PREFACE

This 69th volume of Advances features six contributions that cover a wide diversity

of different aspects of new developments in the carbohydrate field, focusing variously

on synthetic methodology, structural and functional aspects of carbohydrates in the

bacterial cell envelope, and a glycobiology theme concerned with aberrant glycosyl-

ation on the surface of tumor cells and approaches to improved cancer therapies.

The Boston (Massachusetts)-based group led by O’Doherty and his coworkers

Aljahdali, Shi, and Zhong provides a tour de force of organic synthetic virtuosity in

the de novo synthesis of a wide range of monosaccharides and oligosaccharides,

making use of newly introduced asymmetric catalysts to accomplish high enantio-

meric purity in the products.

Early work by Lespieau in Volume 2 of this series and notably by Zamojski in

Volume 34 provided pointers for the synthesis of alditols and aldoses “from scratch”

employing simple organic precursors, but the methodology led mostly to racemic

products. Important later work detailed here by the Boston group has focused on

access to enantiopure products, as exemplified by the asymmetric epoxidation strat-

egy of Sharpless and complementary work by Danishefsky, MacMillan, Dondoni,

Seeberger, and others.

The O’Doherty group has synthesized an impressive series of targets by employing

an extensive range of “name” reactions, specialized reagents, “fine-tuned” versions of

traditional oxidative and reductive procedures, and in particular, the rearrangement

reaction of enones introduced by Achmatowicz, utilizing asymmetric catalysts, along

with numerous applications of palladium chemistry. These targets include the

C-glycosyl framework of the papulacandins, the nojirimycin-type imino sugars,

homoadenosine analogues, the pheromone daumone, the indolizidine alkaloids, ana-

logues of trehalose and cyclitols, cardiac glycosides, the anthrax tetrasaccharide, and

other carbohydrate structures of current biological interest.

The Vienna-based authors Messner, Schaffer, and Kosma detail the glycoconju-

gates of the cell envelope of bacterial and archaeal organisms, where glycosylation

plays a critical role in preserving the integrity of the prokaryotic cell-wall and serves

as a flexible adaption mechanism to evade environmental and host-induced pressure.

Glycosylation is not limited to surface-layer proteins in the cell but is shown to occur

also in pili, flagella, and in the form of secondary-cell-wall polysaccharides. In

contrast to the glycan components in glycoproteins of eukaryotic organisms, these

prokaryotic-associated glycans display a wide range of structural variations. With

their incorporation of numerous unusual monosaccharide components, these glycans

xi

xii PREFACE

manifest a diversity in their constituent monosaccharides comparable to the complex

range of sugar components found in the lipopolysaccharides and capsular polysac-

charides of bacteria.

The discussion of these conjugates covers a range of aspects, from analysis and

structure elucidation to function, biosynthesis, and genetic basis, and to biomedical

and biotechnological applications. The S-layer glycoproteins form ordered structures

through crystallization of the protein component, and a variety of techniques have

helped to develop models for the structure of the cell envelope. Typically, the glycan

component consists of complex linear or branched oligo- or polysaccharides, either

O- or N-glycosylically linked, and the highly diversified structures have been eluci-

dated by chemical and spectroscopic procedures. Their biosynthesis via the

nucleotide-sugar pathway and elucidation of their genetic basis point the way to

important applications in nanotechnology and biomedicine.

The article by Hevey and Ling (Calgary, Alberta) is focused on inhibitors designed to

attenuate the metastasis of tumors through interruption of interaction between cell-

surface lectins (carbohydrate-binding proteins) and those carbohydrate ligands (notably

TF, sialyl Tn, and sialyl Lex) that are typically overexpressed on tumor cells. These

lectin–ligand interactions are correlated with such metastatic processes as cell adhesion,

generation of new blood vessels (neoangiogenesis), and immune-cell evasion. The

suppression of such interactions is a desired goal in seeking improved cancer therapies.

The authors discuss the structural features of the carbohydrate ligands in the tumor

cell and the relation between abnormal glycosylation and tumor metastasis, and the

role of lectins in tumor development. Focusing on the particular lectins involved,

namely, the galectins, selectins, and the siglecs (sialic acid Ig-like lectins), their

structures and binding sites are developed in detail. The key role of the

carbohydrate–lectin interaction suggests a variety of approaches toward novel cancer

therapies. They include the development of inhibitors of the carbohydrate–ligand

interaction, the inhibition of glycosyltransferases and glycosidases involved in the

aberrant glycosylation of tumor cells, and the targeting of the immune system against

cancer cells. Although there have been promising results from clinical trials, espe-

cially from dual-mode therapies, as compared to traditional cancer chemotherapy

agents, there remain significant challenges to be addressed, with a need for carbohy-

drate inhibitors that are more resistant to hydrolytic or metabolic breakdown. Prom-

ising results have been observed by the use of small-molecule inhibitors based on

C-glycosyl structures, which are resistant to acid hydrolysis and glycosylase enzymes,

and polyvalent ligands that have shown enhanced binding down to the nanomolar

level.

The contributions to carbohydrate science of three towering figures in the field are

recognized in this issue with obituary articles that detail their work in sufficient depth

PREFACE xiii

to provide a valuable source for citation. Stephen J. Angyal, who died at the age of 97,

was a Hungarian-born Australian who literally “wrote the book” on the chemistry of

the cyclitols, developed a quantitative understanding of the conformational behavior

of pyranoses in solution, and provided a wealth of practical synthetic procedures

based on the use of cationic complexes to modify the outcome of traditional reactions.

His legacy is recorded here by his colleague John D. Stevens.

The scientific career of J. Grant Buchanan is presented by his colleague Richard

Wightman. Grant’s early studies in Alexander Todd’s group in Cambridge provided a

basis for his long-term interest in sugar phosphates and nucleotide chemistry, which

developed further in his postdoctoral work with Calvin in Berkeley and later back in

Britain at posts in London and inNewcastle. In conjunctionwith Baddiley, he studied the

pneumococcal antigens and the ribitol teichoic acids. He also made major contributions

to our understanding of epoxide migration and cleavage. In a subsequent move to his

native Scotland, to Heriot-Watt University in Edinburgh, he extended his research to the

chemistry and biochemistry of C-nucleosides, and the use of glycosylalkynes in synthe-

sis. The list of his publications details his wide range of research accomplishments.

Saul Roseman was a pioneer American glycobiologist whose six decades of

innovations in the field are documented by his student and coworker Subhash Basu.

Very early in his career, Roseman established the correct structure of neuraminic acid

(sialic acid), and subsequently, he made extensive contributions to our knowledge of

glycoproteins and glycosphingolipids, and the glycosyltransferases involved in their

biosynthesis. Critical to this work was the availability of 14C-labeled nucleotide

sugars produced in collaboration with Khorana in Vancouver. Roseman’s ground-

breaking work on the glycosyltransferases set the stage for development of this theme

in many centers of research around the world.

The deaths are noted of several past contributors to this series. William George

Overend (died on September 18, 2012, aged 90) of Birkbeck College, University of

London, authored with Maurice Stacey an article on Deoxy Sugars in Volume 8, and

with Finch wrote the obituary of Stacey in Volume 52. Robin Ferrier (after whom are

named two “Ferrier Reactions”), of Victoria University, Wellington, New Zealand,

contributed articles on Unsaturated Sugars in Volumes 24 and 58, and one on Boronates

in Volume 35; he died on July 11, 2013, aged 81. Serge David of the University of Paris

authored with Estramareix an article in Volume 52 on Sugars and Nucleotides and the

Biosynthesis of Thiamine. He died on August 1, 2013, aged 92.

With this issue, Jesus Jimenez-Barbero is welcomed as a member of the Board of

Advisors. Professor David C. Baker assisted with the Author Index.

DEREK HORTON

Washington, DC

August, 2013