The thesis is divided in to five chapters. Chapter I: Synthesis of New thiolevomannosan derivatives In this chapter, a general and efficient method for the synthesis of conformationally locked thiosugars has been discussed. An unprecedented synthesis of a novel thioorthoester and its synthetic utility in glycosylation has been demonstrated. Chapter II: Studies on -Mannosidase Inhibitors The synthesis and evaluation of novel, conformationally locked glycomimic, thiolevomannosan and its analogs sulfoxide and sulfone starting from readily available D-mannose is discussed in this chapter. This is the first report of thiosugar derivatives with enhanced potency compared to kifunensine. Docking and biochemical studies have been discussed. Chapter III: Studies on Novel Cyclic Tetraselenides of Mannose In this chapter, the syntheses and structural properties of novel cyclic tetraselenides starting from mannose have been discussed. These tetraselenides are the first of their kind where all four selenium atoms are arranged in a cyclic manner as the backbone of mannose. X-ray structures have been reported for the tetraselenides. Chapter IV: Novel Chalcogenides of Uridine and Thymidine: Synthesis and Applications An efficient and simple method to synthesise disulfides and diselenides of thymidine and uridine derivatives has been demonstrated in this chapter. The utility of these disulfides in various ring opening reactions as well in Michael addition reactions has been demonstrated. Chapter V: Studies on New, Potent Urease Inhibitors In this chapter, a facile one-pot synthesis of thio and selenourea derivatives under mild conditions by the reaction of amines and commercially available Viehe’s iminium salt in the presence of benzyltriethylammonium tetrathiomolybdate as sulfur transfer reagent and tetraethylammonium tetraselenotungstate as selenium transfer reagent has been discussed. A few of the urea derivatives have shown potent inhibitor activity in the nanomolar range for jackbean urease.

Résumé: Le travail rapporté dans cette thèse concerne le développement de nouvelles réactions organométalliques pour la création de liaisons C-S dans des systèmes complexes.Dans Le premier chapitre, nous rapportons une méthode originale de bioconjugation de peptides et protéines dans l'eau à température ambiante. La méthode a été appliquée avec succès à la bioconjugation de l'anticorp Trastuzumab.Le deuxième chapitre est consacré à l'étude de la réactivité des alpha ou béta thiosucres dans le couplage de Buchwald-Hartwig-Mitiga avec différent partenaires électrophiles.Dans un premier sous chapitre, nous rapportons une réaction inattendue de couplage de thiosucres avec le précatalyseur G3-Xanthphos pour conduire à de 2-aminobiphenyl glycosides bifonctionnels. La reaction a lieu à température ambiante et dans l'eau et produit des atropidiastéréomères stables.Dans une seconde partie de ce travail, nous décrivons une méthode originale d'accès à benzothiapinones et benzoxathiapinones glycosylées.Cette méthode fait intervenir un couplage de thiosucres avec des aryls iodés ayant un ester en ortho, suivi d'une lactonisation (ou lactimisation) pour conduire aux produits cyclisés.L'avant dernière partie de ce travail, concerne la synthèse de polysaccharides via une réaction de couplage de 2-iodo glycals avec des thiosucres de configuration définie.Ce travail se termine par l'application de couplage de thiosucres à la synthèse de Carbènes N-Hétérocycliques thioglycosylés (NHCs) hydrosolubles. / Abstract: The work reported in this thesis concerns the development of new organometallic reactions for the creation of C-S bonds in complex systems.In the first chapter, we report an original method of bioconjugation of peptides and proteins in water at room temperature. The method has been successfully applied to the bioconjugation of the antibody Trastuzumab.The second chapter is devoted to the study of the reactivity of alpha or beta-thiosugars in the Buchwald-Hartwig-Mitiga coupling with different electrophilic partners.In a first sub-chapter, we report an unexpected reaction of thiosugar coupling with the G3-Xanthphos precatalyst to yield bifunctional 2-aminobiphenyl glycosides. The reaction takes place at room temperature and in water and produces stable atropidiastereomers.In a second part of this work, we describe an original method of access to glycosylated benzothiapinones (and benzoxathiapinones).This method involves thiosugar coupling with iodinated aryls having an ortho ester, followed by lactonization (or lactimization) to yield cyclized products.The last part of this work concerns the synthesis of polysaccharides via a coupling reaction of 2-iodo glycals with thiosugars of defined configuration.This work ends with the application of thiosugar coupling to the synthesis of water-soluble thioglycosylated N-Heterocyclic Carbenes (NHCs) .

Glycosidases are carbohydrate processing essential enzymes necessary for the growth and development of all organisms such as intestinal digestion, post-translational processing of glycoproteins and the lysosomal catabolism of glycoconjugates. The function of these glycosidases is limited and studies are still in progress to understand their function at cellular level. In recent years, biological role of carbohydrates has resulted in various carbohydrate-based therapeutics2. These carbohydrates serve as a tool to study the function of glycosidases by inhibiting their active site. The concept of inhibition is yet another approach for the discovery of drugs. Glycosidase inhibitors studied are often sugar analogs and a wide range of such inhibitors are reported in the literature.3, 4 Thiosugars, in particular, have gained new perspectives owing to their electronic, geometric, conformational and flexibility differences, as sulfide moiety being less electronegative and more polarizable than the oxygen counter-part.5 These differences make the thiosugars distinct from their oxygen analogs and hence can mimic the active site of the enzyme. Many molecules are reported to be promising glycosidase inhibitors but are not easily accessible due to difficulties in their synthesis. Hence, the chemical synthesis of thio-analogs of carbohydrates, by synthetic routes, remains a major challenge. To address the complexity of synthesis and to make available new strategies, we envisioned the use of benzyltriethylammonium tetrathiomolybdate [BnEt3N]2MoS4, a versatile and efficient sulfur transfer reagent. Objectives of the study: a. Design novel thiosugars as glycosidase inhibitors. b. Devise strategy for the synthesis of novel thiosugars through a simple, practical approach. c. Evaluate the synthesized molecules as glycosidase and HIV-1 protease inhibitors, in silico. d. Study miscellaneous applications of the novel thiosugar-derived thialactones. The thesis is divided into five sections: Section A entitled “Synthesis of deoxythiosugars and thiosugar-based lactones” is divided into two parts, Part A and Part B. Part A – “An introduction and background on thiosugars and sulfur transfer reagents” has been provided. A brief discussion of sulfur transfer reagents in carbohydrate synthesis and earlier work related to the use of benzyltriethylammonium tetrathiomolybdate, [BnEt3N]2MoS4, as an efficient sulfur transfer reagent have been provided. Part B –“Design of inhibitors of glycosidases and HIV-1 protease” deals with the design of inhibitors of glycosidase and HIV-1 protease. The designed thiosugar molecules exhibit the characteristics of sugars and will act as planar molecules to mimic the active site conformation of a good inhibitor. Synthetic methodologies devised and adopted for the synthesis of constrained sugar-derived thialactones include: (a) Double displacement, (b) Displacement-cum-intramolecular thia-Michael addition, (c) Epoxide ring-opening-cum-intramolecular thia-Michael addition, and (d) Displacement-cum-epoxide ring opening in an intramolecular fashion. In all the above mentioned strategies, sulfur transfer step is the crucial step which was achieved by the use of benzyltriethylammonium tetrathiomolybdate [BnEt3N]2MoS46 as the key reagent. (a) Various constrained thialactones synthesized by double displacement strategy using tetrathiomolybdate as the sulfur transfer reagent are shown in Scheme – 1. (b) A number of constrained thialactones were synthesized following nucleophilic displacement-cum-intramolecular thia-Michael addition strategy as shown in Scheme – 2. (c) Synthesis of bicyclic thiolactones was achieved using the strategy of epoxide ring-opening-cum-intramolecular thia-Michael addition. (Scheme – 3) (d) A few bicyclic thialactones were synthesized through displacement-epoxide ring opening-cyclization as shown in Scheme – 4. The methodology was also utilized for the synthesis of thiosugar derivatives and azido-thialactones. (Fig. 1) Figure 1 Synthesis of deoxythiosugars: The bicyclic thialactones (designed as inhibitors) on reduction with borohydride exchange resin (BER) easily furnished the deoxythiosugars (Fig. 2). It is worth mentioning that the synthesis of these thiosugars as reported in the literature involved lengthy procedures whereas the present methodology turns out to be short and concise. Figure 2 Section B entitled “Synthesis of amines, β-amino acids and novel thiosugar-based dehydroamino acids” comprises a brief introduction on the importance of amines, β-amino acids and dehyroamino acids. In this section the effective utilization of benzyltriethylammonium tetrathiomolybdate as a key reagent for reductive transformations and its application in the synthesis of amines, β-amino acids and dehyroamino acids have been presented. A one pot reduction of azides to amines followed by intermolecular aza-Michael addition employing tetrathiomolybdate was achieved to furnish a number of different β-amino esters as shown in Scheme -4: Scheme 4 The study was further extended to the reduction of a few anomeric azides to afford the corresponding anomeric amines and derivatives. (Fig. 3) Figure 3 A one-pot thia-Michael addition-vinyl azide reduction in a tandem fashion employing benzyltriethylammonium tetrathiomolybdate was studied and was shown to be effective for the synthesis of thiosugar derived dehydroamino acid derivatives. (Scheme – 5) Scheme 5 Section C entitled “Molecular docking studies of deoxythiosugar probes” gives an overview of different glycosidases, HIV-1 protease and their inhibitors. This section also deals with a brief introduction on active site conformations of potent inhibitors. In this connection we have studied the crystal conformations of the synthesized molecules whose conformations were the same as that of the existing inhibitors in the active site. (Fig. 4) With this background in silico study of the synthesized deoxythiosugar probes was conducted on human glycosidases: α-mannosidase, α-galactosidase, β-glucosidase and HIV-1 protease, respectively. Figure 4 Molecular docking was carried out using Autodock suite, molecular modeling simulation. Separate docking procedures were employed for the four different receptors. The PDBs representing the four enzyme targets were 2V3D, 3H53, 1X9D and 3I8W for β–glucosidase, α–galactosidase, α–mannosidase and HIV–1 protease respectively. The control compounds used for α–mannosidase were mannostatin and kifunensine. NMB, THK, and BED were the positive controls for HIV–1 protease. Similarly, NBV and cyclophellitol were the controls used for β–glucosidase and NOJ, N–methyl calystegine B2 for α–galactosidase. (Fig. 5) Ligands TGSB68 and TGSB482 had the energy value of –6.49 kcal/mol comparable to that of the average reference value of the positive control, and thus, the potent candidate as identified by molecular docking to HIV-1 protease. (Fig. 6a) The control compounds used for α–mannosidase were mannostatin and kifunensine, which bind with mean binding energy of -9.11 and -5.56. In the case of α–mannosidase, the same compounds TGSB68 and TGSB482 were selected due to comparable energy and a good cluster size with that of positive control. (Fig. 6b) For β– glucosidase, ligands TGSC108 and TGSC236, which had comparable values to that of positive control was identified as the Figure 5 Figure 6 potent candidate. (Fig. 6c) In the case of α–galactosidase, again the ligands TGSB68 and TGSB482 were selected based on binding energies. (Fig. 6d) In conclusion, the concept analogy (deoxy nature, planarity, thiosugar framework, lactone moiety) for the design of inhibitors indeed worked positively. The results are really encouraging. An in vivo study of the synthesized novel thiosugar probes will certainly provide a potent inhibitor. Section D entitled “Research methodology” provides experimental procedures adopted with details of synthesis. Section E entitled “Bibliography” provides the references cited in this work.