No presente trabalho foram desenvolvidas duas rotas sintéticas: uma para a preparação de uma série de seleno-carboidratos quirais, derivados da D-xilose e D-galactose, e outra aplicada à obtenção de glicoconjugados e dissacarídeos, onde as duas unidades básicas encontram-se ligadas por um átomo de selênio. Através de estratégias sintéticas simples e eficientes, obteve-se uma série de compostos heterocíclicos com elevado potencial para aplicação biológica. Para a síntese dos derivados xilofuranosídeos, a D-xilose 1 foi inicialmente convertida no diol 3, passando por um intermediário bis-acetonídeo 2. Tosilação seletiva da hidroxila primária, seguida da reação com nucleófilos de selênio resultou na síntese dos seleno-carboidratos 5a-j. Adicionalmente, o composto 5a foi convertido no derivado metilglicosilado 6, mediante desproteção do acetonídeo e reação com metanol em meio ácido. A reação do tosilato 4 com Li2Se2 e Li2Se resultou na formação do disseleneto 7 e do seleneto 8. Posteriormente, uma série de seleno-carboidratos funcionalizados foi preparada pela clivagem redutiva de 7 e reação do selenolato formado com eletrófilos selecionados. A expansão do escopo do trabalho para síntese de derivados galactopiranosídeos contendo selênio seguiu estratégia à anterior. Assim, a D-galactose 12 foi convertida ao bis-acetonídeo e em seguida, a hidroxila primária foi convertida no correspondente tosilato 13 e mesilato 14. Foi utilizado o mesilato 14 para fornecer os seleno-carboidratos 15a-e e 16. Ainda, o disseleneto 17 foi preparado a partir do tosilato 13, e quando clivado com NaBH4, o selenolato gerado reagiu com eletrófilos selecionados, levando a seleno-piranosídeos funcionalizados. Entre os compostos preparados, o disseleneto 7 reduziu significativamente a atividade in vitro da enzima δ-aminolevulinato desidratase, enquanto o fenilseleneto 5a levou à aumento da atividade enzimática, o que aponta para uma atividade antioxidante promissora. Na segunda parte do trabalho, a reatividade dos seleno-carboidratos foi explorada na síntese de glicoconjugados 22 a partir da abertura regiosseletiva de N-Boc aziridinas quirais 23 (A). Numa segunda estratégia utilizou-se β-amino-disselenetos 24 como fonte de selenolato que reagiu com o tosilato 4 com menor eficiência (B). Adicionalmente, foi desenvolvida uma estratégia para a síntese de dissacarídeos conectados por um átomo de selênio, mediante reação de um selenolato glicosídico com outra unidade glicosídica adequadamente funcionalizada. / In the present work two different synthetic routes for the synthesis of seleno-carbohydrates were developed starting from the readily available carbohydrates D-xylose and D-galactose. Furthermore, we developed a strategy for the synthesis of glycoconjugates and disaccharides, with the two basic units linked by a selenium atom. Through simple and efficient synthetic strategies, we obtained a series of heterocyclic compounds with high potential for biological application. For the synthesis of xilofuranosides derivatives, D-xylose 1 was initially converted into diol 3, through an intermediate bis-acetonide 2. Selective tosylation of the primary hydroxyl, followed by reaction with selenium nucleophiles resulted in the synthesis of seleno-carbohydrate 5a-j. Additionally, the compound 5a was converted into methylglycosyl derivatived 6 by deprotection of the acetonide and reaction with methanol in acidic medium. The reaction of tosylate 4 with Li2Se2 and Li2Se resulted in the formation of the diselenide and selenide 7 and 8. Subsequently, a series of functionalized seleno-carbohydrates were prepared by reductive cleavage of 7 and reaction of the resulting selenide anion with selected electrophiles. In order to expand the scope of the work, the synthesis of galacto-pyranosides containing selenium was pursued, according to the previous strategy. Thus, D-galactose 12 was converted to bis-acetonide and then the primary hydroxyl was converted into the corresponding tosylate and mesylate 13 and 14. Mesylate 14 was used to provide the seleno-carbohydrate 15a-e and 16. Moreover, the diselenide 17 was prepared from tosylate 13, and when cleaved with NaBH4, the resulting selenide anion was trapped with selected electrophiles, leading to functionalized seleno-pyranosides. Among the compounds prepared, the diselenide 7 significantly reduced the in vitro activity of the enzyme δ-aminolevulinate dehydratase, while the phenylselenide 5a increased enzyme activity, which points to a promising antioxidant activity. In the second part of the work, the reactivity of seleno-carbohydrates has been exploited in the synthesis of glycoconjugates 22 from the regioselective opening of chiral N-Boc aziridines 23 (A). In a second strategy β-amino-diselenides 24 were used as a source of the selenium nucleophile, reacting with tosylate 4 with lower efficiency (B). Additionally, we developed a strategy for the synthesis of disaccharides linked by a selenium atom by a reaction glycosylselenolate with another functionalized glycosyl unit.

In conclusion, the studies reported in this thesis suggested that the CHO amount, whether provided by a pre-exercise CHO meal or short-time, i.e., 3-day, CHO loading, plays a pivotal role in regulating the immune responses before, during, and after endurance exercise. Although GI and GL independently affect the exercise performance and immune responses, the amount of CHO consumed remains a determining factor. The potential benefits on immune system and endurance performance after the low GI and low GL diet (L-L) should be noted and warrant further investigation. Although the HGI and LGI meals demonstrated similar effects on endurance performance when large amount of CHO-electrolyte solution consumed during the exercise, pre-exercise LGI meal can hasten the IL-6 responses during the recovery. (Abstract shortened by UMI.) / The aim of this thesis was to investigate the influence of pre-exercise carbohydrate (CHO) meal(s) with different glycemic index (GI) and glycemic load (GL) on endurance running performance, physiological, and immune responses. / The first study (Chapter 4) examined the influence of a pre-exercise meal with different GI and GL on subsequent endurance running performance, physiological, and immune responses. Eight endurance-trained male runners completed three trials in a randomized order, separated by at least seven days. These responses were characterized by a lower CHO oxidation with a concomitant higher glycerol and FFA in the H-L trial. Consumption of a pre-exercise high CHO meal, i.e., H-H and L-L, resulted in less perturbation of circulating numbers of leukocytes, neutrophils, and T lymphocyte subsets, decreased elevation of plasma IL-6 concentrations immediately after exercise and during the 2 h recovery period when compared to the H-L trial. These responses were accompanied by an attenuated increase in plasma IL-10 concentrations and plasma cortisol concentrations at the end of 2 h recovery. It was concluded that the amount of CHO consumed 2 h before endurance exercise appears to be the main influencing factor on immune responses irrespective of its GI and GL value. / The second study (Chapter 5) examined the influence of a 3-day CHO loading with different GI and GL meals on the supercompensation status, running performance, physiological and immune responses. Nine endurance-trained male runners were recruited in this study. The procedures basically involved a 3-day CHO loading with different GI and GL meal [CHO intake (% of energy intake), GI, and GL per day are 73%, 80, and 553 for the high-GI and high-GL (H-H); 73%, 42, and 249 for the low-GI and low-GL (L-L); 31%, 78.5, and 227 for the high-GI and low-GL (H-L) respectively] after a glycogen-lowering exercise. Two hours after the breakfast on day 4, participants performed the running protocol as described in the first study. There was no difference in time to complete the 10-km TT between the two trials with high-CHO loading, i.e., H-H and L-L (51.3 +/- 5.3 min vs 48.6 +/- 1.3 min, NS). These results suggested that 3-day CHO loading with low GI and low GL (L-L) is more effective in improving endurance performance when compared to a high GI but low GL diet (H-L). It appears that the amount of CHO consumed during the 3-day CHO loading remains the key influencing factor on immune responses despite of the differences in the GI and GL value. / The third study (Chapter 6) investigated the influence of pre-exercise meal with different GI on subsequent endurance running performance and immune responses when CHO-electrolyte solution was consumed during exercise. Pre-exercise LGI meal attenuated the increases of cortisol when compared with CON and hastened the recovery of the IL-6 value to baseline when compared to that in HGI and CON trials during the first hour of the recovery. The results suggested that beside of CHO quantity (CHO content), the role of CHO quality (GI) in the diet consumed 2 h before exercise should be considered when investigating the influence of CHO supplementation on the exercise-induced transitory immunosuppressive effects. / Chen Yajun. / "August 2006." / Adviser: Stephen Wong Heung-Sang. / Source: Dissertation Abstracts International, Volume: 68-03, Section: B, page: 1597. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2006. / Includes bibliographical references (p. 199-225). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.

The overwhelming occurrence and structural diversity of carbohydrates in Nature indicate their importance in a range of fundamental life processes. Indeed, it is this diversity that has lead to the two equally diverse groups of carbohydrate-processing enzymes, namely the glycoside hydrolases and glycosyl transferases. Thus, understanding the role of both carbohydrates and their processing enzymes in biological systems has attracted significant attention. This thesis, firstly, describes endeavours towards the synthesis of an inositol ?- amino acid, along with a series of sugar α-substituted carboxylic acid esters, utilising an extension of the modified Corey-Link reaction. The emphasis of the thesis is then shifted towards the synthesis of a putative inhibitor of a family GH26 lichenase from Clostridium thermocellum (CtLic26A). The preparation of 2-deoxy-2-fluoro-β-laminarbiosyl fluoride 1 is described, along with elaboration into oligosaccharides utilising AbgE358G glycosynthase technology. Crystallographic investigations indicated that the transition state adopted by CtLic26A is in stark contrast to that utilised by the related family GH26 mannanase from Pseudomonas cellulose (Man26A). ... Following on from this work, expanding the role of the AbgE358G glycosynthase acceptor repertoire to accommodate inositol substrates was explored, furthering the synthetic utility of this enzyme. Thus, a number of inositol acceptors bearing an aryl anchor, for example 2, were prepared and shown to be surrogates for carbohydrate acceptors. ... The thesis then describes the synthesis of an acetamide derivative of 1-epivalienamine, namely 3, a putative inhibitor of β-N-acetylglucosaminidases. Both the synthesis of 3, along with kinetic data for four β-N-acetylglucosaminidases, is reported; as well, Western blot analysis indicated no inhibition of a recombinant OGTase. ... Related to the preparation of a putative inhibitor of β-N-acetylglucosaminidases was the synthesis of a conformationally rigid carbocycle derivative of PUGNAc 4, along with two other derivatives 5 and 6. These compounds were also tested against four β-N-acetylglucosaminidases and a recombinant OGTase. ... Finally, the synthesis of a mechanism-based inhibitor of family GH3 β-Nacetylglucosaminidases, namely 2-acetamido-2-deoxy-5-fluoro-β-D-glucopyranosyl fluoride 7, is described. The incorporation of an azido moiety allows for the utilisation of 8 as an effective probe of β-N-acetylglucosaminidases. ...

No presente trabalho foram desenvolvidas duas rotas sintéticas: uma para a preparação de uma série de seleno-carboidratos quirais, derivados da D-xilose e D-galactose, e outra aplicada à obtenção de glicoconjugados e dissacarídeos, onde as duas unidades básicas encontram-se ligadas por um átomo de selênio. Através de estratégias sintéticas simples e eficientes, obteve-se uma série de compostos heterocíclicos com elevado potencial para aplicação biológica. Para a síntese dos derivados xilofuranosídeos, a D-xilose 1 foi inicialmente convertida no diol 3, passando por um intermediário bis-acetonídeo 2. Tosilação seletiva da hidroxila primária, seguida da reação com nucleófilos de selênio resultou na síntese dos seleno-carboidratos 5a-j. Adicionalmente, o composto 5a foi convertido no derivado metilglicosilado 6, mediante desproteção do acetonídeo e reação com metanol em meio ácido. A reação do tosilato 4 com Li2Se2 e Li2Se resultou na formação do disseleneto 7 e do seleneto 8. Posteriormente, uma série de seleno-carboidratos funcionalizados foi preparada pela clivagem redutiva de 7 e reação do selenolato formado com eletrófilos selecionados. A expansão do escopo do trabalho para síntese de derivados galactopiranosídeos contendo selênio seguiu estratégia à anterior. Assim, a D-galactose 12 foi convertida ao bis-acetonídeo e em seguida, a hidroxila primária foi convertida no correspondente tosilato 13 e mesilato 14. Foi utilizado o mesilato 14 para fornecer os seleno-carboidratos 15a-e e 16. Ainda, o disseleneto 17 foi preparado a partir do tosilato 13, e quando clivado com NaBH4, o selenolato gerado reagiu com eletrófilos selecionados, levando a seleno-piranosídeos funcionalizados. Entre os compostos preparados, o disseleneto 7 reduziu significativamente a atividade in vitro da enzima δ-aminolevulinato desidratase, enquanto o fenilseleneto 5a levou à aumento da atividade enzimática, o que aponta para uma atividade antioxidante promissora. Na segunda parte do trabalho, a reatividade dos seleno-carboidratos foi explorada na síntese de glicoconjugados 22 a partir da abertura regiosseletiva de N-Boc aziridinas quirais 23 (A). Numa segunda estratégia utilizou-se β-amino-disselenetos 24 como fonte de selenolato que reagiu com o tosilato 4 com menor eficiência (B). Adicionalmente, foi desenvolvida uma estratégia para a síntese de dissacarídeos conectados por um átomo de selênio, mediante reação de um selenolato glicosídico com outra unidade glicosídica adequadamente funcionalizada. / In the present work two different synthetic routes for the synthesis of seleno-carbohydrates were developed starting from the readily available carbohydrates D-xylose and D-galactose. Furthermore, we developed a strategy for the synthesis of glycoconjugates and disaccharides, with the two basic units linked by a selenium atom. Through simple and efficient synthetic strategies, we obtained a series of heterocyclic compounds with high potential for biological application. For the synthesis of xilofuranosides derivatives, D-xylose 1 was initially converted into diol 3, through an intermediate bis-acetonide 2. Selective tosylation of the primary hydroxyl, followed by reaction with selenium nucleophiles resulted in the synthesis of seleno-carbohydrate 5a-j. Additionally, the compound 5a was converted into methylglycosyl derivatived 6 by deprotection of the acetonide and reaction with methanol in acidic medium. The reaction of tosylate 4 with Li2Se2 and Li2Se resulted in the formation of the diselenide and selenide 7 and 8. Subsequently, a series of functionalized seleno-carbohydrates were prepared by reductive cleavage of 7 and reaction of the resulting selenide anion with selected electrophiles. In order to expand the scope of the work, the synthesis of galacto-pyranosides containing selenium was pursued, according to the previous strategy. Thus, D-galactose 12 was converted to bis-acetonide and then the primary hydroxyl was converted into the corresponding tosylate and mesylate 13 and 14. Mesylate 14 was used to provide the seleno-carbohydrate 15a-e and 16. Moreover, the diselenide 17 was prepared from tosylate 13, and when cleaved with NaBH4, the resulting selenide anion was trapped with selected electrophiles, leading to functionalized seleno-pyranosides. Among the compounds prepared, the diselenide 7 significantly reduced the in vitro activity of the enzyme δ-aminolevulinate dehydratase, while the phenylselenide 5a increased enzyme activity, which points to a promising antioxidant activity. In the second part of the work, the reactivity of seleno-carbohydrates has been exploited in the synthesis of glycoconjugates 22 from the regioselective opening of chiral N-Boc aziridines 23 (A). In a second strategy β-amino-diselenides 24 were used as a source of the selenium nucleophile, reacting with tosylate 4 with lower efficiency (B). Additionally, we developed a strategy for the synthesis of disaccharides linked by a selenium atom by a reaction glycosylselenolate with another functionalized glycosyl unit.

Seven-membered cyclic sugars, namely, septanoses and septanosides, are less commonly known sugar homologues. Synthesis of septanoses arise an interest due to their configurational and conformational features and the attendant possibilities to explore their chemical and biological properties. Septanosides derivatives, mostly, deoxy-septanosides were synthesized, by many synthetic methodologies, such as, Knoevengal condensation, ring-closing metathesis, Bayer-Villeger oxidation and ring-expansion of 1,2-cyclopropanted glycals as key steps. Apart from septanosyl monosaccharides, septanoside containing di- and tri-saccharides were also performed using glycosylation and ring expansions. Another area of sustained interest is the studies of the stabilities of glycosidic bonds. Acid- and enzyme-catalyzed hydrolysis of glycosidic bond were investigated intensely in the case of pyranosides and furanosides. The explanation of the hydrolysis of such stereomeric sugars were rationalized on the basis of stereoelectronic effects, such as, (i) antiperiplanarity; (ii) synperiplanarity of lone-pair of electrons involed in the hydrolysis process; (iii) steric effects; (iv) field and hyperconjugative effects; (v) conformational effects; (vi) disarming torsional effects and (vii) substituent effects. Chapter 1 of the thesis describes a survey of (i) synthesis of deoxy-septanosides and septanoside-containing di-and tri-saccharides and (ii) acid-catalyzed hydrolysis of glycopyranosides. In a programme, it was desired to identify a new methodology for the synthesis of 2-deoxy-2-C-septanosides. Synthesis of various septanosides from 2-hydroxy glycals, namely, oxyglycals, involves intermediates, such as, vinyl halide (III) and diketone (IV) (Scheme 1). These intermediates were identified as precursors for the synthesis of desired 2-deoxy-2-C-septanosides. Scheme 1 reactions, namely, Heck, Suzuki and Sonogashira reaction for the formation of hither-to unknown septanoside, branching out at C-2. Heck coupling and Suzuki coupling reaction of bromo-oxepine was performed using activated alkenes, acrylates and substituted boronic acid, respectively, in presence of Pd(OAc)2, to furnish 2-deoxy-2-C-alkyl/aryl septanoside derivatives (Scheme 2). Scheme 2 2-deoxy-2-C-alkynyl septanoside derivatives (Scheme 3). Scheme 3 BnO OOMe BnO OOMePd(PPh3)2Cl2,CuIBr BnO R BnO DMF:THF:Et3N(3:2:1)BnO OBn 98 oC, 72 h BnO OBn R=Ph,SiMe3,C6H13 One of the 2-deoxy-2-C-alkyl septanoside derivative was converted to the corresponding protecting-group free 2-deoxy-2-C-alkyl septanoside, using hydrogenolysis (Pd/C, H2) and NaBH4-mediated reduction. Chapter 2 presents details of the synthesis of 2-deoxy-2-C-alkyl/aryl/alkynyl septanoside derivatives from a bromo-oxepine. Continuing the efforts to extend the ring-opening of oxyglycal derived gem-dihalo-1,2¬cyclopropanted sugar, a Lewis acid-catalyzed ring-opening was considered important. The presence of an additional substituent in C-2 of oxyglycal switches reactivity as compared to glycals. For example, ring-opening of glycal derived gem-dihalo-1,2-cyclopropane generates 2-C-branched pyranoside, whereas corresponding oxyglycal generates oxepines even when both the reactions were performed under a mild basic condition, illustrating a sufficient reactivity difference between a glycal and an oxyglycal. Thus, ring-opening reaction of gem-dichloro-1,2-cyclopropanted oxyglycal in the presence of a Lewis acid, hither-to unknown, was examined. In this event, it was found that ring-opening reaction led to chloro-oxepine derivatives in the presence of AgOAc, using alcohol as nucleophiles. Primary, secondary, unsaturated and aromatic alcohols were used in the ring-opening reaction. The ring-opening reaction was stereoselective and only α-anomer was obtained in a good yield in each case (Scheme 5). The counter-anion also reacted in an instance, so as to furnish O-acetyl chloro-oxepine during the ring-opening reaction. Scheme 5 The course of the reaction in the absence of alcohol led to afford only the O-acetyl chloro-oxepine (Scheme 6). Scheme 6 It became pertinent to compare the result this work with that of AgOAc-catalyzed ring-opening of glycal derived gem-dihalo-1,2-cyclopropanated sugar, which led to C-furanoside derivative, as reported by Harvey and co-workers. The sequence of reactions involved were protonation of the endo-cyclic oxygen, followed by ring-opening to generate resonance stabilized allylic ion, which rearranged to C-furanoside. In contrast, oxyglycal derived gem-dihalo-1,2-cyclopropane studied herein led to chloro-oxepine exclusively, without subsequent rearrangement. Ring-opening of glucal derived gem-dihalo-1,2-cyclopropanated sugars, followed by cyclization to C-furanoside were likely to have occurred, due to isomerisation of less-substituted endo-cyclic double bond at C2-C3 of oxepine to C1-C2 unsaturated vinyl ether. Such a reaction was related closely to the acid-catalyzed rearrangement in less-substituted oxepine systems. On the other hand, gem-dichloro-1,2¬cyclopropanated oxyglycal derived chloro-oxepine did not undergo such an isomerisation, possibly due to unsaturation being present at highly substituted C2-C3 carbons (Scheme 7). Thus, the presence of an additional oxy-substituent at C-2 in oxyglycal derived cyclopropane derivative plays a major role to control the reactivity, as compared to glycal derived cyclopropane derivatives. Scheme 7 without undergoing further reactions, was confirmed further by the following reactions: (i) RuCl3¬NaIO4 mediated oxidation; (ii) NaBH4 reduction and (iii) Pd/C mediated hydrogenolysis (Scheme 8). Scheme 8 1,2-cyclopropane to exclusive formation of chloro-oxepine in the presence of AgOAc. It was planned further to synthesize a 1,7-linked-α-D-diseptanoside, through the oxyglycal route. Ring-opening of oxyglycal derived gem-dihalo-1,2-cyclopropanated derivative with 6¬hydroxy glycal led to 1,7-α-linked disaccharide unit. The following reactions were performed in order to synthesize 1,7-linked-α-diseptanoside 2: (i) cyclopropanation of the glycal double bond; (ii) ring opening of the gem-dihalo cyclopropane; (iii) RuO4 mediated oxidation; (iv) NaBH4 reduction and (v) hydrogenolysis using Pd/C, H2 (Scheme 9). Similar methodology was used for the synthesis of monoseptanoside, namely, n-pentyl-D-glycero-D-galacto-septanoside. Scheme 9 1 Oxyglycal route was also used for the synthesis of 2-chloro-2-deoxy septanoside 3, using hydrogenolysis (Pd/C, H2) and NaBH4 mediated reduction of chloro-oxepine (Scheme 10). Scheme 10 A kinetic study of the hydrolytic stabilities of mono-and diseptanoside was undertaken using an acid-catalysis, in a subsequent investigation. In the course of studies, it was observed that glycosidic bond in the reducing-end hydrolyzed twice faster than that at the non-reducing end, whereas glycosidic bond in monosaccharide 1 hydrolyzed 1.5 times faster than of reducing-end glycosidic bond in diseptanoside 2. Further, it was found that the replacement of the C-2 hydroxyl group by a chloride group reduced the rate of hydrolysis (Table 1). Table 1. First order rate constants and thermodynamic parameters for the acid-catalyzed hydrolysis of glycosidic bond in septanosides 1, 2 and 3. Compound Rate of hydrolysis ΔH# ΔS# ΔG# (kobs) (104 s-1) (kcal/mol) (cal/mol K) (kcal/mol) 35 oC 45 oC 85 oC 90 oC a non-reducing end of 2. A computational study was conducted, in order to gain further insight into the hydrolysis, using B3LYP/6-311G* level theory in the Gaussian 09 program packages. Calculations using the PCM solvent model with water as the solvent showed that the orientation of hydroxylmethyl group plays an important role. In the case of 1, the gg conformer was calculated stable by 2.12 kcal/mol, as compared, to tg-conformer. In the gg conformation, the optimal positioning of the dipole C7-O7 stabilized the oxo-carbonium ion in the transition state (Figure 1). Also, hydroxyl group at C4 stabilized the transition state, through non-covalent interaction (Figure 1). The transition state for the hydrolysis of 1 was found to present activation barrier (∆G#) of 19.9 kcal/mol, which was in good agreement with value for 1 (∆G# = 23.26 kcal/mol), as calculated from Erying plot (Table 1). On the other hand, inductive effect of the chloride group, as well as, the tg-orientation of the hydroxymethyl group appeared to contribute to the slower rate of the hydrolysis. Figure 1. gg- and tg-conformations in the ground state of 1. Chapter 4 describes synthesis of 1,7-linked-α-D-diseptanoside, 2-chloro-2-deoxy septanoside and their acid-catalyzed hydrolysis studies. Solid-state and solution phase conformation of septanosides are rare at present even when solid-state structures of pyranoside and furanosides are known commonly, that provide rich information of covalent and non-covalent interactions. In this context, single crystal X-ray structural analysis of septanosides, namely, n-pentyl-2-chloro-2-deoxy-α-D-manno-sept-3-uloside 4 and p-bromo phenyl 4,5,7-tri-O-benzyl-β-D-glycero-D-talo-septanoside 5 were analyzed. It was observed that the solid-state structure of 4 adopted twist-chair conformation, namely, 5,6TC3,4, whereas 5 adopted O,1TC2,3 conformation (Figure 2). An analysis of non-covalent interactions revealed that a dense network of O−H···O and C−H···O stabilized the crystal lattice of 4, whereas O−H···O and C−H···π stabilized the crystal lattice of 5. Chapter 5 describes the detailed analysis of X-ray crystal structure of two septanoside derivatives including non-covalent interactions responsible for the stabilization of crystal lattice. Figure 2. ORTEP of 4 and 5 with displacement ellipsoids, at a 10 % and 50 % probability level. In summary, the thesis established the following major results: (i) synthesis of 2-deoxy-2-C¬alkyl/aryl septanoside from a bromo-oxepine, using organometallic C-C bond forming reactions; (ii) the ring-opening reaction of oxyglycal derived gem-dihalo-1,2-cyclopropane in the presence of AgOAc and the effect of additional C-2 oxy-substituent in the reactivity, in comparison to glycal; (iii) an oxyglycal route for the synthesis of 1,7-linked-α-D-diseptanoside, 2-chloro-2-deoxy septanoside and their acid-catalyzed hydrolysis studies and (iv) solid-state X-ray crystal structural analysis and computational analysis of the conformation and non-covalent interactions associated with the stabilization of crystal lattice. Overall, the studies presented in the thesis provide a new insight into the synthesis, acid-catalyzed hydrolysis and solid-state structural analysis of septanoside derivatives.

A dose response relationship between carbohydrate (CHO) ingestion and exercise performance has not been consistently reported. Additionally the underlying metabolic and neuromuscular explanations for an improvement in performance with increasing doses of CHO have not been fully explained. In Chapter 2 of this thesis 20 male cyclists completed 2 h of submaximal exercise followed by a time trial task (531 ± 48KJ). Three CHO electrolyte beverages, plus a control (water), were administered during a 2 h ride providing 0, 20, 39 or 64 g CHO·h-1 at a fluid intake rate of 1 L·h-1. Performance was assessed by time to complete the time trial task, mean power output sustained, and pacing strategy used. Mean task completion time (min:sec ± SD) for 39 g·h-1 (34:19.5 ± 03:07.1, p=0.006) and 64 g·h-1 (34:11.3 ± 03:08.5 p=0.004) of CHO were significantly faster than control (37:01.9 ± 05:35.0). The mean percentage improvement from control was -6.1% (95% CI: -11.3 to -1.0) and -6.5% (95% CI: -11.7 to -1.4) in the 39 and 64 g·h-1 trials respectively. The 20 g·h-1 (35:17.6 ± 04:16.3) treatment did not reach statistical significance compared to control (p = 0.126) despite a mean improvement of -3.7% (95% CI -8.8 to 1.5%). These data demonstrate that consuming CHO at a rate between 39 to 64 g·h-1 is likely to be optimal for most individuals looking to utilise a single source CHO as an ergogenic aid during endurance performances lasting less than 3 hrs. Attempts have been made to try and understand the acute metabolic regulation that occurs when ingesting increasing amounts of CHO. However, no one study has fully investigated the metabolic mechanisms underlying graded increments of CHO ingestion. In Chapter 3 we aimed to utilise stable isotopes and blood metabolite profiles to examine the integrated physiological responses to CHO ingestion when ingested at rates throughout the range where performance gains appear greatest. Twenty well-trained male cyclists completed 2 h constant load ride (95% lactate threshold, 185 ± 25W) where one of three CHO beverages, or a control (water), were administered every 15 min, providing participants with 0, 20, 39 or 64 g CHO·h-1 at a fixed fluid intake rate of 1L·h-1. Dual glucose tracer techniques (6,6,2H2 glucose and U13C labelled glucose) were used to determine glucose kinetics and exogenous carbohydrate oxidation (EXO) during exercise. Endogenous CHO contribution was suppressed in the second hour of exercise when consuming 39 and 64 g·h-1 in comparison to 0 g·h-1 (-7.3%, 95%CI: -13.1 to -1.6 and -11.2%, 95%CI: -16.9 to -5.5 respectively). Additionally, consuming 64 g·h-1 suppressed the endogenous CHO contribution by -7.2% (95%CI: -1.5 to -13.0) compared to the 20 g·h-1 treatment. Exogenous CHO oxidation rate increased by 0.13 g·min-1 (95%CI: 0.10 to 0.15) and 0.29 g·min-1 (95%CI: 0.27 to 0.31) when consuming 39 and 64 g·h-1 in comparison to 20 g·h-1 of CHO. Peak exogenous CHO oxidation rates were 0.34 (0.06), 0.54 (0.09) and 0.78 (0.19) g·min-1 for 20, 39 and 64 g·h-1 respectively. Plasma NEFA concentration was 0.10 (95%CI: 0.07 to 0.13), 0.12 (95%CI: 0.10 to 0.16) and 0.16 (95%CI: 0.13 to 0.19) mmol.L-1 higher when consuming 0 g·h-1 in comparison to 20, 39 and 64 g·h-1 respectively. Both 39 and 64 g·h-1 were effective at sparing endogenous CHO stores of which it is estimated that most of this is liver glycogen sparing, but the measured response was highly variable between individuals. Consuming 39 g·h-1 of CHO appears to be the minimum ingestion rate required to have a significant metabolic effect that results in an increase in performance. Recent research has indicated a key role of endogenous CHO sensing and oral glucose sensing in maintaining central drive and peripheral function during endurance exercise tasks. Consuming 39 and 64 g·h-1 of CHO elicits the greatest improvements in performance and also demonstrate a similar metabolic response. The improvement in subsequent time trial performance when consuming 39 and 64 g·h-1 coincided with significant alterations in whole body substrate usage that lead to endogenous CHO sparing at the same ingestion rates. In Chapter 4 we aimed to utilise gold standard neuromuscular function assessment techniques, alongside novel measures, to investigate the effect of consuming different rates of CHO on neuromuscular function during and following prolonged cycling exercise. In a double-blind, randomised cross-over design, well-trained male cyclists (n=20, mean±SD, age 34 ± 10 y, mass 75.8 ± 9 kg, peak power output 394 ± 36 W, V̇O2max 62 ± 9 ml·kg-1·min-1) completed 2 familiarisation trials then 4 experimental trials. Trials involved a 2 h submaximal ride followed by a high intensity time trial task lasting approx. 35 min with each of 0, 20, 39 and 64 g·h-1 CHO ingestion rates during submaximal exercise. Each trial involved pre and post exercise assessments (MVC, Mwave twitch potentiation and force, motor unit recruitment and firing rate assessment using high density EMG) and during exercise (gross EMG amplitude). MVC peak torque values were reduced post exercise by -20.4 nM (95%CI: -26.5 to -14.4) in comparison to pre value on all trials with no differences between trials. The firing rates of early recruited motor units significantly increased by 1.55 pps (95%CI: 0.51 to 2.59) following exercise in comparison to pre-exercise rates. Gross EMG during the 2 h cycling bout revealed a main effect of treatment (p<0.01) but post hoc comparisons provided no clarity and likely reflect methodological issues. Consuming CHO at ingestion rates between 20 and 64 g·h-1 had little to no impact on the neuromuscular function of well-trained cyclists when comparing pre and post fatiguing exercise values. Despite differences in time trial completion time between trials, following exercise to fatigue in an endurance task, no post exercise differences were detected.

Lok Cheuk-ming, Andy. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2002. / Includes bibliographical references (leaves 62-73). / Text in English; abstracts in English and Chinese. / Lok Cheuk-ming, Andy. / Acknowledgments --- p.i / Abstract --- p.iii / Table of Contents --- p.vi / List of Tables --- p.viii / List of Figures --- p.ix / Chapter CHAPTER1 --- Introduction --- p.1 / Chapter 1.1 --- Background --- p.1 / Chapter 1.2 --- Purpose --- p.4 / Chapter 1.3 --- Significance of Study --- p.4 / Chapter CHAPTER2 --- Review of Literature --- p.5 / Chapter 2.1 --- "Energy Metabolism During Prolonged, Submaximal Exercise" --- p.5 / Chapter 2.1.1 --- Energy Metabolism in Humans / Chapter 2.1.2 --- Amount of Energy Stores in Body / Chapter 2.1.3 --- Substrates Utilization during Prolonged Exercise / Chapter 2.2 --- Importance of Pre-exercise Nutrition on Exercise Performance --- p.9 / Chapter 2.2.1 --- Pre-exercise CHO Supplementation / Chapter 2.2.2 --- Timing of CHO and Transient Hypoglycemia / Chapter 2.2.3 --- Type of CHO / Chapter 2.2.4 --- Other Nutrients / Chapter 2.3 --- Application of the Glycemic Index to Pre-exercise Nutrition --- p.14 / Chapter 2.3.1 --- Definition of Glycemic Index (GI) / Chapter 2.3.2 --- Ingestion of GI Foods Before Exercise / Chapter 2.3.3 --- Summary of the Previous Findings / Chapter CHAPTER3 --- Methodology --- p.23 / Chapter 3.1 --- General Methods --- p.23 / Chapter 3.2 --- Participants --- p.34 / Chapter 3.3 --- Experimental Design --- p.34 / Chapter 3.4 --- Procedures --- p.37 / Chapter 3.5 --- Prescribed Glycemic Index Meals --- p.39 / Chapter 3.6 --- Analysis --- p.40 / Chapter 3.7 --- Statistical Analysis --- p.41 / Chapter CHAPTER4 --- Results --- p.42 / Chapter 4.1 --- Running Performance --- p.42 / Chapter 4.2 --- Dietary Analysis --- p.43 / Chapter 4.3 --- Physiological Changes At Rest and During Exercise --- p.44 / Chapter 4.5 --- Changes in Perceptual Variables and Heart Rates At Rest and During Exercise --- p.54 / Chapter CHAPTER5 --- Discussion --- p.56 / Recommendation and Applications --- p.61 / References --- p.62 / Appendices --- p.74

A nos jours, la résistance des microorganismes aux antibiotiques est l'un des plus gros problèmes de la santé publique. La recherche de nouvelles familles de composés naturelles ou synthétiques nous amène vers la découverte des méthodologies innovantes conduisant à de nouveaux antibiotiques. Dans le présent travail, nous vous invitons à plonger dans le "nouveau monde" de la synthèse, la réactivité et l'activité biologique de 1,3-oxazoline-2-thiones (OXTs). En effet, cet hétérocycle peu exploré est un facilement obtenu par condensation entre _-hydroxycarbonyle et l'acide thiocyanique. Lorsque l'hétérocycle est ancré sur un modèle de glucides, des structures originales sont attendus tels que OZTs fusionnées à cinq ou six chaînons et OXTs liées par une liaison C-C aux sucres, avec un vaste potentiel chimique et biologique. Nous avons alors étudié la synthèse et la réactivité de OXT simple et thionocarbamates fusionnées ou liés à des glucides modèles, conduisant à la formation de nouveaux carbohydrates fusionnées aux oxazolidinones (OZOs) ainsi que des pseudo C-iminosucres et oxazoles. Nous avons également exploré l'électrophilie de la fonction thioamide dans les couplages croisés de type Suzuki et Stille. Une nouvelle modification de la réaction de Sonogashira a été élaborée en utilisant le cuivre (I) comme cofacteur en quantité catalytique, et sa faisabilité a été démontrée pour une variété de substrats. / The resistance of microorganisms to antibiotics is, in our days, one of the biggest problems in terms of public health. The research for new artificial and natural families of compounds throws us towards innovative methodologies leading to novel antibiotics.In the present work, we are invited to dive in the “new world” of 1,3-oxazoline-2-thiones (OXTs) synthesis, reactivity and biological activity. In fact, this unexplored heterocycle is a simple synthon readily obtained by condensation of thiocyanic acid with an _-hydroxycarbonyl species. When the heterocycle is anchored on a carbohydrate template, original structures are expected such as OZTs fused to five- or six-membered rings and OXTs C-C linked to sugars, with a broad potential in organic chemistry and bioorganic applications. We have then investigated the synthesis and reactivity of simple OXT and thionocarbamates fused or linked to carbohydrate templates, leading to the formation of new carbohydrate-fused oxazolidinones (OZOs) as well as pseudo-C-iminosugars and oxazoles. We have also explored the use of thioxo compounds as electrophiles in Pd-assisted cross-coupling methods, such as Suzuki and Stille reactions. A new modified Sonogashira cross-coupling reaction, in which copper (I) is used in catalytic amount, was developed and its feasibility was proven for a variety of substrates. Finally, our attention was focused on the biological potential of the new molecules. We have targeted a broad spectrum of antimicrobial activity for some OXTs and OZTs, to which was added a screening of glycosidases inhibition for the pseudo C-iminosugars.

Il a été montré que la consommation de Lactobacillus pouvait avoir des conséquences sur le poids de l’hôte, et ce, en fonction de la souche inoculée. Nous avons voulu comprendre le mécanisme par lequel ces microorganismes prolifèrent dans le tube digestif et induisent un changement de poids. Nous avons exploré la production de bactériocines permettant aux souches de Lactobacillus de croître au détriment des autres micro-organismes. Nous avons constitué une base de données de bactériocines nommée BUR et recherché les bactériocines dans les génomes de bactéries du tube digestif humain. Nous avons observé une abondance de bactériocines dans les génomes des bactéries du tube digestif, majoritairement dans les Firmicutes. Aussi, nous avons approfondi l’étude du profil métabolique des souches de Lactobacillus par une approche génomique et dans une analyse in vitro. Nous avons constaté que les souches de Lactobacillus dont la consommation induit une perte de poids possèdent des enzymes qui empêchent l'obésité en réduisant les niveaux de glucose dans le sang, les niveaux de triacylglycérols sériques, la masse corporelle et l'accumulation de graisse, tandis que les génomes des souches dont la consommation induit un gain de poids codent pour plusieurs enzymes favorisant la production de fructose, et mobilisent l'énergie et le carbone stocké dans les acides gras. De ce fait, nous pouvons dire que les espèces de Lactobacillus jouent un rôle important dans la digestion des nutriments, avec un effet direct sur le changement de poids. / It has been shown that Lactobacillus consumption could affect the weight of the host, and led consequently to significant weight gain or loss, depending on the strain. We wanted to understand the mechanism by which these microorganisms induce weight change. We explored the various known mechanisms, including the production of bacteriocins, allowing Lactobacillus strains to grow at the expense of other microorganisms. We established a bacteriocin database, named BUR, and search for bacteriocins in the genomes of human gut bacteria. We observed an abundance of bacteriocins in the genomes of bacteria in the digestive tract, predominantly in Firmicutes. We also have deepened the study of the metabolic profile of Lactobacillus strains, both by a genomic approach and in an in vitro assay, to better understand the pathophysiology of obesity. We have found that Lactobacillus strains whose consumption induces weight loss possess enzymes which prevent obesity by reducing glucose levels in blood, serum triacylglycerols levels, body weight and the accumulation of fat, whereas the genomes of strains whose consumption leads to weight gain encode several enzymes promoting the production of fructose and mobilize energy and the carbon stored in the fatty acids. Therefore, we can say that Lactobacillus species are important in the digestion of nutrients and can have a great influence on carbohydrate and lipid metabolism, with direct effect on weight change.

La durabilité du bois de teck (Tectona grandis) est une propriété pouvant varier selon le génotype et les facteurs environnementaux. Chez le teck, le degré d'implication des extractibles dans la durabilité naturelle est controversé. A partir d'une approche quantitative incluant les aspects biologiques et technologiques conduites sur des échantillons de bois séchés à l'air ambiant, cette thèse s'est attachée à rechercher les déterminants chimiques de nature phénolique de la durabilité naturelle. Nous avons tout d'abord mis en évidence que les formes osidiques stockées dans l'aubier sont transformées en extractibles de nature quinonique. Nous avons ainsi caractérisé deux composés, l'un dans l'aubier le forsythoside B, un trisaccharide de l'acide caféique et l'autre dans le duramen, le 4',5'-dihydroxy-épiisocatalponol qui ont été identifiés pour la première fois dans le bois de teck. Nous avons mis en évidence que le second composé inhibe la croissance de Trametes versicolor indiquant son rôle directe dans la propriété de durabilité naturelle du bois de teck. Ainsi, les composés du métabolisme des naphthoquinones sont les plus impliqués dans la durabilité naturelle du bois de teck à l'égard de Trametes versicolor et de Poria placenta. Les mécanismes de transformation des sucres pourraient indiquer le niveau de durabilité naturelle des espèces. Ces nouvelles données contribueront aussi à l'amélioration de la qualité du bois qui par ailleurs assure la pérennité des arbres. / Teak (Tectona grandis) wood natural durability is a property which can vary with genotype and environmental factors. The implication of quinonic extractives in the property of natural durability is controversial. Using a quantitative approach including biological and technological conducted on air-dried wood samples, this thesis aimed to search chemical attributes of natural durability. We first demonstrated that osidic forms stored in the sapwood were transformed into quinone derivative. We have characterized two compounds the forsythoside B, a trisaccharide of cafeic acid in the sapwood and in the heartwood, the 4',5'-dihydroxy(epi)isocatalponol that were identified for the first time in teakwood. The latter compound exhibited strong fungicidal activity against Trametes versicolor indicating that its direct implication in decay resistance of teak wood. We have shown that compounds from naphthoquinones metabolism were involved in decay resistance of teak wood against Trametes versicolor and Poria placenta. The mechanisms of sugars transformation may indicate the natural durability level of sustainable species. There these new data will contribute to improve the wood quality that ensures the perennity of trees.