug lead against TB
The development of S-glycosylcysteine derivatives for use in glycan-binding assays
Full text linkThis dissertation concerns the development of a synthetic route towards novel cysteine-based glycan-binding probes, for incorporation into glycoarrays and or similar applications used in assays of glycan-recognition phenomena. The need to systematically characterize the glycome and decipher the range of glycosylation patterns found in living cells, has prompted the development of molecular tools such as glycoarrays and related systems for immobilizing defined carbohydrate structures. The preparation of these probes requires access to building blocks where the core structure has defined glycans together with appropriate linkers, and the amino acid cysteine is explored here as one such structure. In particular, this dissertation describes the synthesis of a S-glucosylcysteine derivative SGC, or methyl N-(6-aminohexanoyl)-S-(β-D-glucopyranosyl)-L-cysteinate trifluoroacetate 67, as well as its 2-acetamido analogue SAGC, or methyl N-(6-aminohexanoyl)-S-(2-acetamido-2-deoxy-β-D-glucopyranosyl)-L-cysteinate trifluoroacetate 74. The first approach involved initial preparation of N-(4-azidobutanoyl)-L-cysteine 12 and attempted reaction of this with 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose 3 to form the initial target of this dissertation, bis-glucoside 13. This was not successful, but repetition of the reported reaction involving the use of N-acetyl-L-cysteine 4 provided a modest yield of partially purified bis-glucosyl cysteine (BGC, 1). A mechanism for this one-pot, sequential bis-glucosylation is proposed. The limitations of the one-pot procedure led to investigation of alternative methods for the step-wise introduction of sugar units to the cysteine core. For this purpose the cysteine derivative, methyl N-(6-((tert-butoxycarbonyl)amino)hexanoyl)-L-cysteinate 40, was prepared and reacted with 3 to obtain a fully protected precursor of the target SGC. However, inefficiencies in this procedure led to investigation of an alternative strategy for preparation of SGC
New synthetic routes to functionalized 2-C-alkylglucosides, precursors of potential inhibitors of mycothiol biosynthesis in the Mycobacteria
No full textThis thesis was concerned with the design and synthesis of compounds which are either substrate-mimics or inhibitors of MshB, a N-deacetylase involved in the biosynthesis of mycothiol in the Mycobacteria, including M. tuberculosis, the causative agent of TB. Mycothiol is a low molecular weight thiol produced by Mycobacteria as a defense against oxidative stress and xenobiotics, and the enzymes involved in its biosynthesis are postulated to be viable drug targets
Synthesis of analogues of mycothiol as possible inhibitors of enzymes in the biosynthesis of mycothiol
No full textBibliography: leaves 175-182.Mycobacterium tuberculosis is the causative agent of tuberculosis and is a leading pathogenic cause of death worldwide. The rise of mycobacterial resistance to common antituberculars such as isoniazid and rifampicin, along with the lethal alliance of HIV and M. tuberculosis co-infection, has led to interest in developing novel, effective, non-toxic antituberculosis agents
Towards the total synthesis of novenamine and its analogues with modifications at C-4 and C-5
No full textIncludes bibliographical references.Novenamine, a known antibacterial agent, is composed of 3-0-carbamoyl noviose (novobiose) glycosidically linked to a 4-hydroxy-3-amino-coumarin unit. Its activity as a DNA-gyrase inhibitor and the absence of analogues containing 4-epi-noviose provided the rationale for developing new synthetic routes to these analogues. This thesis describes the total synthesis of the methyl glycosides of noviose and C-4-epi-noviose, methodology for the introduction of the C-3 carbamoyl group to both isomers, an alternative synthesis of the coumarin component, progress towards a C-5 analogue of 4-epi-noviose and a model study of methodology for the glycosidic coupling of the coumarin unit to suitably activated sugars
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Progress in the synthesis of stabilized glycoconjugate vaccine candidates against Neisseria meningitides group A
No full textIncludes bibliographical references.Meningitis is the inflammation of the lining membranes of human brains and spinal cord. It is a deadly disease that has claimed millions of lives throughout the world in particular in developing countries. Neisseria meningitidis serogroup A is among the leading causative agents of meningitis in Sub-Saharan Africa. Its capsular polysaccharide antigen consists of a homopolymer of a-(
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