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Abstract

N-Acetylneuraminic acid (1) is a common sugar in many biological recognition processes. Neuraminidase enzymes recognize and cleave terminal sialic acids from cell surfaces. Viral entry into host cells requires neuraminidase activity, thus inhibition of neuraminidase is a useful strategy for development of drugs for viral infections. A recent crystal structure for influenza viral neuraminidase with sialic acid bound shows that the sialic acid is in a boat conformation [Prot Struct Funct Genet 14: 327 (1992)]. Our studies seek to determine if structural pre-organization can be achieved through the use of sialyllactones. Determination of whether siallylactones are pre-organized in a binding conformation requires conformational analysis. Our inability to find a systematic study comparing the results obtained by various computational methods for carbohydrate modeling led us to compare two different conformational analysis techniques, four different force fields, and three different solvent models. The computational models were compared based on their ability to reproduce experimental coupling constants for sialic acid, sialyl-1,4-lactone, and sialyl-1,7-lactone derivatives. This study has shown that the MM3 forcefield using the implicit solvent model for water implemented in Macromodel best reproduces the experimental coupling constants. The low-energy conformations generated by this combination of computational methods are pre-organized toward conformations which fit well into the active site of neuraminidase.

Chemoselective Synthesis of Sialic Acid 1,7-Lactones

“…Thus, we devised to attempt the lactonization of Neu5Ac 1 , activating its carboxylic group by benzyloxycarbonyl chloride (CbzCl), a bulky, scarcely reactive, acyl chloride . In fact, the extensive work of Ogura and of Gervay, on the formation of peracylated or partially acylated 1,7- and 1,4-lactones of Sias, under acylation conditions, showed, as a common feature, the formation of lactones with an acylated anomeric hydroxyl group, even in compounds containing some free alcoholic hydroxyls. This suggested that any lactone, eventually obtained in the reaction promoted by CbzCl, should be a stable and easily isolable compound, since it was protected at the anomeric hydroxyl.…”

The first synthesis of N-acetylneuraminic acid 1,7-lactone

“…In our work, we did not consider the direct lactonization of Neu5Ac 1 by means of N,N-dicyclohexylcarbodiimide (DCC) in pyridine since it was reported that, in these conditions, a partial 1,4-intramolecular lactonization of Neu5Ac 1 occurs to afford a mixture of the bicyclic 1,4lactone 9,10 5a and of the starting Neu5Ac 1. We excluded also the lactonization mediated by usual acylic chlorides or anhydrides on the basis of the extensive work of Ogura and coworkers [11][12][13] and of Gervay et al 8,14,15 who reported the formation of a variety of peracylated and partially acylated 1,7-lactones 4b and 4c, and of peracylated 1,4-lactones 5b. Also some preliminary attempts to perform a direct chemoselective 1,7-lactonization of Neu5Ac 1, under catalysis of protic and aprotic acids, performed in our laboratory, were unsuccessful.…”

Conformational studies of blood group A and blood group B oligosaccharides using NMR residual dipolar couplings

“…28 Better quality structures were obtained using the GB/ SA continuum solvent model 29 implemented in MACRO-MODEL mimicking water dielectric values. This protocol has been reported as a suitable one in reproducing experimental coupling constants for sialyllactones, 30 and more generally for sampling carbohydrate conformations. 31 The general theoretical expression accounting for dipolar couplings is:…”