Carbohydrates in Drug Design (Z. J. Witczak and K. A. Nieforth (eds.) Marcel Dekker Inc., New York, 1977, 703 p.)

G. Ya. Wiederschain

The book Carbohydrates in Drug Design contains 16 chapters written by specialists from the United States, Germany, France, Japan, Australia, and other countries.

Chapter 1 (Z. Witczak) serves as introduction and contains a brief description of the biological role of glycoconjugates and their use in the design of new drugs. Biologically active compounds are classified according to their therapeutic action: anti-inflammatory, antitumor, antiviral, etc. Topiromats, fructose-based drugs, exemplify anticonvulsant agents. Derivatives of neuraminic acid are examples of antiviral drugs effective against viruses A and B. Azasugars have been found to be effective against HIV infections. A variety of inhibitors of alpha-glucosidases which have been isolated from various sources and later synthesized in the laboratory are used in combination with insulin as hypoglycemic drugs. A hydroxyethyl derivative of deoxynojirimycin (miglitol) is undergoing clinical trial in patients with type II diabetes. An oligosaccharide pool from Actinoplanes called acarbose (precose), which inhibits the activity of alpha-glucosidases, is used in the treatment of patients with diabetes who do not respond satisfactorily to dietary treatment alone. Two amino sugars with antibiotic activity, steptozotocin and prumycin, attract attention as antitumor drugs. Oligosaccharides containing a sialyl-Le^x antigenic determinant represent another group of antitumor drugs. Structurally different polysaccharides, e.g., glucans from various sources, possess antitumor activity as well. beta-Glucans also stimulate cytotoxins, enhance wound healing, and are active as hematopoietic stimulators. A beta-(1,3)-glucan from a modified strain of Saccharomyces cerevisiae shows antitumor activity. Based on this polysaccharide, Alfa-Beta Technology developed a new drug (Betafectin) which is used in major chest and abdominal surgery. Particular attention has been given to biologically active carbohydrate-containing antibiotics and anticoagulants.

Chapter 2 (M. Itzstein, M. Kiefel) discusses analogs of sialic acids as potential antimicrobial agents. The authors give data on the structure of sialic acids, enzymatic and chemical methods for their large-scale preparation, and methods for synthesis of various sialyl-containing biologically active compounds. Emphasis is given to sialyl-containing antiviral drugs.

In chapter 3 (R. Roy) sialyl-containing compounds are considered as anti-inflammatory and antiviral drugs. A special section is devoted to multivalent sialyl-containing preparations as inhibitors of influenza virus hemagglutinin.

In chapter 4 (F. Hasegawa, M. Kiso) problems of the design and synthesis of carbohydrate ligands that are potential inhibitors of cell adhesion are discussed. Synthetic analogs of sialyl- and sulfo-Le^x antigenic determinants which are potential inhibitors of selectin--carbohydrate binding are discussed in particular.

Chapter 5 (M. Witvrow, C. Panneccouque, E. Clerg) discusses polysulfates as potential antitumor agents. Structural features of such polysulfates as dextran sulfate, pentosan sulfate, sucralfate, heparin, and their derivatives are considered. A section is devoted to the chemistry of dermatan sulfate and sulfates of xylomannan, galactan, and cyclodextrin. Another section is devoted to the mechanisms of the therapeutic action of various polysulfates in HIV infection.

In chapter 6 (S. Alban), carbohydrates having anticoagulant/antithrombin activities are discussed. The structure and function of heparin, its biosynthesis, and its importance in medicine are considered in detail. Of other antithrombin glycosaminoglycans, heparan and dermatan sulfates, as well as natural and synthetic low-molecular-mass fragments of heparin, are examined. The medical use of sulfated polysaccharides from sea flora and fauna, such as carrageenans, fucoidans, chitosans, etc. is quite promising. Antithrombin activities of structurally different carbohydrate-containing biopolymers are compared.

In chapter 7 (R. Linhardt, T. Toida) the use of oligosaccharide derivatives of heparin as therapeutic agents is considered. Data on the structure, biosynthesis, biological activity, and medical use of heparin are discussed. In addition to the well-known antithrombin activity of heparin, the authors discuss its anti-sclerotic action by stimulation of triglyceride lipolysis. Heparin inhibits proliferation of smooth muscle cells of the vascular endothelium and activation of complement and exhibits anti-inflammatory activity by interaction with selectins and chemokines. The influence of heparin on angiogenesis is also noted. A separate section is devoted to the strategy of the choice of synthetic analogs which might replace heparin.

Chapter 8 (S. Ozaki, L. Lei) describes chemo-enzymatic syntheses of optically active myo-inositol polyphosphates.

In chapter 9 (R. Bruzik) problems of the design and synthesis of inhibitors of phosphatidylinositol phospholipase C are considered. This enzyme is known to play an important role in cell signal transduction in most prokaryotic and eukaryotic microorganisms.

Chapter 10 (S. Ogawa) is devoted to carbosugars as components of aminocyclitol antibiotics. Some of these compounds inhibit a number of enzymes. In particular, acarbose, an efficient inhibitor of amylase, is an effective drug in diabetes.

Chapter 11 (L. Broek) presents data on the biological activity of azasugars as potential anti-HIV agents. These compounds strongly inhibit specific enzymes involved in glycoconjugate processing. Azasugars suppress HIV replication in host cells and thereby influence the glycosylation of compounds important for binding of the virus to target cells, e.g., glycoproteins gp120 and gp41. As a result, the virulence of the virus decreases.

In chapter 12 (S. Szernecki, J. Valery) analogs of pyrimidine nucleotides having antiviral activity are considered. Synthetic approaches to such analogs, which are used mainly as anti-HIV agents, are described.

Chapter 13 (J. Beach) discusses the synthesis of 3´-heteronucleosides using carbohydrate matrixes. The resulting compounds possess antiviral activity and have been used in the treatment of HIV infection.

Chapter 14 (W. Priebe, R. Perez-Soler) presents data on the synthesis of antracyclins modified with a sugar residue. These compounds are suggested to possess a wide spectrum of activities and may be used as anticancer agents in different types of cancer, e.g., leukemia, lymphoma, breast cancer, and sarcoma.

Chapter 15 (O. Achmatowicz, B. Szechner) discusses the organic chemistry of lincomycin, an antibiotic that exhibits bactericidal activity against a wide spectrum of anaerobic and aerobic microorganisms. The antimicrobial activity of this antibiotic is defined by its ability to suppress protein synthesis on the ribosome. Methods of chemical synthesis of lincomycin and a variety of its derivatives are given.

Chapter 16 (A. Misaki, M. Kakuta) covers data on the structure, methods of preparation, and pharmaceutical application of fungal 1,3-beta-D-glucans. Particular emphasis is placed on such glucans as lentinan, schizophyllan, and curdlan that possess antitumor activity.

Assessing the book as a whole, it can be said with confidence that the book contains important information on the application of carbohydrates and carbohydrate-containing compounds as effective therapeutic agents. In fact, the book is the first handbook which summarizes the numerous experimental works on the biological activity of carbohydrates.

Importantly, each chapter of the book contains an extensive bibliography; this helps to present the issues in question in their entirety. The book contains a useful subject index that allows rapid location of information of interest.

The book will surely find a wide audience of specialists: biochemists, chemists, pharmacists, and physicians in different fields. It will rightly become the most widely used handbook summarizing different approaches to the use of carbohydrates as therapeutic agents.