Abstract
Sialic acids are a diverse family of more than 50 naturally occurring 2-keto-3-deoxy-nononic acids, amongst which N-acetylneuraminic acid is the most ubiquitous. Sialic acid-containing carbohydrates is widely distributed in nature. Because of their terminal location and negative charge, sialic acids have numerous roles in many aspects of immunity. These monosaccharides have the potential to contribute intermolecular and intercellular interactions. Sialic acids expressed on cell surfaces involve many physiological and pathological communications, and serve as ligands for receptor mediated intercellular interactions, cell-cell adhesion, host cell-pathogen recognition processes. Therefore, the synthesis of sialic acid-containing glycans is essential for the design of therapeutics. In my 2nd chapter, we describe the exploitation of the 150-cavity in the active site of group 1 neuraminidase for the design and synthesis of new 1,4-disubstituted 1,2,3 triazole-containing N-acyl derivatives related to zanamivir. We studied the inhibitory activities of these derivatives against influenza virus of group 1 (H1N1) and group 2 (H3N2). The inhibition studies revealed that several of them are good inhibitors, with IC50 values in the low nanomolar (2.3 to 31 nM) range. . Substituents that form stable van der Waals interaction with the 150-cavity residues play crucial roles in NA inhibition as demonstrated by the potency of 42a (H1N1 IC50 = 2.3 nM, and H3N2 IC50 = 2.9 nM). Docking studies indicated that the cyclohexane-substituted triazole ring extended toward the hydrophobic region in the active site of group 1 NA in open form. The high potency observed for inhibitor 42a may be attributable to the highly favorable hydrophobic interactions in this region. We anticipate that this molecular insight may xx contribute to the design of novel selective inhibitors against these NAs, potentially leading to a new generation of structurally unique anti-influenza drugs. In my third chapter, we focused on the synthesis of the sulfated and non-sulfated oligosialic acid chain of the sperm binding protein. My initial and major focus has been on the synthesis of 9-sulfated derivative 1a. The synthesis is based on the model compound non-sulfated 1b. I have approached this first by installing the sulfate at the 9’-position of the -(2→5)-Neu5Gc disialoside followed by an amide coupling reaction with sialyl-Tn disaccharide. Two different strategies for the synthesis of non-sulfated derivative (1b) and sulfated derivative (1a) were explored. The synthetic strategy is based on the use of allyl alcohol to achieve an exclusive -sialylation product (12) which was transformed into glycolic acid moiety (33). These two building blocks were then used for the synthesis of disialoside 31 following similar sequence of reaction. For the synthesis of (2→6)-sialyl-Tn disaccharide, we followed chemoenzymatic approach starting from ManCbz in an one-pot manner. We employed 91 as an ‘acceptor’ and NmCSS and Pd26ST to synthesize 93 in 54% yield. The disaccharide building blocks 88 and 95 were then transformed tetrasaccharide 97. The subsequent deprotection of this protected tetrasaccharide completed the synthesis of the target sulfated compound 1a.