Os aminoglicosídeos são antibióticos utilizados para o tratamento de muitas infecções bacterianas graves. A maioria é produzida por microorganismos (gêneros Streptomyces e Actinomyces), mas a semi-síntese resultam na descoberta de notáveis aminoglicosídeos. Apesar de seu mecanismo de ação seletivo, os aminoglicosídeos são extremamente tóxicos. A nefrotoxicidade e ototoxicidade são mais freqüentemente observadas. Sabe-se que a Doença de Ménière pode ser tratada através da destruição seletiva das células vestibulares, preservando-se as células cocleares (tecidos da orelha interna). Antibióticos aminoglicosídeos são usados para esta finalidade, mas podem paralelamente causar danos cocleares (surdez). O estudo de relação estrutura-toxicidade dos resíduos de fragmentação de antibióticos aminoglicosídeos pode originar produtos simplificados, com atividade vestibular seletiva, dissociada da atividade coclear, mais seguros para o tratamento da Doença de Ménière. Em trabalhos anteriores, os ensaios envolvendo 2-desoxi-estreptamina e estreptidina demonstraram que não são tóxicos ao tecido coclear, quando comparados com os compostos originais. Neamina, outro fragmento de neomicina, se mostrou mais tóxica ao vestíbulo que a própria neomicina, mas aprensentou também grande toxicidade coclear. A substituição da unidade diamino-glicosídica de neamina, contendo o grupo 2-desoxi-estreptamina, por outras unidades glicosídicas (glicose, galactose, glicosamina) representa uma tentativa de eliminar a atividade cocleotóxica e manter a atividade vestibulotóxica original (100%). A mesma idéia pode ser também aplicada ao resíduo de estreptidina. Desta forma, foram sintetizados, dois pseudos-dissacarídeos, 2-desoxi-estreptamina ligado a galactose (48) e 2-desoxi-estreptamina ligado a glicose (49), ambas as ligações em posição referente ao carbono glicosídico anomérico. Apenas o pseudo-dissacarídeo 2-desoxi-estreptamina ligado a galactose (48) foi obtido com massa suficiente para analise ototóxica, o qual apresentou atividade vestibular seletiva como desejado, no tratamento da doença de Ménière. Ensaios de atividade antimicrobiana foram realizados empregando ambos pseudos-dissacarídeos sintetizados, 2-desoxi-estreptamina ligada a galactose (48) e 2-desoxi-estreptamina ligada a glicose (49), porém não apresentaram uma concentração inibitória mínima (MIC) significativa para as cepas testadas. / Aminoglycosides are antibiotics used for the treatment of many serious bacterial infections. Most are produced by microorganisms (genera Streptomyces and Actinomyces), but products obtained by semi-synthesis resulted in the discovery of remarkable aminoglycosides. Despite their selective mechanism of action, the aminoglycosides are highly toxic. The nephrotoxicity and ototoxicity are more frequently observed. It is known that Ménière\'s disease can be treated by selective destruction of the vestibular cells, preserving the cells cochlear (inner ear tissues). Aminoglycoside antibiotics are used for this purpose but may cause cochlear damage (deafness). The study of structure-toxicity of residues fragmentation of aminoglycoside antibiotics may lead to simplified products, with selective vestibular activity, dissociated from the cochlear activity, safer for the treatment of Ménière\'s disease. In previous work, the experiments involving 2-deoxy-streptamine and streptidine demonstrated that they are not toxic to the cochlear tissue, when compared with the original compound. Neamina, another fragment of neomycin, was more toxic to the vestibular tissue than neomycin, but also presented great cochlear toxicity. The replacement of the diamino-glycoside unit of neamina containing the 2-deoxy-streptamine by other glycosidic units (glucose, galactose, glucosamine) is an attempt to eliminate the cochlear toxicity and maintain the original vestibular toxicity (100%). The same idea can also be applied to the streptidine residue. Thus, two pseudo-disaccharides, 2-deoxy-streptamine linked to galactose (48) and 2-deoxy-streptamine linked to glucose (49), both linked to the position on the glycoside anomeric carbon. Only the pseudo-disaccharide 2-deoxy-streptamine linked to galactose (48) was obtained in sufficient quantity to perform the ototoxic assay, which presented selective vestibular activity as desired in the treatment of Ménière\'s disease. Antimicrobial activity assays were performed with both pseudo-disaccharides synthesized 2-deoxy-streptamine linked to galactose (48) and 2-deoxy- streptamine linked to glucose (49), but did not show a minimum inhibitory concentration (MIC) significant against the strains tested.

Carbohydrates are a family of polyfunctional natural products and can be chemically modified in numerous ways. The primary significance of carbohydrates rests in their importance in biological functions. A particular class of sugars, namely, 2-deoxy or C-2 modified sugars has received a special attention, due to their importance in biological functions. These sugars are defined as carbohydrates carrying a hetero-atom, other than the hydroxyl group, and their derivatives. There is an ever-leading requirement to synthesize various carbohydrates-containing natural and un-natural products, such as, oligonucleotides, glycopeptides, antitumor drugs and cardiac glycosides, having C-2 modified sugars. Chapter 1 describes various synthetic modifications, particularly at the C-2 of a monosaccharide, as relevant to the work presented in this Thesis. 1, 2-Unsaturated glycopyranosides, namely, glycals, are versatile synthetic intermediates for the elaboration to a number of functionalized glycosyl derivatives. A major utility of the glycals is their conversion to the 2-deoxy glycosyl derivatives. In a programme, it was desired to identify a synthetic method to prepare 2-deoxy sugar derivatives that are endowed with an anomeric activation. In particular, a thioglycoside activation was desired. In the event, a methodology was identified, which allowed the synthesis of activated 2-deoxy-1-thioglycosides.The method involved reaction of a glycal with EtSH, in the presence of ceric ammonium nitrate (CAN) as the catalyst. The reaction was applicable to different epimeric glycals. Apart from the 2-deoxy-1-thioglycosides, formation of the 2, 3-unsaturated enoses, corresponding to the Ferrier product, also observed. Optimal conditions for the formation of the 2-deoxy-1-thioglycosides were identified (Scheme 1) and the reaction was proposed to proceed through a radical oxocarbenium ion and a thiolate intermediate. (Fig) Scheme1 Upon synthesis of 2-deoxy-1-thioglycosides, few glycosylation reactions with both aglycosyl and glycosyl acceptors were performed and the α-anomeric 2-deoxy glycosides were obtained exclusively. Chapter 2 summarizes synthesis, characterization of 2-deoxy-1-thioglycosides and their glycosyl donor properties towards several glycosyl acceptors. Many naturally-occurring antibiotic and antitumor drugs contain 2-deoxy glycosides as important structural components. For example, 2,6-dideoxy-hexopyranoses are common structural units of chromomycin A3, olivomycin A and mithramycin. The most common structural features of these molecules are: (i) the presence of 2-deoxy sugar residues and (ii) the sugar residues are connected to the aromatic moiety, through a β-glycosidic linkage. The synthesis of these biologically important 2-deoxy glycosides encounters difficulties, due to the absence of stereoelectronic influences at C-2 of the 2-deoxy glycosyl derivatives. Direct glycosylation of phenols and naphthols with activated 2-deoxy-1-thio-glycosides, in the presence of the thiophilic activator N-iodosuccinimide/triflic acid (NIS/TfOH), lead to the formation of the α-anomer, as the major glycosylated product (Scheme 2). (Fig) An effort was under taken to identify methods to prepare the 2-deoxy aryl glycosides, in the β-anomeric configuration. A nucleophilic substitution reaction was anticipated to lead to the formation of β-anomeric glycosides. A halide substitution at C-1 for an effective nucleophilic substitution was adopted. Thus, conversion of the activated 2-deoxy-1-thioglycosides with Br2 in the first step, followed by reaction of the resulting bromide with aryloxy anions, led to the facile conversion to 2-deoxy glycosides in a nearly quantitative f-anomeric configuration at C-1(Scheme 3). Scheme 3 (Fig) Chapter 3 presents details of the methodologies that allow a facile preparation of each of the anomers of aryl 2-deoxy-D-glycosides from a common precursor, namely, 2-deoxy-1-thio-glycosides. An easy access to activated 2-deoxy-1-thioglycosides from the 1, 2-unsaturated sugar and their synthetic utility towards various glycosyl and aglycosyl acceptors led towards synthesis of 2-deoxy disaccharides. Synthesis of six new 2-deoxy-arabino-hexopyranosyl and 2-deoxy-lyxo-hexopyranosyl sugar containing disaccharides were accomplished. These are: (i) 2-deoxy-α-D-arabino-hexopyranosyl-(1→4)-D-glucopyranose (2'-deoxy maltose); (ii) 2-deoxy-α-D-lyxo-hexopyranosyl-(1→4)-D-glucopyranose; (iii) 2-deoxy-α-D-arabino-hexopyranosyl-(1→4)-2-deoxy-D-arabino-hexopyranose (2,2'-dideoxy maltose); (iv) 2-deoxy-α-D-lyxo- hexopyranosyl-(1→4)-2-deoxy-D-arabino-hexopyranose; (v) α-D-glucopyranosyl-(1→4)-2 deoxy-D-arabino-hexopyranose (2-deoxy maltose) and (vi) β-D-galactopyranosyl-(1→4)- deoxy-D-arabino-hexopyranoside (2-deoxy lactose). The 2'-deoxy and 2, 2'-dideoxydisaccharides were synthesized using a 2-deoxy glycosyl donor and a normal glycosyl acceptor (in case of 2'-deoxy disaccharides) and a 2-deoxy glycosyl acceptor (in case of 2, 2'-dideoxy disaccharides) with a free OH group at C-4, while the remaining hydroxyl groups protected suitably (Scheme 4). Scheme 4 (Fig) On the other hand, the syntheses of 2-deoxy disaccharides were initiated from a D-maltose and D-lactose, respectively. The conversion of these disaccharides to a disaccharide glycals was targeted first and conversion of these glycals to a 2-deoxy-1-thioglycosides or a 2-deoxy-1-acetates, followed by a hydrolysis of the thiol moiety or the acetate group, afforded the 2-deoxy disaccharides (Scheme 5). (Fig) Chapter 4 describes synthesis, characterization of 2-deoxy, 2,2'-dideoxy and 2'-deoxy disaccharides. Continuing the efforts to establish the utility of 2-deoxy-1-thioglycosides as potential glycosyl donor, synthesis of 2-deoxy cyclic and linear oligosaccharides was undertaken. Prominent among cyclic oligosaccharides are the cyclodextrins. Due to their unique structural and physical properties, cyclodextrins find manifold applications. Known methods to synthesize cyclic oligosaccharides are (i) the cyclization of linear oligosaccharides to produce the cyclic oligosaccharides and (ii) the synthesis of designed monomers and subjecting them to cyclooligomerization protocols. The cyclooligomerization was adopted to synthesize new types of 2-deoxy cyclic-and linear oligosaccharides. After a series of trials, a disaccharide monomer, namely, ethyl 4-O-(6-O-benzoyl-2,3-di-O-methyl-α-D-glucopyranosyl)-2-deoxy-3,6-di-O-methyl-arabino-hexopyranoside (1), was identified as a suitable monomer for thecyclooligomerization protocol. For an effective oligomerization, the concentration of the monomer and the choice of the reagents are important. The reaction was conducted at three different monomer concentrations, 2 mM, 10 mM and 25 mM, using two thiophilic activators, namely, (i) NIS/TfOH and (ii) NIS/AgOTf. Better yields of the cyclic oligosaccharides, namely, the cyclic tetrasaccharide (2) (40 %) and cyclic hexasaccharide (3) (25 %), were isolated when the monomer (1) concentration was 25 mM and NIS/TfOH acid was used as the promoter (Scheme 6). The formation of linear disaccharide (4) (10 %) and tetrasaccharide (5) (18 %) was also observed at this concentration. On the other hand, when the reaction of the monomer was performed in the presence of NIS/AgOTf, the oligomerization reaction led to the formation of linear oligosaccharides, consisting of di-to eicosa-saccharides. Synthesis of different monomers, their characterization and oligomerization reaction using these monomers through a polycondensation protocol are discussed in Chapter 5. Scheme 6(fig) In summary, the Thesis establishes the chemistry of 2-deoxy sugars, formation of activated 2-deoxy sugars, formation of alkyl and aryl glycosides, 2-deoxy disaccharides, 2-deoxy cyclic and linear oligosaccharides. Routine physical methods were used to characterize the newly formed 2-deoxy sugars and the oligosaccharides. Single crystal X-ray structural determination was performed for an aryl 2-deoxyglycosides, which provided the solid state configurational features of the 2-deoxy pyranose. (For structural formula pl see the pdf file)

Bien que le rôle actif des sucres soit connu dans la stabilisation des membranes cellulaires lors de fortes déshydratations, il s'avère que les processus à l'origine de cette protection ne sont pas encore bien compris. Néanmoins, la très grande affinité de l'eau pour le sucre, comme en témoigne la formation de très nombreuses liaisons hydrogène, est semble-t-il responsable en partie de cette propriété exceptionnelle. L'étude expérimentale de la dynamique des molécules de sucre et d'eau permettra ainsi de quantifier l'importance de ces interactions. <br /> Dans ce travail, nous nous sommes principalement intéressés à des solutions de mono- et disaccharides (glucose, fructose et tréhalose). La diffusion quasi-élastique des neutrons a permis de mesurer, à l'échelle de la picoseconde, la dynamique de l'eau et du sucre en solution et sous confinement dans des matériaux poreux présentant un mimétisme d'échelle avec le vivant. Les deux matrices sélectionnées, c'est-à-dire un gel de silice aqueux et des nanosphères de silice mésoporeuse de type MCM-41, qui présentent des diamètres de pores de 18 et 3 nm respectivement, ont été caractérisées grâce à un large panel de techniques expérimentales (SANS, MET, MEB, Spectroscopie Raman, BET, DRX). L'effet du confinement sur la dynamique et sur les transitions de phase solide-liquide a ainsi pu être exploré, ainsi que l'effet protecteur des sucres grâce à une étude de déshydratation in-situ suivie par diffusion des neutrons aux petits angles.

No / Mono- and disaccharide-functionalised conjugates of the fluoroquinolone antibiotic ciprofloxacin have been synthesised and used as chemical probes of the bacterial uptake of glycosylated ciprofloxacin. Their antimicrobial activities against a panel of clinically relevant bacteria were determined: the ability of these conjugates to inhibit their target DNA gyrase and to be transported into the bacteria was assessed by using in vivo and in vitro assays. The data suggest a lack of active uptake through sugar transporters and that although the addition of monosaccharides is compatible with the inhibition of DNA gyrase, the addition of a disaccharide results in a significant decrease in antimicrobial activity.

Infectious diseases remain a threat to critically ill patients, particularly with the rise of antibiotic-resistant bacteria. Septic shock carries a mortality of up to ∼40% with no compelling evidence of promising therapy to reduce morbidity or mortality. Septic shock survivors are also prone to nosocomial infections. Treatment with toll-like receptor 4 (TLR4) agonists have demonstrated significant protection against common nosocomial pathogens in various clinically relevant models of infection and septic shock. TLR4 agonists are derived from a bacteria cell wall or synthesized de novo, and more recently novel small molecule TLR4 agonists have also been developed. TLR4 agonists augment innate immune functions including expansion and recruitment of innate leukocytes to the site of infection. Recent studies demonstrate TLR4-induced leukocyte metabolic reprogramming of cellular metabolism to improve antimicrobial function. Metabolic changes include sustained augmentation of macrophage glycolysis, mitochondrial function, and tricarboxylic acid cycle flux. These findings set the stage for the use of TLR4 agonists as standalone therapeutic agents or antimicrobial adjuncts in patient populations vulnerable to nosocomial infections.