Angela Barkley's research while affiliated with National Research Council Canada and other places

In the area of peptide and nucleic acid chemistry and biology, high-throughput synthesis has played an important role in providing useful small-molecule-based chemical probes in understanding the structure and function relationships. The past several years, there has been a constant rise in interest toward understanding the biological roles and functions of another important class of biomolecules, i.e., carbohydrates and carbohydrate conjugates. Although at early stages, in recent years, several groups have developed high-throughput synthetic methods to obtain complex carbohydrates or carbohydrate-like small-molecules. The present review article summarizes some of these developments.

A fully automated method for the synthesis of artificial glycopeptides having two (similar or different) carbon-linked glycosyl moieties on a dipeptide scaffold has been developed. By use of this approach that combines the diversity of peptide/pseudopeptide and glycosides, different glycoside moieties can be incorporated onto the peptide/pseudopeptide backbone in a highly controlled manner. The approach utilizes a stepwise reductive amination with glycoside aldehyde derivatives (model 1) or (ii) glycoside reductive amination followed by glycoside amide bond formation (model 2). Further, an automated method has been utilized in the high-throughput library synthesis of 4 x 96 artificial glycopeptides. These libraries were tested as chemical probes/inhibitors of enzyme systems that convert a glucose moiety into rhamnose prior to incorporation of the rhamnose unit and the conversion of UDP-galactopyranose to UDP-galactofuranose via UDP-galactopyranose mutase enzyme during the biosynthesis of the mycobacterium cell wall.

Combinatorial chemistry has contributed significantly to understanding the structure–function relationships of biologically important molecules such as proteins and nucleic acids. However, carbohydrates and carbohydrate conjugates, which have been identified as key modulators of several biological functions have not enjoyed the same measure of success. The complexity and synthetic challenges of carbohydrate conjugates have resulted in a number of conceptual approaches to rapidly access sufficient quantities of these biomolecules. This article summarizes these combinatorial approaches and also highlights fully automated library synthesis of artificial glycopeptides with the goals of understanding their biological roles.

A programmed synthesis of neoglycopeptides has been developed in which two, similar or different, glycoside moieties could be attached either (i) at the N-terminal of short peptides or (ii) one at the N-internal and the other(s) at the N-terminal site, in a highly flexible and controlled manner. A stepwise branching of N-terminal peptides has been achieved by glycoside aldehyde reductive amination followed by the glycoside carboxylic acid coupling (model 1). In another approach, after N-alkylation with glycoside aldehyde, the N-glycosylated derivative is subjected to peptide synthesis. This is then followed by the attachment of the second glycoside moiety at the N-terminal using either glycoside aldehyde or glycoside carboxylic acid derivative (model 2). Alternatively, the attachment of second and third glycoside derivatives could be achieved simultaneously, by reductive amination/carboxylic acid couplings (model 3). The methodologies presented here are highly versatile and combine diversity in both peptides/pseudopeptides and glycoside moieties.